transforming-growth-factor-beta and Marfan-Syndrome

Marfan syndrome (MFS) is a systemic connective tissue disorder that is inherited in an autosomal dominant pattern with variable penetrance. While clinically this disease manifests in many different ways, the most life-threatening manifestations are related to cardiovascular complications including mitral valve prolapse, aortic insufficiency, dilatation of the aortic root, and aortic dissection. In the past 30 years, research efforts have not only identified the genetic locus responsible but have begun to elucidate the molecular pathogenesis underlying this disorder, allowing for the development of seemingly rational therapeutic strategies for treating affected individuals. In spite of these advancements, the cardiovascular complications still remain as the most life-threatening clinical manifestations. The present chapter will focus on the pathophysiology and clinical treatment of Marfan syndrome, providing an updated overview of the recent advancements in molecular genetics research and clinical trials, with an emphasis on how this information can focus future efforts toward finding betters ways to detect, diagnose, and treat this devastating condition.

Topics: Aorta; Aortic Dissection; Fibrillin-1; Humans; Marfan Syndrome; Transforming Growth Factor beta

Fibrillins constitute a family of large extracellular glycoproteins which multimerize to form microfibrils, an important structure in the extracellular matrix. It has long been assumed that fibrillin-2 was barely present during postnatal life, but it is now clear that fibrillin-2 molecules form the structural core of microfibrils, and are masked by an outer layer of fibrillin-1. Mutations in fibrillins give rise to heritable connective tissue disorders, including Marfan syndrome and congenital contractural arachnodactyly. Fibrillins also play an important role in matrix sequestering of members of the transforming growth factor-β family, and in context of Marfan syndrome excessive TGF-β activation has been observed. TGF-β activation is highly dependent on integrin binding, including integrin αvβ8 and αvβ6, which are upregulated upon TGF-β exposure. TGF-β is also involved in tumor progression, metastasis, epithelial-to-mesenchymal transition and tumor angiogenesis. In several highly vascularized types of cancer such as hepatocellular carcinoma, a positive correlation was found between increased TGF-β plasma concentrations and tumor vascularity. Interestingly, fibrillin-1 has a higher affinity to TGF-β and, therefore, has a higher capacity to sequester TGF-β compared to fibrillin-2. The previously reported downregulation of fibrillin-1 in tumor endothelium affects the fibrillin-1/fibrillin-2 ratio in the microfibrils, exposing the normally hidden fibrillin-2. We postulate that fibrillin-2 exposure in the tumor endothelium directly stimulates tumor angiogenesis by influencing TGF-β sequestering by microfibrils, leading to a locally higher active TGF-β concentration in the tumor microenvironment. From a therapeutic perspective, fibrillin-2 might serve as a potential target for future anti-cancer therapies.

Topics: Animals; Arachnodactyly; Connective Tissue; Contracture; Disease Models, Animal; Endothelium, Vascular; Fibrillin-2; Humans; Marfan Syndrome; Mutation; Neoplasms; Neovascularization, Pathologic; Transforming Growth Factor beta; Tumor Microenvironment

Marfan syndrome is an autosomal dominant connective tissue disease with an estimated incidence of 1 in 5000 individuals. In 90% of cases it is caused by mutations in the gene for fibrillin-1, the main constituent of extracellular microfibrils. Studies on animal models of Marfan syndrome have revealed that fibrillin-1 mutations interfere with local TGF-β signaling, in addition to impairing tissue integrity. The cardinal features involve the cardiovascular, ocular and skeletal systems. The diagnosis of Marfan syndrome is made according to the revised Ghent nosology. Early identification and appropriate management are critical for patients with Marfan syndrome, who are prone to the life-threatening cardiovascular complications of aortic aneurysms and aortic dissection. The standard treatment includes prophylactic beta-blockers in order to slow down dilation of the ascending aorta, and prophylactic aortic surgery. The success of current medical and surgical treatment of aortic disease in Marfan syndrome has substantially improved mean life expectancy, extending it above 72 years. This review aims to provide an overview of this hereditary disorder.

Topics: Adrenergic beta-Antagonists; Animals; Aorta; Aortic Aneurysm; Aortic Dissection; Fibrillin-1; Marfan Syndrome; Mutation; Transforming Growth Factor beta

Patients with connective tissue diseases (CTDs) are suspected to be at higher risk for cerebrovascular involvement, such as intracranial aneurysms, dissections and strokes, than the general population. Particularly, Marfan Syndrome (MFS) has been reported as associated with an increased risk of cerebrovascular alterations. Literature data report different prevalence of intracranial aneurysms in MFS, ranging from 4 % to 29 %, suggesting a role of genetic cause that involves the regulation of the TGF-β signaling. Ischemic and hemorrhagic strokes have been also reported in MFS, but with an estimated prevalence from 3 % to 4 %. However, the aetiology of both events appears to be reliable more to a cardiac source than to the primary connective tissue defect. Finally, the available literature suggests that MFS patients have a higher prevalence of arterial tortuosity of neck and head vessels and these findings may be related to an enhanced chance of dissection. Overall, despite of the lack of studies, we could affirm that it may exists an increased prevalence of some neurovascular findings in MFS patients. Nevertheless, further studies are required to determine the true prevalence of these features and investigate specific gene mutations involved in MFS.

Topics: Arteries; Hemorrhagic Stroke; Humans; Intracranial Aneurysm; Ischemic Stroke; Joint Instability; Marfan Syndrome; Prevalence; Signal Transduction; Skin Diseases, Genetic; Transforming Growth Factor beta; Vascular Malformations

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the fibrillin-1 gene. Acute aortic dissection is the leading cause of death in patients suffering from MFS and consequence of medial degeneration and aneurysm formation. In addition to its structural function in the formation of elastic fibers, fibrillin has a major role in keeping maintaining transforming growth factor β (TGF-β) in an inactive form. Dysfunctional fibrillin increases TGF-β bioavailability and concentration in the extracellular matrix, leading to activation of proinflammatory transcription factors. In turn, these events cause increased expression of matrix metalloproteinases and cytokines that control the migration and infiltration of inflammatory cells into the aorta. Moreover, TGF-β causes accumulation of reactive oxygen species leading to further degradation of elastin fibers. All these processes result in medial elastolysis, which increases the risk of vascular complications. Although MFS is a hereditary disease, symptoms and traits are usually not noticeable at birth. During childhood or adolescence affected individuals present with severe tissue weaknesses, especially in the aorta, heart, eyes, and skeleton. Considering this, even young patients should avoid activities that exert additional stress and pressure on the aorta and the cardiovascular system. Thus, if the diagnosis is made and prophylactic treatment is initiated in a timely fashion, MFS and its preliminary pathophysiologic vascular remodeling can be successfully ameliorated reducing the risk of life-threatening complications. This commentary focuses on new research opportunities and molecular findings on MFS, discusses future challenges and possible long-term therapies.

Topics: Adrenergic beta-Antagonists; Fibrillins; Humans; Long-Term Care; Marfan Syndrome; Matrix Metalloproteinases; Muscle, Smooth, Vascular; Transforming Growth Factor beta; Vascular Remodeling

Mutations in fibrillin-1 cause Marfan syndrome (MFS), the most common heritable disorder of connective tissue. Fibrillin-1 assemblies (microfibrils and elastic fibers) represent a unique dual-function component of the architectural matrix. The first role is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals. The multifunctional, tissue-specific nature of fibrillin-1 assemblies is reflected in the variety of clinical manifestations and disease mechanisms associated with the MFS phenotype. Characterization of mice with ubiquitous or cell type-restricted fibrillin-1 deficiency has unraveled some pathophysiological mechanisms associated with the MFS phenotype, such as altered mechanotransduction in the heart, dysregulated TGFβ signaling in the ascending aorta and perturbed stem cell fate in the bone marrow. In each case, potential druggable targets have also been identified. However, the finding that distinct disease mechanisms underlie different organ abnormalities strongly argues for developing multi-drug strategies to mitigate or even prevent both life-threatening and morbid manifestations in pediatric and adult MFS patients.

Topics: Animals; Disease Models, Animal; Fibrillin-1; Humans; Marfan Syndrome; Mechanotransduction, Cellular; Mutation; Myocardium; Signal Transduction; Stem Cells; Transforming Growth Factor beta

Topics: Animals; Aortic Aneurysm; Aortic Dissection; Humans; Marfan Syndrome; Mutation; Transforming Growth Factor beta

Thoracic aortic diseases, including aneurysms and dissections of the thoracic aorta, are a major cause of morbidity and mortality. Risk factors for thoracic aortic disease include increased hemodynamic forces on the ascending aorta, typically due to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease either disrupt smooth muscle cell (SMC) contraction or adherence to an impaired extracellular matrix, or decrease canonical transforming growth factor beta (TGF-β) signaling. Paradoxically, TGF-β hyperactivity has been postulated to be the primary driver for the disease. More recently, it has been proposed that the response of aortic SMCs to the hemodynamic load on a structurally defective aorta is the primary driver of thoracic aortic disease, and that TGF-β overactivity in diseased aortas is a secondary, unproductive response to restore tissue function. The engineering of mouse models of inherited aortopathies has identified potential therapeutic agents to prevent thoracic aortic disease.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Aortic Aneurysm, Thoracic; Aortic Dissection; Disease Models, Animal; Genetic Predisposition to Disease; Humans; Losartan; Marfan Syndrome; Mechanoreceptors; Mice; Muscle, Smooth, Vascular; Signal Transduction; Transforming Growth Factor beta

Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture.

Topics: Aged; Aging; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Disease Progression; Epigenesis, Genetic; Extracellular Matrix; Female; Genetic Predisposition to Disease; Humans; Inflammation; Lipids; Male; Marfan Syndrome; Models, Genetic; Muscle, Smooth; Mutation; Polymorphism, Single Nucleotide; Risk Factors; Sequence Analysis, DNA; Smoking; Transforming Growth Factor beta

Recent progress in the study of hereditary large vessel diseases such as Marfan syndrome (MFS) have not only identified responsible genes but also provided better understanding of the pathophysiology and revealed possible new therapeutic targets. Genes identified for these diseases include FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SKI, EFEMP2, COL3A1, FLNA, ACTA2, MYH11, MYLK and SLC2A10, as well as others. Their dysfunction disrupts the function of transforming growth factor-β (TGF-β) signaling pathways, as well as that of the extracellular matrix and smooth muscle contractile apparatus, resulting in progression of structural damage to large vessels, including aortic aneurysms and dissections. Notably, it has been shown that the TGF-β signaling pathway has a key role in the pathogenesis of MFS and related disorders, which may be important for development of strategies for medical and surgical treatment of thoracic aortic aneurysms and dissections.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Ehlers-Danlos Syndrome; Fibrillin-1; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mutation; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is a rare, autosomal-dominant, multisystem disorder, presenting with skeletal, ocular, skin, and cardiovascular symptoms. Significant clinical overlap with other systemic connective tissue diseases, including Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the MASS phenotype, has been documented. In MFS and LDS, the cardiovascular manifestations account for the major cause of patient morbidity and mortality, rendering them the main target for therapeutic intervention. Over the past decades, gene identification studies confidently linked the aforementioned syndromes, as well as nonsyndromic aneurysmal disease, to genetic defects in proteins related to the transforming growth factor (TGF)-β pathway, greatly expanding our knowledge on the disease mechanisms and providing us with novel therapeutic targets. As a result, the focus of the developing pharmacological treatment strategies is shifting from hemodynamic stress management to TGF-β antagonism. In this review, we discuss the insights that have been gained in the molecular biology of MFS and related disorders over the past 25 years.

Topics: Angiotensin Receptor Antagonists; Animals; Arachnodactyly; Craniosynostoses; Gene Expression Regulation; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mitral Valve Prolapse; Myopia; Signal Transduction; Skin Diseases; Transforming Growth Factor beta

Skeletal muscle possesses remarkable ability to change its size and force-producing capacity in response to physiological stimuli. Impairment of the cellular processes that govern these attributes also affects muscle mass and function in pathological conditions. Myostatin, a member of the TGF-β family, has been identified as a key regulator of muscle development, and adaptation in adulthood. In muscle, myostatin binds to its type I (ALK4/5) and type II (ActRIIA/B) receptors to initiate Smad2/3 signalling and the regulation of target genes that co-ordinate the balance between protein synthesis and degradation. Interestingly, evidence is emerging that other TGF-β proteins act in concert with myostatin to regulate the growth and remodelling of skeletal muscle. Consequently, dysregulation of TGF-β proteins and their associated signalling components is increasingly being implicated in muscle wasting associated with chronic illness, ageing, and inactivity. The growing understanding of TGF-β biology in muscle, and its potential to advance the development of therapeutics for muscle-related conditions is reviewed here.

Topics: Adaptation, Physiological; Animals; Cachexia; Homeostasis; Humans; Marfan Syndrome; Muscle Development; Muscular Dystrophies; Regeneration; Sarcopenia; Signal Transduction; Transforming Growth Factor beta

The 10-12 nm diameter microfibrils of the extracellular matrix (ECM) impart both structural and regulatory properties to load-bearing connective tissues. The main protein component is the calcium-dependent glycoprotein fibrillin, which assembles into microfibrils at the cell surface in a highly regulated process involving specific proteolysis, multimerization and glycosaminoglycan interactions. In higher metazoans, microfibrils act as a framework for elastin deposition and modification, resulting in the formation of elastic fibres, but they can also occur in elastin-free tissues where they perform structural roles. Fibrillin microfibrils are further engaged in a number of cell matrix interactions such as with integrins, bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β (TGFβ). Fibrillin-1 (FBN1) mutations are associated with a range of heritable connective disorders, including Marfan syndrome (MFS) and the acromelic dysplasias, suggesting that the roles of 10-12 nm diameter microfibrils are pleiotropic. In recent years the use of molecular, cellular and whole-organism studies has revealed that the microfibril is not just a structural component of the ECM, but through its network of cell and matrix interactions it can exert profound regulatory effects on cell function. In this review we assess what is known about the molecular properties of fibrillin that enable it to assemble into the 10-12 nm diameter microfibril and perform such diverse roles.

Topics: Animals; Connective Tissue; Dwarfism; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfibrils; Microfilament Proteins; Mutation; Osteochondrodysplasias; Transforming Growth Factor beta

Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Aneurysm; Disease Management; Fibrillin-1; Humans; Loeys-Dietz Syndrome; Losartan; Marfan Syndrome; Signal Transduction; Transforming Growth Factor beta

The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-β (TGFβ). The involvement of TGFβ in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem.

Topics: Angiotensin-Converting Enzyme Inhibitors; Aortic Aneurysm; Aortic Dissection; Connective Tissue; Fibrillin-1; Fibrillins; Gene Expression Regulation; Humans; Joint Instability; Marfan Syndrome; Microfilament Proteins; Mitral Valve Prolapse; Peptidyl-Dipeptidase A; Signal Transduction; Transforming Growth Factor beta

Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor β (TGFβ) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFβ pathway. While TGFβ antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFβ signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

Topics: Animals; Aortic Aneurysm, Thoracic; Arachnodactyly; Cardiovascular Abnormalities; Craniosynostoses; Fibrillin-1; Fibrillins; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mice; Microfilament Proteins; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations in the extracellular matrix protein fibrillin-1. While MFS patients are considered to be at high risk of dental disorders and cardiovascular complications, little causal relationship has been provided to date. It is well known that an elevated level of active TGF-β in the plasma is a major manifestation of MFS. TGF-β is known to play a critical role in the development of cardiovascular diseases and its levels were also elevated in the serum and saliva of periodontitis patients. These findings may suggest an association between periodontitis and the cardiovascular complications of MFS. In this article, we review the influence of periodontitis in MFS patients with cardiovascular complications in order to identify critical therapeutic targets of TGF-β.

Topics: Humans; Marfan Syndrome; Periodontitis; Transforming Growth Factor beta

Marfan syndrome (MFS) is a genetic disorder that affects multiple organs. Mortality imposed by aortic aneurysm and dissections represent the most serious clinical manifestation of MFS. Progressive pathological aortic root enlargement as the result of degeneration of microfibril architecture and consequential loss of extracellular matrix integrity due to fibrillin-1 (FBN1) mutations are commonly diagnosed clinical manifestations of MFS. However, overlapping clinical manifestations with other aneurysmal disorders present a significant challenge in early and accurate diagnosis of MFS. While FBN1 mutations, abnormal transforming growth factor-β signaling and dysregulated matrix metalloproteinases have been implicated in MFS, clinically accepted risk-stratifying biomarkers have yet to be reliably identified. In this review, we summarize current consensus and recent insights in the understanding of MFS pathogenesis. Finally, we introduce the application of induced pluripotent stem cells (iPSCs) as cellular models for MFS and its potential as a novel platform into providing better appreciation of mechanisms underlying MFS diverse manifestations in the cardiovascular system.

Topics: Fibrillin-1; Fibrillins; Humans; Induced Pluripotent Stem Cells; Marfan Syndrome; Matrix Metalloproteinases; Microfilament Proteins; Transforming Growth Factor beta

The fibrillins, large extracellular matrix molecules, are polymerized to form "microfibrils." The fibrillin microfibril scaffold is populated by microfibril-associated proteins and by growth factors, which are likely to be latent. The scaffold, associated proteins, and bound growth factors, together with cellular receptors that can sense the microfibril matrix, constitute the fibrillin microenvironment. Activation of TGFβ signaling is associated with the Marfan syndrome, which is caused by mutations in fibrillin-1. Today we know that mutations in fibrillin-1 cause the Marfan syndrome as well as Weill-Marchesani syndrome (and other acromelic dysplasias) and result in opposite clinical phenotypes: tall or short stature; arachnodactyly or brachydactyly; joint hypermobility or stiff joints; hypomuscularity or hypermuscularity. We also know that these different syndromes are associated with different structural abnormalities in the fibrillin microfibril scaffold and perhaps with specific cellular receptors (mechanosensors). How does the microenvironment, framed by the microfibril scaffold and populated by latent growth factors, work? We must await future investigations for the molecular and cellular mechanisms that will answer this question. However, today we can appreciate the importance of the fibrillin microfibril niche as a contextual environment for growth factor signaling and potentially for mechanosensation.

Topics: Animals; Bone Morphogenetic Proteins; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Mechanotransduction, Cellular; Microfibrils; Microfilament Proteins; Transforming Growth Factor beta

This review focusses on impact of a better knowledge of pathogenic mechanisms of Marfan and related disorders on their treatment strategies. It was long believed that a structural impairment formed the basis of Marfan syndrome as deficiency in the structural extracellular matrix component, fibrillin-1 is the cause of Marfan syndrome. However, the study of Marfan mouse models has revealed the strong involvement of the transforming growth factor-β signalling pathway in the pathogenesis of Marfan. Similarly, this pathway was demonstrated to be key in the pathogenesis of Loeys-Dietz and Shprintzen-Goldberg syndrome. The elucidation of the underlying pathogenic mechanisms has led to new treatment strategies, targeting the overactive TGF-β pathway. Various clinical trials are currently investigating the potential new treatment options. A meta-analysis will contribute to a better understanding of the various trial results.

Topics: Animals; Arachnodactyly; Craniosynostoses; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Signal Transduction; Transforming Growth Factor beta; Translational Research, Biomedical

Marfan syndrome (MFS) is a relatively common and often lethal disease of connective tissue. Medical, surgical and basic research advances over the last two decades have had a major positive impact on the clinical management of MFS patients. Life expectancy has increased significantly, more discriminating diagnostic criteria have been developed, a number of new clinical entities have been recognized, and exciting opportunities for drug-based therapy have emerged. Despite such a remarkable progress, MFS diagnosis remains difficult and aortic disease progression is very heterogeneous and clinical outcome is unpredictable. Ongoing research efforts are therefore exploiting animal models of MFS to identify novel diagnostic and prognostic biomarkers, genetic, epigenetic and environmental modifiers and druggable biological targets.

Topics: Adrenergic beta-Antagonists; Animals; Antibodies, Neutralizing; Connective Tissue; Disease Progression; Epigenesis, Genetic; Eye; Fibrillins; Genes, Dominant; Heart; Humans; Life Expectancy; Marfan Syndrome; Mice, Transgenic; Microfilament Proteins; Mutation; Transforming Growth Factor beta

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that cosegregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic root dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. Given the evidence of increased transforming growth factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in this relationship. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, heritable connective tissue syndromes related to TGF-β receptor (TGFBR) mutations, and discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Antibodies, Neutralizing; Aortic Aneurysm, Thoracic; Aortic Valve; Bicuspid Aortic Valve Disease; Gene Expression Regulation; Heart Defects, Congenital; Heart Valve Diseases; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mutation; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

The starting point, in Marfan syndrome (MFS) appears to be the mutation of fibrillin-1 gene whose deconstructed protein product cannot bind transforming growth factor beta (TGF-b), leading to an increased TGF-b tissue level. The aim of this review is to review the already known features of the cellular signal transduction downstream to TGF-b and its impact on the tissue homeostasis of microfibrils, and elastic fibers. We also investigate current data on the extracellular regulation of TGF-b level including mechanotransduction and the feedback cycles of integrin-dependent and independent activation of the latent TGF-b complex. Together these factors, by the destruction of the connective tissue fibers, may play an important role in the development of the diverse cardiac and extracardiac manifestations of MFS and many of them could be a target of conservative treatment. We present currently investigated drugs for the treatment of the syndrome, and explore possible avenues of research into pathogenesis of MFS in order to improve understanding of the disease.

Topics: Animals; Aortic Aneurysm; Humans; Marfan Syndrome; Prognosis; Signal Transduction; Transforming Growth Factor beta

The extracellular matrix (ECM) is a complex entity with structural proteins (such as fibrillins, collagen, elastin), ground substance (proteoglycans), modifying enzymes (ADAMTS, PLOD, lysyloxidases (LOX)) and cytokines that regulate morphogenesis, growth, homeostasis and repair (transforming growth factor-beta [TGF-beta], bone morphogenic protein [BMP]). Over the last decade, the intimate relationship between structural proteins and these growth factors has emerged. The study of the extracellular matrix in human conditions and relevant mouse models is gradually unmasking the key role of these structural molecules in the regulation of the bio-availability of these growth factors. Major progress has been made in the study of the cardiovascular system (1) and the first clues in the skeletal system have emerged. (2) In this review, we will discuss the clinical, molecular, and pathogenic aspects of Marfan syndrome, Loeys-Dietz syndrome and related disorders with emphasis on the role of fibrillins and TGF-beta.

Topics: Animals; Bone Morphogenetic Proteins; Extracellular Matrix; Fibrillins; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mice; Microfilament Proteins; Transforming Growth Factor beta

This review on Marfan syndrome is focused on the clinical heterogeneity and variability, the new diagnostic criteria as delineated by an expert group in 2010, the current knowledge on the molecular and pathogenetic etiology, and the options of the medical and surgical treament. Defined clinical findings, family history and mutations in the FBN1 gene only differentiate Marfan syndrome from the other aortic syndromes. The involvement of the cellular TGF-beta-signaling in pathogenesis allows new approach for medical treatment with ATR-blockers for which, however, evidence based indications are still lacking. Finally, a suggestion is made how to arrange the diagnostic workup, appropriate treatment and follow-up of the Marfan patients in the Finnish health care.

Topics: Fibrillin-1; Fibrillins; Finland; Humans; Marfan Syndrome; Microfilament Proteins; Mutation; Transforming Growth Factor beta

Transforming growth factor beta (TGFβ) is a multipotent cytokine that is sequestered in the extracellular matrix (ECM) through interactions with a number of ECM proteins. The ECM serves to concentrate latent TGFβ at sites of intended function, to influence the bioavailability and/or function of TGFβ activators, and perhaps to regulate the intrinsic performance of cell surface effectors of TGFβ signal propagation. The downstream consequences of TGFβ signaling cascades in turn provide feedback modulation of the ECM. This review covers recent examples of how genetic mutations in constituents of the ECM or TGFβ signaling cascade result in altered ECM homeostasis, cellular performance and ultimately disease, with an emphasis on emerging therapeutic strategies that seek to capitalize on this refined mechanistic understanding.

Topics: Animals; Cell Membrane; Cytokines; Extracellular Matrix; Fibrillins; Homeostasis; Humans; Integrins; Marfan Syndrome; Mice; Microfilament Proteins; Mutation; Phenotype; Signal Transduction; Syndrome; Transforming Growth Factor beta

Although historically Marfan syndrome (MFS) has always been considered as a condition caused by the deficiency of a structural extracellular matrix protein, fibrillin-1, the study of Marfan mouse models and Marfan-related conditions has shifted our current understanding to a pathogenic model that involves dysregulation of the cytokine-transforming growth factor beta (TGF-β) signaling.. In this review, we focus on the impact of the revised MFS clinical diagnostic criteria. We discuss lessons that have been learned from molecular findings in relevant Marfan-related conditions, such as sporadic thoracic aortic aneurysm/dissection, stiff skin syndrome, acromelic dysplasias and Loeys-Dietz syndrome. We explore the latest insights into the role of the alternative TGF-β signaling pathways in MFS pathogenesis. Finally, we give an update on the current and future treatment strategies.. The recent insights into the pathogenesis of MFS and related disorders have offered a prime example of translational medicine with immediate bridge between molecular findings and therapeutic options.

Topics: Acromegaly; Adolescent; Aortic Aneurysm, Thoracic; Child; Child, Preschool; Female; Fibrillin-1; Fibrillins; Humans; Loeys-Dietz Syndrome; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is a hereditary connective tissue disorder. Studies of MFS have established the critical contribution of fibrillin-1 deficiency to disease progression through altered cell-matrix interactions and dysregulated TGF-β signalling. It is now known that the disease is caused by altered regulation of TGF-β. As a result, the definition of MFS- and MFS-related diseases as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and tissue remodelling.

Topics: Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Mutation; Signal Transduction; Transforming Growth Factor beta

We report a rare case of acute lymphoblastic leukemia (ALL) in a 7-year-old boy with Marfan's syndrome. He was diagnosed as having Marfan's syndrome by clinical findings at the age of 2 years, and the diagnosis was confirmed by the detection of gene mutation in FBN1. He was referred to our hospital because of the swelling of cervical lymph nodes at the age of 7 years. Findings on bone marrow examination demonstrated T lymphoblastic ALL. He obtained complete remission after induction therapy, and had no serious side effects including cardiotoxicity during chemotherapy. He has remained in continuous complete remission for 34 months following diagnosis. To our knowledge, only three cases of leukemia in patients with Marfan's syndrome were reported previously. We speculate that increased activity of TGF-β, which is known as a tumor suppressor factor, in patients with Marfan's syndrome may diminish the risk of developing leukemia, although such a thesis was not proven in this case.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Fibrillin-1; Fibrillins; Humans; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Transforming Growth Factor beta

Marfan syndrome has changed over the last few years: new diagnostic criteria have been proposed, new clinical entities recognised and life expectancy increased. The role of fibrillin 1, which was initially thought to be mainly structural, has been shown to also be functional. The altered transforming growth factor β pathway is better understood, the importance of epigenetic factors has been demonstrated and recent data suggest that many of the observations made in Marfan syndrome can actually be made in thoracic aortic aneurysm from diverse aetiologies. Besides transforming growth factor β, the role of metalloproteinase, the fibrinolytic/coagulation system, is being suggested in the progression of the disease. A relationship between the type of fibrillin 1 (FBN1) gene mutation and the mechanism for the disease (haplo-insufficiency vs negative dominance), as well as some genotype/phenotype correlations, has been observed, although the main challenge of recognising gene modifiers has yet to explain tremendous variability despite similar mutation. This progress has led to new hopes for tomorrow's therapies, some of which are being tested in clinics, whereas others are still in the field of animal models. Here we review some of the new data obtained in the understanding of the pathophysiology and genetics of this disease.

Topics: Diagnostic Techniques, Cardiovascular; DNA; Fibrillin-1; Fibrillins; France; Genetic Predisposition to Disease; Genotype; Humans; Immunohistochemistry; Marfan Syndrome; Microfilament Proteins; Morbidity; Mutation; Prognosis; Survival Rate; Transforming Growth Factor beta

Tissue microfibrils contain fibrillin-1 as a major constituent. Microfibrils regulate bioavailability of TGFβ superfamily growth factors and are structurally crucial in the ocular zonule. FBN1 mutations typically cause the Marfan syndrome, an autosomal dominant disorder manifesting with skeletal overgrowth, aortic aneurysm, and lens dislocation (ectopia lentis). Infrequently, FBN1 mutations cause dominantly inherited Weill-Marchesani syndrome (WMS), isolated ectopia lentis (IEL), or the fibrotic condition, geleophysic dysplasia (GD). Intriguingly, mutations in ADAMTS [a disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif] family members phenocopy these disorders, leading to recessive WMS (ADAMTS10), WMS-like syndrome (ADAMTS17), IEL (ADAMTSL4 and ADAMTS17) and GD (ADAMTSL2). An ADAMTSL2 founder mutation causes Musladin-Lueke syndrome, a fibrotic disorder in beagle dogs. The overlapping disease spectra resulting from fibrillin-1 and ADAMTS mutations, interaction of ADAMTS10 and ADAMTSL2 with fibrillin-1, and evidence that these ADAMTS proteins accelerate microfibril biogenesis, constitutes a consilience suggesting that some ADAMTS proteins evolved to provide a novel mechanism regulating microfibril formation and consequently cell behavior.

Topics: ADAM Proteins; Amino Acid Motifs; Animals; Binding Sites; Dogs; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Metalloendopeptidases; Mice; Microfibrils; Microfilament Proteins; Multigene Family; Mutation; Thrombospondins; Transforming Growth Factor beta

Marfan syndrome (MFS) is a systemic disorder of the connective tissue with pleiotropic manifestations due to heterozygous FBN1 mutations and consequent upregulation of TGFβ signaling in affected tissues. Myxomatous thickening and elongation of the mitral valve (MV) leaflets commonly occur in this condition. Investigation of murine models of this disease has led to improved understanding of the mechanisms that underlie many of the phenotypic features of MFS, including MV disease. Loeys-Dietz syndrome (LDS) is a related disorder due to heterozygous mutations in the genes encoding subunits of the TGFβ receptor, and it may also involve the MV leaflets with similar elongation and thickening of the MV leaflets. Although the genetic basis and pathogenesis of nonsyndromic MV prolapse has been elusive to date, insights derived from monogenic disorders like MFS and LDS can be informative with regard to novel gene discovery and investigation into the pathogenesis of MV disease. This manuscript will review the prevalence of MV disease in MFS, its pathogenic basis as determined in mice with Fbn1 mutations, and ongoing studies that seek to better understand MV disease in the context of fibrillin-1 deficiency or excessive TGFβ signaling.

Topics: Animals; Disease Models, Animal; Fibrillin-1; Fibrillins; Genetic Predisposition to Disease; Heart Valve Diseases; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mice; Mice, Transgenic; Microfilament Proteins; Mitral Valve; Phenotype; Receptor, Angiotensin, Type 2; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

The growth factor TGF-β is secreted in a latent complex consisting of three proteins: TGF-β, an inhibitor (latency-associated protein, LAP, which is derived from the TGF-β propeptide) and an ECM-binding protein (one of the latent TGF-β binding proteins, or LTBPs). LTBPs interact with fibrillins and other ECM components and thus function to localize latent TGF-β in the ECM. LAP contains an integrin-binding site (RGD), and several RGD-binding integrins are able to activate latent TGF-β through binding this site. Mutant mice defective in integrin-mediated activators, and humans and mice with fibrillin gene mutations, show the critical role of ECM and integrins in regulating TGF-β signaling.

Topics: Animals; Extracellular Matrix; Fibrillins; Humans; Integrins; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Microfilament Proteins; Models, Biological; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome is a systemic connective tissue disorder that is inherited in an autosomal-dominant pattern with variable penetrance. Although there are many clinical manifestations of this disease, the most life threatening are cardiovascular complications, including mitral valve prolapse and aortic root aneurysm. When the primary defect was discovered in the fibrillin-1 gene, it was hypothesized that mutations in fibrillin-1 resulted in a weakened and disordered elastic architecture. However, recent evidence has suggested that the Marfan syndrome is caused by more than just a disordered microfibril matrix. Interest was stimulated when it was discovered that fibrillin-1 mutations enhanced the release of sequestered latent transforming growth factor-beta, a well-described mediator of vascular remodeling. This article focuses on the pathophysiology of aortopathy in the Marfan syndrome and related diseases, with special emphasis on the role of transforming growth factor-beta in mediating the pathogenesis of this disease.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Mitral Valve Prolapse; Mutation; Risk Factors; Signal Transduction; Transforming Growth Factor beta

Hypertension is a well known risk factor for cerebral small vessel disease (SVD) characterized by MRI white matter hyperintensities called "leukoaraiosis". However, the molecular basis of SVD remains to be elucidated. Both twin and family studies have shown that leukoaraiosis is the most heritable cerebrovascular phenotype with a heritability estimated to be between 55% and 71%, suggesting genetic factors for SVD. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is hereditary SVD lacking hypertension. We have recently identified the causative gene, FHtrA1, for CARASIL by genome-wide linkage study and a candidate gene approach. HtrA1 is a serine protease that represses signaling by TGF-β family members. We found that mutated HtrA1 did not repress signaling by the TGF-β family members (BMP2, BMP4, and TGF-β1), resulting in vascular fibrosis with synthesis of extracellular matrix proteins. Our results indicate that disinhibition of TGF-β signaling underlies the molecular basis of CARASIL. Marfan's syndrome is an autosomal dominant connective tissue disorder caused by disinhibition of TGF-β signaling associated with FBN1 mutations. In a small cohort study, angiotensin II-receptor blockers (ARBs) therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilatation. This study provides a potential for developing a therapy targeting TGF-β signaling for SVD.

Topics: CADASIL; Cerebral Small Vessel Diseases; Fibrillin-1; Fibrillins; Genome-Wide Association Study; High-Temperature Requirement A Serine Peptidase 1; Humans; Marfan Syndrome; Microfilament Proteins; Molecular Targeted Therapy; Mutation; Serine Endopeptidases; Signal Transduction; Transforming Growth Factor beta

Thoracic aortic aneurysms (TAAs) are potentially devastating, and due to their asymptomatic behavior, pose a serious health risk characterized by the lack of medical treatment options and high rates of surgical morbidity and mortality. Independent of the inciting stimuli (biochemical/mechanical), TAA development proceeds by a multifactorial process influenced by both cellular and extracellular mechanisms, resulting in alterations of the structure and composition of the vascular extracellular matrix (ECM). While the role of enhanced ECM proteolysis in TAA formation remains undisputed, little attention has been focused on the upstream signaling events that drive the remodeling process. Recent evidence highlighting the dysregulation of transforming growth factor-beta (TGF-beta) signaling in ascending TAAs from Marfan syndrome patients has stimulated an interest in this intracellular signaling pathway. However, paradoxical discoveries have implicated both enhanced TGF-beta signaling and loss of function TGF-beta receptor mutations, in aneurysm formation; obfuscating a clear functional role for TGF-beta in aneurysm development. In an effort to elucidate this subject, TGF-beta signaling and its role in vascular remodeling and pathology will be reviewed, with the aim of identifying potential mechanisms of how TGF-beta signaling may contribute to the formation and progression of TAA.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Disease Progression; Ehlers-Danlos Syndrome; Extracellular Matrix; Genetic Predisposition to Disease; Humans; Marfan Syndrome; Mutation; Peptide Hydrolases; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

Many patients with congenital cardiac disease are at risk for progressive aortic dilation. The mechanisms underlying aortic dilation in this patient cohort are described, and the similarities to the pathophysiologic alterations seen in Marfan syndrome are highlighted. Indications for treatment are discussed.

Topics: Aortic Diseases; Dilatation, Pathologic; Heart Defects, Congenital; Humans; Marfan Syndrome; Transforming Growth Factor beta

Elastic system fibers are composed of two distinct elements, elastin, which is an amorphous component crosslinked in the core, and microfibril, localized in the periphery of elastin. As microfibrillar proteins, fibrillins, microfibril-associated glycoproteins (MAGPs), latent TGF-beta-binding proteins (LTBPs), microfibril-associated proteins (MFAPs), and fibulins are known. Fibrillin-1 is a major microfibrillar protein and characterized by calcium binding EGF-like (cbEGF) domain. Association between fibrillin-1 and TGF-beta is a recent topic of this field and this interaction is known to inactivate and target TGF-beta action. FBN1 encoding fibrillin-1 is a responsible gene for Marfan syndrome type 1 (MIM #154700), characterized by increased height and long limbs, ectopia lentis, and cardiovascular disorders, such as mitral valve prolapse and aortic dilation and regurgitation. Animal models suggest that the abnormal TGF-beta signaling is underlying as the pathogenesis of these conditions. Besides skeletal, ocular and cardiovascular conditions, severe periodontitis is frequently seen in affected patients. To clarify the unknown function of elastic system fibers in the periodontal ligament (PDL), PDL-cells were isolated from a Marfan syndrome type 1 patient who was with the severe periodontitis and had a mutation in one of the cbEGF domain of fibrillin-1. These results suggested that wild-type fibrillin-1 was required for the normal cell alignment and tissue architecture of PDLs. Evidences are now accumulated to suggest that fibrillin-1 is one of the molecule involved in the interaction between cell and extracellular matrix.

Topics: Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Periodontal Diseases; Periodontium; Reference Values; Signal Transduction; Transforming Growth Factor beta

Fibrillin-1 (FBN-1) is the main component of the 10-12 nm microfibrils found in the extracellular matrix (ECM). ECM displays a structural role in the tissue-specific organization and takes part in the regulation of various cytokines and growth factors. A growing body of evidences supports a narrow relationship between FBN-1 and TGF-beta. Homology between FBN-1 and latent TGF-beta (LTGF) allows microfibrills to be a reservoir for this cytokine. The Marfan syndrome (MFS), a prototypic fibrillinopathy, highlights these relationships as it relates to 2 major genes that are FBN1 and TGF-beta type II receptor (TGFBR2) genes. In a mouse model of MFS, an up-regulation of the TGF-beta pathway is partly responsible for the phenotype. This FBN-1/TGF-beta relationship may play also a role in systemic sclerosis (SSc), a multigenic disease characterized by excessive generalised ECM deposit. Indeed, two related animal models results from both gene mutations: the Tight Skin 1 mouse is due to a partial in-frame duplication of the Fbn1 gene and another model conditionally overexpresses TGF-beta type I receptor. A better understanding of FBN-1/TGF-beta relationship appears of great importance in fibrillinopathies: it may allow reconsidering the nosologic framework of these diseases including the TGF-beta signalopathies and could lead to innovative therapeutic strategies.

Topics: Extracellular Matrix; Fibrillin-1; Fibrillins; Homeostasis; Humans; Marfan Syndrome; Microfilament Proteins; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Scleroderma, Systemic; Transforming Growth Factor beta

Aortic aneurysms are an important cause of mortality in the western world. Monogenic disorders such as the Marfan syndrome (MFS) are good genetic models for the pathogenesis of aortic aneurysm. In the MFS, progressive dilatation of the aortic root leads to aortic aneurysm and dissection, often associated with precocious death. Early pathogenetic models for MFS focused upon structural weakness of the tissues imposed by microfibrillar deficiency. However, recent studies of transgenic mouse models have challenged this model and demonstrated a central role for the upregulation of the TGFbeta signaling pathway. The discovery of a new aortic aneurysm syndrome, the Loeys-Dietz syndrome (LDS), confirmed the importance of the cytokine TGFbeta in aneurysm pathogenesis. The main distinguishing features between LDS and MFS include the presence of hypertelorism, cleft palate/bifid uvula and arterial tortuosity. LDS is caused by mutations in the genes encoding the receptors for TGFbeta (TGFBR1/2). This insight helped to elucidate the pathogenesis of another rare autosomal recessive connective tissue disorder, arterial tortuosity syndrome. This disease is caused by mutations in the SLC2A10 gene, coding for GLUT10, a member of the glucose transporter family. In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS. Finally, all these insights have also lead to new therapeutic insights. In transgenic mouse models it was shown that losartan, an angiotensin II type 1 receptor with known inhibiting effects on TGFbeta, rescues the aortic phenotype. If these promising results are confirmed in human trials, losartan might have beneficial effects in the treatment of more common nonhereditary aortic aneurysms.

Topics: Abnormalities, Multiple; Animals; Animals, Genetically Modified; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Disease Models, Animal; Humans; Marfan Syndrome; Mice; Models, Genetic; Transforming Growth Factor beta; Up-Regulation

Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome.. Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression.. It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome.. There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Aneurysm, Thoracic; Cohort Studies; Disease Models, Animal; Follow-Up Studies; Genetic Markers; Humans; Losartan; Marfan Syndrome; Mice; Microfilament Proteins; Risk Assessment; Survival Rate; Transforming Growth Factor beta; Treatment Outcome

In contrast with adults, thoracic aortic aneurysms in children are usually associated with connective tissue defect syndromes. As such, there are phenotypic clues to identify patients at risk. Marfan syndrome, Loeys-Dietz syndrome, and bicuspid aortic valve syndrome account for the majority of these aneurysms. Indications for surgery as well as surgical options differ according to diagnosis and are reviewed herein.

Topics: Aortic Aneurysm, Thoracic; Aortic Valve; Blood Vessel Prosthesis Implantation; Child; Ehlers-Danlos Syndrome; Humans; Marfan Syndrome; Mutation; Phenotype; Syndrome; Transforming Growth Factor beta

Marfan syndrome (MFS, OMIM #154700) is a hereditary connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In classical MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. However, some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recent studies manipulating mouse Fbn1 have provided new insights into the molecular pathogenesis of MFS. Dysregulation of transforming growth factor beta (TGFbeta) signaling in lung, mitral valve and aortic tissues has been implicated in mouse models of MFS. TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders, including Loeys-Dietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987). These data indicate that genetic heterogeneity exists in MFS and its related conditions and that regulation of TGFbeta signaling plays a significant role in these disorders.

Topics: Abnormalities, Multiple; Animals; Aortic Aneurysm, Thoracic; Craniosynostoses; Fibrillin-1; Fibrillins; Germ-Line Mutation; Humans; Marfan Syndrome; Mice; Microfilament Proteins; Models, Genetic; Transforming Growth Factor beta

Marfan syndrome is a connective tissue disorder with ocular, musculoskeletal and cardiovascular manifestations that are caused by mutations in fibrillin-1, the major constituent of extracellular microfibrils. Mouse models of Marfan syndrome have revealed that fibrillin-1 mutations perturb local TGFbeta signaling, in addition to impairing tissue integrity. This discovery has led to the identification of a new syndrome with overlapping Marfan syndrome-like manifestations that is caused by mutations in TGFbeta receptor types I and II. It has also prompted the idea that TGFbeta antagonism will be a productive treatment strategy in Marfan syndrome and perhaps in other related disorders. More generally, these studies have established that Marfan syndrome is part of a group of developmental disorders with broad and complex effects on morphogenesis, homeostasis and organ function.

Topics: Animals; Connective Tissue; Gene Expression Regulation; Humans; Marfan Syndrome; Microfilament Proteins; Signal Transduction; Transforming Growth Factor beta

Important recent understandings of fibrillins and fibrillin-associated microfibril proteins suggest new ways these proteins might contribute to tissue fibrosis seen in systemic sclerosis by regulating latent transforming growth factor-beta. This review discusses mutant-fibrillin mouse models of Marfan syndrome and SSc (Tsk mice), and studies suggesting that alterations in microfibrils might contribute to human SSc.. Fibrillin-1 mutations associated with Marfan syndrome have recently been shown to induce genes activated by TGF-beta. The inhibition of TGF-beta in these mouse models largely reverses phenotypic and pathologic disease manifestations. Recent studies suggest that alterations in the fibrillin-1 structure from mutant Tsk fibrillin cause hypodermal fibrosis and associated changes in dermal gene expression, suggesting stimulation of cytokine-mediating signals. Genetic mutations in fibrillin-1, in a higher frequency in SSc patient populations, and autoantibodies to fibrillin provide potential links to human SSc.. Fibrillin is placed centrally not only as the primary structural component of microfibrils, but also a key regulator of cytokines in the TGF-beta superfamily. Fibrillin may thus communicate alterations in matrix to fibroblast gene expression. These observations complement emerging understandings of the effects of Tsk fibrillin, and genetic and autoimmune studies of human fibrillin on dermal fibrosis.

Topics: Animals; Disease Models, Animal; Extracellular Matrix Proteins; Fibrillin-1; Fibrillins; Gene Expression Regulation; Humans; Marfan Syndrome; Mice; Mice, Mutant Strains; Microfibrils; Microfilament Proteins; Mutation; Scleroderma, Systemic; Skin; Transforming Growth Factor beta

Marfan syndrome (MFS) is a systemic disorder of the connective tissue that is inherited as an autosomal dominant trait and which displays variable manifestations in the ocular, skeletal, and cardiovascular systems. These pleiotropic manifestations are accounted for by mutations in fibrillin-1, the building block of extracellular microfibrils. During the past 10 years, we have witnessed significant progress in delineating the pathological events responsible for the manifestations of MFS. Much of this progress has been based on the creation and analysis of fibrillin-1 mutant mouse lines that faithfully recapitulate the spectrum of clinical severity of MFS. These studies have established the critical contribution of fibrillin-1 deficiency to disease progression through altered cell-matrix interactions and dysregulated TGF-beta signaling. As a result, our definition of MFS as the prototypical structural disorder of the connective tissue has changed to that of a developmental abnormality with broad and complex effects on the morphogenesis and function of multiple organ systems. Importantly, new biological targets have emerged that may yield exciting new opportunities for the development of productive treatment strategies in MFS.

Topics: Animals; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Mice; Microfibrils; Microfilament Proteins; Mutation; Phenotype; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Connective Tissue Diseases; Fibrillins; Genetic Predisposition to Disease; Genetic Testing; Humans; Marfan Syndrome; Microfilament Proteins; Molecular Diagnostic Techniques; Mutation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Aortic dissection and aneurysm are common clinical problems with life-threatening consequences; they are also the hallmark of several genetic diseases, including Marfan's syndrome (MFS). In spite of clinical and surgical advances that have increased life expectancy for affected patients, cardiovascular manifestations remain significant contributors to morbidity and mortality in MFS. Dissecting aortic aneurysm in this disorder is accounted for by mutations in fibrillin-1, the major component of the microfibrils associated with elastin in the elastic fibers of the aortic media. Genetic studies of human patients and murine models have yielded invaluable insights into the pathophysiology of aneurysm formation and progression in MFS. They have also revealed a previously unappreciated role of microfibrils in regulating transforming growth factor and bone morphogenetic protein signaling. As a result, exciting new hypotheses have emerged regarding the pathogenesis of MFS, as well as opportunities to explore translational applications of this information that may be relevant to various manifestations of the disease.

Topics: Adrenergic beta-Antagonists; Animals; Aortic Aneurysm; Aortic Dissection; Disease Progression; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfibrils; Microfilament Proteins; Mutation; Transforming Growth Factor beta; Vascular Surgical Procedures

Growth factors of the transforming growth factor-beta family are potent regulators of the extracellular matrix formation, in addition to their immunomodulatory and regulatory roles for cell growth. TGF-beta s are secreted from cells as latent complexes containing TGF-beta and its propeptide, LAP (latency-associated peptide). In most cells LAP is covalently linked to an additional protein, latent TGF-beta binding protein (LTBP), forming the large latent complex. LTBPs are required for efficient secretion and correct folding of TGF-beta s. The secreted large latent complexes associate covalently with the extracellular matrix via the N-termini of the LTBPs. LTBPs belong to the fibrillin-LTBP family of extracellular matrix proteins, which have a typical repeated domain structure consisting mostly of epidermal growth factor (EGF)-like repeats and characteristic eight cysteine (8-Cys) repeats. Currently four different LTBPs and two fibrillins have been identified. LTBPs contain multiple proteinase sensitive sites, providing means to solubilize the large latent complex from the extracellular matrix structures. LTBPs are now known to exist both as soluble molecules and in association with the extracellular matrix. An important consequence of this is LTBP-mediated deposition and targeting of latent, activatable TGF-beta into extracellular matrices and connective tissues. LTBPs have a dual function, they are required both for the secretion of the small latent TGF-beta complex as well as directing bound latent TGF-beta to extracellular matrix microfibrils. However, it is not known at present whether LTBPs are capable of forming microfibrils independently, or whether they are a part of the fibrillin-containing fibrils. Most LTBPs possess RGD-sequences, which may have a role in their interactions with the cell surface. At least LTBP-1 is chemotactic to smooth muscle cells, and is involved in vascular remodelling. Analyses of the expressed LTBPs have revealed considerable variations throughout the molecules, generated both by alternative splicing and utilization of multiple promoter regions. The significance of this structural diversity is mostly unclear at present.

Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Carrier Proteins; Extracellular Matrix Proteins; Fibrillins; Humans; Intracellular Signaling Peptides and Proteins; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Microfilament Proteins; Molecular Sequence Data; Multigene Family; Transforming Growth Factor beta

The major clinical problem of Marfan syndrome (MFS) is the aortic root aneurysm, with risk of dissection when the root diameter approximates 5 cm. In MFS, a key molecule, transforming growth factor-beta (TGF-beta), normally bound to the extracellular matrix, is free and activated. In an experimental setting, TGF-beta blockade prevents the aortic root structural damage and dilatation. The angiotensin receptor 1 blockers (sartanics) exert an anti-TGF-beta effect; trials are now ongoing for evaluating the effect of losartan compared with atenolol in MFS. beta-Adrenergic blockers are the drugs most commonly used in MFS. The third-generation beta-adrenergic blocker nebivolol retains the beta-adrenergic blocker effects on heart rate and further exerts antistiffness effects, typically increased in MFS.. The open-label phase III study will include 291 patients with MFS and proven FBN1 gene mutations, with aortic root dilation (z-score > or =2.5). The patients will be randomized to nebivolol, losartan and the combination of the two drugs. The primary end point is the comparative evaluation of the effects of losartan, nebivolol and the association of both on the progression of aortic root growth rate. Secondary end points include the pharmacokinetics of the two drugs, comparative evaluation of serum levels of total and active TGF-beta, quantitative assessment of the expression of the mutated gene (FBN1, both 5' and 3'), pharmacogenetic bases of drug responsiveness. The quality of life evaluation in the three groups will be assessed. Statistical evaluation includes an interim analysis at month 24 and conclusive analyses at month 48.. The present study will add information about pharmacological therapy in MFS, supporting the new application of angiotensin receptor 1 blockers and finding beta-adrenergic blockers that may give more specific effects. Moreover, the study will further deepen understanding of the pathogenetic mechanisms that are active in Marfan syndrome through the pharmacogenomic and transcriptomic mechanisms that may explain MFS phenotype variability.

Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Angiotensin II Type 1 Receptor Blockers; Aortic Aneurysm; Benzopyrans; Child; Child, Preschool; Dilatation, Pathologic; Disease Progression; Ethanolamines; Female; Fibrillin-1; Fibrillins; Humans; Infant; Losartan; Male; Marfan Syndrome; Microfilament Proteins; Middle Aged; Mutation; Nebivolol; Quality of Life; Research Design; Time Factors; Transforming Growth Factor beta; Treatment Outcome; Young Adult

Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor beta (TGF-beta) that can be mitigated by treatment with TGF-beta antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement.. We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs.. The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy.. In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial.

Topics: Adolescent; Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Aorta; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Child; Child, Preschool; Drug Therapy, Combination; Female; Heart Rate; Humans; Infant; Irbesartan; Linear Models; Losartan; Male; Marfan Syndrome; Prospective Studies; Tetrazoles; Transforming Growth Factor beta

Aortic stiffness is increased in Marfan syndrome contributing to aortic dilatation and rupture, the major cause of premature death in this population. Angiotensin-converting enzyme inhibitors have been shown to reduce arterial stiffness.. To determine whether perindopril therapy reduces aortic stiffness and attenuates aortic dilatation in patients with Marfan syndrome.. A randomized, double-blind, placebo-controlled trial of 17 patients with Marfan syndrome (mean [SD], 33 [6] years) taking standard beta-blocker therapy, initiated in January 2004 and completed in September 2006, at Alfred Hospital Marfan Syndrome Clinic, Melbourne, Australia.. Patients were administered 8 mg/d of perindopril (n = 10) or placebo (n = 7) for 24 weeks.. Indices of arterial stiffness were assessed via systemic arterial compliance, and central and peripheral pulse wave velocities. Aortic root diameters were assessed at 4 sites via transthoracic echocardiography.. Perindopril reduced arterial stiffness as indicated by increased systemic arterial compliance (mean [SEM], 0.33 [0.01] mL/mm Hg at baseline to 0.54 [0.04] mL/mm Hg at 24 weeks in perindopril group vs 0.30 [0.01] mL/mm Hg to 0.29 [0.01] mL/mm Hg in placebo group, P = .004), and reduced central (7.6 [0.4] m/s to 5.9 [0.3] m/s in perindopril group, P < .001 vs placebo) and peripheral (10.9 [0.4] m/s to 8.7 [0.4] m/s in perindopril group, P < .001 vs placebo) pulse wave velocities. In addition, perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (P<.01 to P < .001 for all comparisons between groups). Although perindopril marginally reduced mean arterial pressure (from 81 [2] mm Hg to 80 [1] mm Hg in perindopril group vs 83 [2] mm Hg to 84 [3] mm Hg in placebo group, P = .004), the observed changes in both stiffness and left ventricular outflow tract diameter remained significant when mean arterial pressure was included as a covariate. Transforming growth factor beta (TGF-beta), which contributes to aortic degeneration in Marfan syndrome, was reduced by perindopril compared with placebo in both latent (59 [6] ng/mL to 45 [3] ng/mL in perindopril group, P = .01 vs placebo) and active (46 [2] ng/mL to 42 [1] ng/mL in perindopril group, P = .02 vs placebo) forms.. Perindopril reduced both aortic stiffness and aortic root diameter in patients with Marfan syndrome taking standard beta-blocker therapy, possibly through attenuation of TGF-beta signaling. Large clinical trials are needed to assess the clinical benefit of angiotensin II blockade in Marfan syndrome.. clinicaltrials.gov Identifier: NCT00485368.

Topics: Adrenergic beta-Antagonists; Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Aorta; Arteries; Blood Flow Velocity; Blood Pressure; Double-Blind Method; Echocardiography; Female; Humans; Male; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Perindopril; Transforming Growth Factor beta; Ultrasonography, Doppler; Vasodilation

Although abnormal TGFβ signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, its precise role in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to elucidate the role of TGFβ signaling in three Fbn1 mutant mouse models representing a range of aortic disease from microdissection (without aneurysm) to aneurysm (without rupture) to aneurysm and rupture. Results indicated that reduced TGFβ signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGFβ signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGFβ signaling, were associated with aortic rupture. Our data indicate that TGFβ signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.

Topics: Aortic Aneurysm, Thoracic; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Transforming Growth Factor beta

Elevated transforming growth factor-beta (TGF-β) signalling has been implicated in the pathogenesis of Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). In this study, we provide a qualitative and quantitative analysis of the craniofacial and functional features among the LDS subtypes and SGS.. We explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans.. The most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS.. This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-β signalling pathway, with a particularly severe phenotype associated with

Topics: Arachnodactyly; Craniosynostoses; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Receptor, Transforming Growth Factor-beta Type II; Transforming Growth Factor beta; Transforming Growth Factors

Aortic root aneurysm is a common cause of morbidity and mortality in Loeys-Dietz and Marfan syndromes, where perturbations in transforming growth factor beta (TGFβ) signaling play a causal or contributory role, respectively. Despite the advantages of cross-species disease modeling, animal models of aortic root aneurysm are largely restricted to genetically engineered mice. Here, we report that zebrafish devoid of the genes encoding latent-transforming growth factor beta-binding protein 1 and 3 (ltbp1 and ltbp3, respectively) develop rapid and severe aneurysm of the outflow tract (OFT), the aortic root equivalent. Similar to syndromic aneurysm tissue, the distended OFTs display evidence for paradoxical hyperactivated TGFβ signaling. RNA-sequencing revealed significant overlap between the molecular signatures of disease tissue from mutant zebrafish and a mouse model of Marfan syndrome. Moreover, chemical inhibition of TGFβ signaling in wild-type animals phenocopied mutants but chemical activation did not, demonstrating that TGFβ signaling is protective against aneurysm. Human relevance is supported by recent studies implicating genetic lesions in LTBP3 and, potentially, LTBP1 as heritable causes of aortic root aneurysm. Ultimately, our data demonstrate that zebrafish can now be leveraged to interrogate thoracic aneurysmal disease and identify novel lead compounds through small-molecule suppressor screens. This article has an associated First Person interview with the first author of the paper.

Topics: Animals; Aortic Aneurysm, Thoracic; Dilatation; Humans; Larva; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Transforming Growth Factor beta; Zebrafish; Zebrafish Proteins

Marfan syndrome (MFS) is associated with TGF (transforming growth factor) β-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFβ induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta.. We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in. In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.

Topics: Animals; Antibodies, Neutralizing; Aorta; Aortic Diseases; Disease Models, Animal; Elastin; Fibrosis; Immunoglobulin G; Inflammation; Interleukin-11; Interleukin-11 Receptor alpha Subunit; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Muscle, Smooth, Vascular; Receptors, Interleukin-11; Transforming Growth Factor beta

A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFβ modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining the Cre-LoxP recombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGFβ signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGFβ-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grown in vitro were longer and released less TGFβ than the wild-type counterparts. Moreover, addition of recombinant TGFβ1 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGFβ signaling locally and improper GP differentiation distally.

Topics: Animals; Fibrillin-1; Fibrillin-2; Fibrillins; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Microfilament Proteins; Transforming Growth Factor beta

Thoracic aortic aneurysm (TAA) formation is a multifactorial process that results in diverse clinical manifestations and drug responses. Identifying the critical factors and their functions in Marfan syndrome (MFS) pathogenesis is important for exploring personalized medicine for MFS. Methylenetetrahydrofolate reductase

Topics: Animals; Disease Models, Animal; Fibrillin-1; Folic Acid; Humans; Marfan Syndrome; Mice; Mice, Transgenic; Mutation, Missense; Signal Transduction; Transforming Growth Factor beta

Marfan Syndrome (MFS) and Loeys-Dietz Syndrome (LDS) represent heritable connective tissue disorders that segregate with a similar pattern of cardiovascular defects (thoracic aortic aneurysm, mitral valve prolapse/regurgitation, and aortic dilatation with regurgitation). This pattern of cardiovascular defects appears to be expressed along a spectrum of severity in many heritable connective tissue disorders and raises suspicion of a relationship between the normal development of connective tissues and the cardiovascular system. With overwhelming evidence of the involvement of aberrant Transforming Growth Factor-beta (TGF-β) signaling in MFS and LDS, this signaling pathway may represent the common link in the relationship between connective tissue disorders and their associated cardiovascular complications. To further explore this hypothetical link, this chapter will review the TGF-β signaling pathway, the heritable connective tissue syndromes related to aberrant TGF-β signaling, and will discuss the pathogenic contribution of TGF-β to these syndromes with a primary focus on the cardiovascular system.

Topics: Aortic Aneurysm, Thoracic; Cardiovascular System; Connective Tissue; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factors

Thoracic aortic aneurysm is a potentially life-threatening disease with a strong genetic contribution. Despite identification of multiple genes involved in aneurysm formation, little is known about the specific underlying mechanisms that drive the pathological changes in the aortic wall. The aim of our study was to unravel the molecular mechanisms underlying aneurysm formation in Marfan syndrome (MFS). We collected aortic wall samples from

Topics: Adult; Animals; Aorta; Aortic Diseases; Cell Respiration; Female; Fibrillin-1; Gene Expression Profiling; Gene Expression Regulation; Genomics; Humans; Male; Marfan Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Signal Transduction; Transforming Growth Factor beta

The molecular and cellular processes leading to aortic aneurysm development in Marfan syndrome (MFS) remain poorly understood. In this study, we examined the changes of aortic cell populations and gene expression in MFS by performing single-cell RNA sequencing (scRNA seq) on ascending aortic aneurysm tissues from patients with MFS (

Topics: Adult; Aortic Aneurysm, Thoracic; Case-Control Studies; Cell Differentiation; Female; Gene Expression Regulation; Humans; Male; Marfan Syndrome; Receptors, Transforming Growth Factor beta; Signal Transduction; Single-Cell Analysis; Transforming Growth Factor beta; Young Adult

Shprintzen-Goldberg syndrome (SGS) is a multisystemic connective tissue disorder, with considerable clinical overlap with Marfan and Loeys-Dietz syndromes. These syndromes have commonly been associated with enhanced TGF-β signaling. In SGS patients, heterozygous point mutations have been mapped to the transcriptional co-repressor SKI, which is a negative regulator of TGF-β signaling that is rapidly degraded upon ligand stimulation. The molecular consequences of these mutations, however, are not understood. Here we use a combination of structural biology, genome editing, and biochemistry to show that SGS mutations in SKI abolish its binding to phosphorylated SMAD2 and SMAD3. This results in stabilization of SKI and consequently attenuation of TGF-β responses, both in knockin cells expressing an SGS mutation and in fibroblasts from SGS patients. Thus, we reveal that SGS is associated with an attenuation of TGF-β-induced transcriptional responses, and not enhancement, which has important implications for other Marfan-related syndromes.

Topics: Arachnodactyly; Craniosynostoses; DNA-Binding Proteins; Female; Humans; Male; Marfan Syndrome; Mutation; Proto-Oncogene Proteins; Signal Transduction; Transforming Growth Factor beta

We investigated the effect of a potent TGFβ (transforming growth factor β) inhibitor peptide (P144) from the betaglycan/TGFβ receptor III on aortic aneurysm development in a Marfan syndrome mouse model.. We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFβ signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfβ1 and Tgfβ2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFβ signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfβ1 and Tgfβ2 mRNA levels.. P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFβ signaling during the early stages of aortic disease progression.

Topics: Animals; Aorta; Aortic Aneurysm; Dependovirus; Dilatation, Pathologic; Disease Models, Animal; Female; Fibrillin-1; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Male; Marfan Syndrome; Mice, Inbred C57BL; Peptide Fragments; Proteoglycans; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is an autosomal dominant disease affecting cardiovascular, ocular and skeletal systems. It is caused by mutations in the fibrillin-1 (FBN1) gene, leading to structural defects of connective tissue and increased activation of TGF-β. Angiotensin II (ang-II) is involved in TGF-β activity and in bone mass regulation. Inhibition of TGF-β signaling by blockage of the ang-II receptor 1 (AT1R) via losartan administration leads to improvement of cardiovascular and pulmonary phenotypes, but has no effect on skeletal phenotype in the haploinsufficient mouse model of MFS mg

Topics: Animals; Female; Fibrillin-1; Kyphosis; Losartan; Male; Marfan Syndrome; Mice; Transforming Growth Factor beta

Aortic root aneurysm formation is a cardinal feature of Marfan syndrome (MFS) and likely TGF-β driven via Smad (canonical) and ERK (non-canonical) signalling. The current study assesses human MFS vascular smooth muscle cell (SMC) phenotype, focusing on individual contributions by Smad and ERK, with Notch3 signalling identified as a novel compensatory mechanism against TGF-β-driven pathology. Although significant ERK activation and mixed contractile gene expression patterns were observed by traditional analysis, this did not directly correlate with the anatomic site of the aneurysm. Smooth muscle cell phenotypic changes were TGF-β-dependent and opposed by ERK in vitro, implicating the canonical Smad pathway. Bulk SMC RNA sequencing after ERK inhibition showed that ERK modulates cell proliferation, apoptosis, inflammation, and Notch signalling via Notch3 in MFS. Reversing Notch3 overexpression with siRNA demonstrated that Notch3 promotes several protective remodelling pathways, including increased SMC proliferation, decreased apoptosis and reduced matrix metalloproteinase activity, in vitro. In conclusion, in human MFS aortic SMCs: (a) ERK activation is enhanced but not specific to the site of aneurysm formation; (b) ERK opposes TGF-β-dependent negative effects on SMC phenotype; (c) multiple distinct SMC subtypes contribute to a 'mixed' contractile-synthetic phenotype in MFS aortic aneurysm; and (d) ERK drives Notch3 overexpression, a potential pathway for tissue remodelling in response to aneurysm formation.

Topics: Aorta; Aortic Aneurysm; Apoptosis; Cell Line; Cell Proliferation; Humans; Inflammation; Marfan Syndrome; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Receptor, Notch3; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate that cbEGF domain calcium binding decreases under mechanical stress (i.e. cbEGF domains are mechanosensitive). We further demonstrate the disulfide bonds in cbEGF domains uniquely orchestrate protein unfolding by showing that MFS disulfide bond mutations markedly disrupt normal mechanosensitive calcium binding dynamics. These results point to a potential mechanosensitive mechanism for fibrillin-1 in regulating extracellular transforming growth factor beta (TGFB) bioavailability and microfibril integrity. Such mechanosensitive "smart" features may represent novel mechanisms for mechanical hemostasis regulation in extracellular matrix that are pathologically activated in MFS.

Topics: Biological Availability; Calcium; Disulfides; Epidermal Growth Factor; Extracellular Matrix; Fibrillin-1; Humans; Infant, Newborn; Marfan Syndrome; Mechanotransduction, Cellular; Microfibrils; Molecular Dynamics Simulation; Mutation; Protein Binding; Protein Domains; Transforming Growth Factor beta

Topics: Androgens; Animals; Aortic Aneurysm, Thoracic; Fibrillin-1; Male; Marfan Syndrome; Mice; Transforming Growth Factor beta

Marfan syndrome (MFS) represents a genetic disorder with a range of clinical features, including proximal aortic aneurysms. Extensive research has revealed an abundance of transforming growth factor beta from a mutation in fibrillin-1 to be the key biochemical mechanism of aneurysm formation. Many important signaling pathways downstream of transforming growth factor beta have been further characterized. Our laboratory has previously demonstrated a unique murine model of MFS resulting in the accelerated formation of ascending aortic aneurysms and dilated cardiomyopathies. This study aims to characterize the relevance of this model to known signaling mechanisms in MFS.. Mice with MFS displayed downstream regulation in both the canonical (Smad2) and noncononical (extracellular signal-regulated kinases and P38) pathways characteristic of MFS. However, these downstream signals were exaggerated in the MFS mice supplemented with angiotensin II (accelerated model), matching the observed phenotypic severity of this model.. The murine MFS model depicted here accelerates ascending aortic aneurysm formation and cardiomyopathies via well-characterized MFS signaling cascades. The mechanistic relevance of the accelerated murine MFS model suggests that it could be an important tool in future studies hoping to characterize MFS signaling in an expedited experimental design.

Topics: Angiotensin II; Animals; Aorta; Aortic Aneurysm; Cardiomyopathies; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Fibrillin-1; Genetic Predisposition to Disease; Heterozygote; Marfan Syndrome; Mice, Mutant Strains; Mutation; Myocardium; p38 Mitogen-Activated Protein Kinases; Phenotype; Phosphorylation; Signal Transduction; Smad2 Protein; Time Factors; Transforming Growth Factor beta

Topics: Animals; Bone and Bones; Female; Fibrillin-1; Humans; Male; MAP Kinase Signaling System; Marfan Syndrome; Mice; Mice, Mutant Strains; Sex Characteristics; Transforming Growth Factor beta

Recessive variants in LTBP2 are associated with eye-restricted phenotypes including (a) primary congenital glaucoma and (b) microspherophakia/megalocornea and ectopia lentis with/without secondary glaucoma. Nosology of LTBP2 pathology in humans is apparently in contrast with the consolidated evidence of a wide expression of this gene in the developing embryo. Accordingly, in previously published patients with LTBP2-related eye disease, additional extraocular findings have been occasionally reported and include, among others, high-arched palate, tall stature, and variable cardiac involvement. Anyway, no emphasis was put on such systemic manifestations. Here, we report two unrelated Roma/Gypsy patients first ascertained for a multisystem disorder mainly characterized by primary congenital glaucoma, complex congenital heart defect, tall stature, long fingers, skin striae and dystrophic scarring, and resembling Marfan syndrome. Heart involvement was severe with polyvalvular heart dysplasia in one, and transposition of great arteries, thoracic arterial tortuosity, polyvalvular heart dysplasia, and neo-aortic root dilatation in the other. Both patients were homozygous for the recurrent c.895C>T[p.(R299X)] variant, typically found in individuals of Roma/Gypsy descent with an eye-restricted phenotype. Our findings point out LTBP2 as responsible of a systemic phenotype coherent with the community of syndromes related to anomalies in genes involved in the TGFβ-pathway. Among these disorders, LTBP2-related systemic disease emerges as a distinct condition with expanding prognostic implications and autosomal recessive inheritance.

Topics: Adolescent; Child; Corneal Diseases; Ectopia Lentis; Eye Diseases, Hereditary; Female; Genetic Diseases, X-Linked; Glaucoma; Heart; Heart Defects, Congenital; Homozygote; Humans; Iris; Latent TGF-beta Binding Proteins; Male; Marfan Syndrome; Phenotype; Roma; Transforming Growth Factor beta

Mutations in extracellular matrix and smooth muscle cell contractile proteins predispose to thoracic aortic aneurysms in Marfan syndrome (MFS) and related disorders. These genetic alterations lead to a compromised extracellular matrix-smooth muscle cell contractile unit. The abnormal aortic tissue responds with defective mechanosensing under hemodynamic stress. Aberrant mechanosensing is associated with transforming growth factor-beta (TGF-β) hyperactivity, enhanced angiotensin-II (Ang-II) signaling, and perturbation of other cellular signaling pathways. The downstream consequences include enhanced proteolytic activity, expression of inflammatory cytokines and chemokines, infiltration of inflammatory cells in the aortic wall, vascular smooth muscle cell apoptosis, and medial degeneration. Mouse models highlight aortic inflammation as a contributing factor in the development of aortic aneurysms. Anti-inflammatory drugs and antioxidants can reduce aortic oxidative stress that prevents aggravation of aortic disease in MFS mice. Targeting TGF-β and Ang-II downstream signaling pathways such as ERK1/2, mTOR, PI3/Akt, P38/MAPK, and Rho kinase signaling attenuates disease pathogenesis. Aortic extracellular matrix degradation and medial degeneration were reduced upon inhibition of inflammatory cytokines and matrix metalloproteinases, but the latter lack specificity. Treating inflammation associated with aortic aneurysms in MFS and related disorders could prove to be beneficial in limiting disease pathogenesis.

Topics: Animals; Aortic Aneurysm, Thoracic; Inflammation; Marfan Syndrome; Mice; Transforming Growth Factor beta

Formation of aortic aneurysms as a consequence of augmented transforming growth factor β (TGF-β) signaling and vascular smooth muscle cell (VSMC) dysfunction is a potentially lethal complication of Marfan syndrome (MFS). Here, we examined VSMC senescence in patients with MFS and explored the potential mechanisms that link VSMC senescence and TGF-β. Tissue was harvested from the ascending aorta of control donors and MFS patients, and VSMCs were isolated. Senescence-associated β-galactosidase (SA-β-gal) activity and expression of senescence-related proteins (p53, p21) were significantly higher in aneurysmal tissue from MFS patients than in healthy aortic tissue from control donors. Compared to control-VSMCs, MFS-VSMCs were larger with higher levels of both SA-β-gal activity and mitochondrial reactive oxygen species (ROS). In addition, TGF-β1 levels were much higher in MFS- than control-VSMCs. TGF-β1 induced VSMC senescence through excessive ROS generation. This effect was suppressed by Mito-tempo, a mitochondria-targeted antioxidant, or SC-514, a NF-κB inhibitor. This suggests TGF-β1 induces VSMC senescence through ROS-mediated activation of NF-κB signaling. It thus appears that a TGF-β1/ROS/NF-κB axis may mediate VSMC senescence and aneurysm formation in MFS patients. This finding could serve as the basis for a novel strategy for treating aortic aneurysm in MFS.

Topics: Aorta; Aortic Aneurysm; beta-Galactosidase; Cellular Senescence; Humans; Marfan Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Reactive Oxygen Species; Transforming Growth Factor beta

The objective of the present study was to 1) analyze the ascending aortic proteome within a mouse model of Marfan syndrome (MFS; Fbn1

Topics: Animals; Aorta; Aortic Aneurysm; Cell Movement; Cell Proliferation; Cells, Cultured; Chromatography, High Pressure Liquid; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Fibrillin-1; Genetic Predisposition to Disease; Integrin beta3; Male; Marfan Syndrome; Mass Spectrometry; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Protein Serine-Threonine Kinases; Proteomics; Rapamycin-Insensitive Companion of mTOR Protein; Signal Transduction; Time Factors; Transforming Growth Factor beta

Marfan syndrome (MFS) represents a genetic disorder with variable phenotypic expression. The main cardiovascular sequelae of MFS include aortic aneurysm/dissection and cardiomyopathy. Although significant advances in the understanding of transforming growth factor beta signaling have led to promising therapeutic targets for the treatment of aortopathy, clinical studies have tempered this optimism. In particular, these studies suggest additional signaling pathways that play a significant role in disease progression. To date, studies aimed at elucidating molecular mechanisms involved in MFS-induced disease progression have been hampered by the lack of an accelerated disease model.. This accelerated murine MFS model replicates increased mortality from MFS-related maladies (20.0%, 39.3%, and 52.9% at 10, 14, and 28 days, respectively). Aortic diameters in accelerated MFS mice were significantly enlarged at 10 days after minipump implantation and correlated with a higher degree of elastin fragmentation. Accelerated MFS mice also demonstrated dilated cardiomyopathy at 14 days, even without aortic insufficiency, suggesting an intrinsic etiology.. A novel in vivo model consisting of subcutaneously delivered angiotensin II in MFS mice reproducibly causes accelerated aortic aneurysm formation and cardiomyopathy. This model allows for better investigation of MFS sequelae by rapid experimental processes.

Topics: Animals; Aortic Aneurysm, Thoracic; Cardiomyopathies; Disease Models, Animal; Disease Progression; Echocardiography; Heart Ventricles; Marfan Syndrome; Mice; Mice, Mutant Strains; Signal Transduction; Transforming Growth Factor beta

Genetic aortic syndromes (GAS) include Marfan, Loeys-Dietz, vascular Ehlers-Danlos, and Turner syndrome as well as congenital bicuspid aortic valve. The clinical management of these diseases has certain similarities and differences. We employed medical strategy analysis to test the utility of genetic diagnostics in the management of GAS. We chose the standpoint of the cardiologist for our analysis. In the first step, the medical goals in the management of GAS are specified. In the second step, the accuracy of genetic diagnostics for GAS is examined. Finally, conclusions can be drawn about the utility of genetic diagnostics in managing GAS. We found that genetic diagnostics is necessary to exclude GAS, to diagnose GAS, and to specify disease types. Second, combining phenotype with genotype information maximizes the predictability of the course of disease. Third, with genetic diagnostics it is possible to predict the birth of children with causative mutations for GAS and to initiate drug therapy to prevent the onset of aortic dilatation or to slow down its progression to aortic aneurysm. Finally, genetic diagnostics improves prognostic predictions and thereby contributes to a better timing of elective surgery and to a better choice of procedures. The findings of our medical strategy analysis indicate the high utility of genetic diagnostics for managing GAS.

Topics: Aortic Diseases; DNA Mutational Analysis; Female; Genetic Predisposition to Disease; Genetic Testing; Genotype; Humans; Infant, Newborn; Marfan Syndrome; Microfibrils; Phenotype; Pregnancy; Prenatal Diagnosis; Transforming Growth Factor beta

TGF-β-related heritable connective tissue disorders are characterized by a similar pattern of cardiovascular defects, including aortic root dilatation, mitral valve prolapse, vascular aneurysms, and vascular dissections and exhibit incomplete penetrance and variable expressivity. Because of the phenotypic overlap of these disorders, panel-based genetic testing is frequently used to confirm the clinical findings. Unfortunately in many cases, variants of uncertain significance (VUSs) obscure the genetic diagnosis until more information becomes available. Here, we describe and characterize the functional impact of a novel VUS in the

Topics: Adult; Humans; Loeys-Dietz Syndrome; Male; Marfan Syndrome; Mutation; Mutation, Missense; Phosphorylation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta

Thoracic aortic aneurysm and dissection are life-threatening complications of Marfan syndrome (MFS). Studies of human and mouse aortic samples from late stage MFS demonstrate increased TGF-β activation/signaling and diffuse matrix changes. However, the role of the aortic smooth muscle cell (SMC) phenotype in early aneurysm formation in MFS has yet to be fully elucidated. As our objective, we investigated whether an altered aortic SMC phenotype plays a role in aneurysm formation in MFS. We describe previously unrecognized concordant findings in the aortas of a murine model of MFS, mgR, during a critical and dynamic phase of early development. Using Western blot, gelatin zymography, and histological analysis, we demonstrated that at postnatal day (PD) 7, before aortic TGF-β levels are increased, there is elastic fiber fragmentation/disorganization and increased levels of MMP-2 and MMP-9. Compared to wild type (WT) littermates, aortic SMCs in mgR mice express higher levels of contractile proteins suggesting a switch to a more mature contractile phenotype. In addition, tropoelastin levels are decreased in mgR mice, a finding consistent with a premature switch to a contractile phenotype. Proliferation assays indicate a decrease in the proliferation rate of mgR cultured SMCs compared to WT SMCs. KLF4, a regulator of smooth muscle cell phenotype, was decreased in aortic tissue of mgR mice. Finally, overexpression of KLF4 partially reversed this phenotypic change in the Marfan SMCs. This study indicates that an early phenotypic switch appears to be associated with initiation of important metabolic changes in SMCs that contribute to subsequent pathology in MFS.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Cell Differentiation; Cell Proliferation; Elastic Tissue; Extracellular Matrix; Gene Expression Regulation; Humans; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Transgenic; Myocytes, Smooth Muscle; Phenotype; Primary Cell Culture; Signal Transduction; Transforming Growth Factor beta; Tropoelastin

Marfan syndrome (MFS) involves a deficiency of the structural extracellular matrix component fibrillin-1 and overactivation of the transforming growth factor-β (TGF-β) signalling pathway. The TGF-β signalling pathway also actively participates in malignant transformation. Although anecdotal case reports have suggested associations between MFS/MFS-like conditions and several haematological and solid malignancies, such associations have not been thoroughly evaluated in large-scale studies. We sought to use a nationwide healthcare insurance claim database to evaluate whether patients with MFS are at increased risk of malignancy.. We conducted a nested case-control analysis using a database extracted from Taiwan's National Health Insurance Research Database. All medical conditions for each case and control were categorised using the International Classification of Diseases, 9th Revision classifications. ORs and 95% CIs for associations between MFS and malignancies were estimated using conditional logistic regression and adjusted for comorbidities.. Our analyses included 1 153 137 cancer cases and 1 153 137 propensity score-matched controls. Relative to other subjects, patients with MFS had a significantly higher risk of having a malignancy (adjusted OR 3.991) and hypertension (adjusted OR 1.964) and were significantly more likely to be men. Malignancies originating from the head and neck and the urinary tract were significantly more frequent among patients with MFS than among subjects without MFS.. Patients with MFS are at increased risk of developing various malignancies. Healthcare professionals should be aware of this risk when treating such patients, and increased cancer surveillance may be necessary for these patients.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Comorbidity; Female; Fibrillin-1; Humans; Logistic Models; Male; Marfan Syndrome; Middle Aged; Multivariate Analysis; Neoplasms; Taiwan; Transforming Growth Factor beta

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-β inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.

Topics: Aortic Aneurysm; Apoptosis; Fibrillin-1; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Marfan Syndrome; Models, Biological; Muscle, Smooth, Vascular; p38 Mitogen-Activated Protein Kinases; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is caused by mutations in the gene encoding fibrillin-1 (FBN1); however, the mechanisms through which fibrillin-1 deficiency causes MFS-associated aortopathy are uncertain. Recently, attention was focused on the hypothesis that MFS-associated aortopathy is caused by increased transforming growth factor-β (TGF-β) signaling in aortic medial smooth muscle cells (SMC). However, there are many reasons to doubt that TGF-β signaling drives MFS-associated aortopathy. We used a mouse model to test whether SMC TGF-β signaling is perturbed by a fibrillin-1 variant that causes MFS and whether blockade of SMC TGF-β signaling prevents MFS-associated aortopathy.. MFS mice (Fbn1. In young Fbn1

Topics: Animals; Aorta; Aortic Aneurysm, Thoracic; Aortic Diseases; Disease Models, Animal; Fibrillin-1; Marfan Syndrome; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

Topics: Animals; Cardiomegaly; Fibrillin-1; Fibrillins; Fibrosis; Hemodynamics; Male; MAP Kinase Signaling System; Marfan Syndrome; Mice; Mice, Inbred C57BL; Microfilament Proteins; Mitral Valve Insufficiency; Myocardium; p38 Mitogen-Activated Protein Kinases; Phenotype; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Ultrasonography; Ventricular Function, Left

Mutations in the microfibrillar protein fibrillin-1 or the absence of its binding partner microfibril-associated glycoprotein (MAGP1) lead to increased TGFβ signaling due to an inability to sequester latent or active forms of TGFβ, respectively. Mouse models of excess TGFβ signaling display increased adiposity and predisposition to type-2 diabetes. It is therefore interesting that individuals with Marfan syndrome, a disease in which fibrillin-1 mutation leads to aberrant TGFβ signaling, typically present with extreme fat hypoplasia. The goal of this project was to characterize multiple fibrillin-1 mutant mouse strains to understand how fibrillin-1 contributes to metabolic health. The results of this study demonstrate that fibrillin-1 contributes little to lipid storage and metabolic homeostasis, which is in contrast to the obesity and metabolic changes associated with MAGP1 deficiency. MAGP1 but not fibrillin-1 mutant mice had elevated TGFβ signaling in their adipose tissue, which is consistent with the difference in obesity phenotypes. However, fibrillin-1 mutant strains and MAGP1-deficient mice all exhibit increased bone length and reduced bone mineralization which are characteristic of Marfan syndrome. Our findings suggest that Marfan-associated adipocyte hypoplasia is likely not due to microfibril-associated changes in adipose tissue, and provide evidence that MAGP1 may function independently of fibrillin in some tissues.

Topics: Adipose Tissue, Brown; Animals; Body Composition; Calcification, Physiologic; Contractile Proteins; Extracellular Matrix Proteins; Fibrillin-1; Lipid Metabolism; Male; Marfan Syndrome; Mice, Inbred C57BL; Mice, Transgenic; Microfibrils; Organ Size; Organ Specificity; RNA Splicing Factors; Signal Transduction; Subcutaneous Fat; Transforming Growth Factor beta

Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm(2); Marfan Nox4(-/-): 8,795 ± 824 μm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.

Topics: Animals; Arterial Pressure; Cerebrovascular Disorders; Collagen; Disease Models, Animal; Disease Progression; Female; Fibrillin-1; Genetic Predisposition to Disease; Male; Marfan Syndrome; Mechanotransduction, Cellular; Mice, Knockout; Middle Cerebral Artery; NADH, NADPH Oxidoreductases; NADPH Oxidase 1; NADPH Oxidase 4; NADPH Oxidases; Phenotype; Reactive Oxygen Species; Stress, Mechanical; Time Factors; Transforming Growth Factor beta; Vascular Remodeling; Vascular Stiffness

Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations of fibrillin-1. While MFS patients are at a high risk of periodontitis and aortic diseases, little causal information has been provided to date. To clarify the relationship, their oral condition and sinus of Valsalva (SoV) were evaluated.The subjects were patients with MFS (n = 33) who attended the University of Tokyo Hospital. We divided them into two groups; MFS patients with highly dilated (the diameters were equal to or more than 39 mm) SoV (high group, n = 18) and MFS patients with mildly dilated (less than 39 mm) SoV (mild group, n = 15). Blood examinations, echocardiograms, and full-mouth clinical measurements, including number of teeth, probing pocket depth (PPD), bleeding on probing (BOP), and community periodontal index (CPI) were performed.We found that the high group patients had greater rates of BOP compared to that of the mild group. Furthermore, the high group tended to have higher serum levels of C-reactive protein, matrix metalloproteinase-9, and transforming growth factor-β compared to the mild group.Periodontitis may deteriorate SoV dilatation in MFS patients.

Topics: Adult; Biomarkers; C-Reactive Protein; Dilatation, Pathologic; Female; Hospitals, University; Humans; Japan; Male; Marfan Syndrome; Matrix Metalloproteinase 9; Periodontal Index; Periodontitis; Predictive Value of Tests; Sensitivity and Specificity; Sinus of Valsalva; Transforming Growth Factor beta

Marfan's syndrome is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix microfibrils and chronic tissue growth factor (TGF)-β signaling. TGF-β is a potent regulator of the vascular smooth muscle cell (VSMC) phenotype. We hypothesized that as a result of the chronic TGF-β signaling, VSMC would alter their basal differentiation phenotype, which could facilitate the formation of aneurysms. This study explores whether Marfan's syndrome entails phenotypic alterations of VSMC and possible mechanisms at the subcellular level.. Immunohistochemical and Western blotting analyses of dilated aortas from Marfan patients showed overexpression of contractile protein markers (α-smooth muscle actin, smoothelin, smooth muscle protein 22 alpha, and calponin-1) and collagen I in comparison with healthy aortas. VSMC explanted from Marfan aortic aneurysms showed increased in vitro expression of these phenotypic markers and also of myocardin, a transcription factor essential for VSMC-specific differentiation. These alterations were generally reduced after pharmacological inhibition of the TGF-β pathway. Marfan VSMC in culture showed more robust actin stress fibers and enhanced RhoA-GTP levels, which was accompanied by increased focal adhesion components and higher nuclear localization of myosin-related transcription factor A. Marfan VSMC and extracellular matrix measured by atomic force microscopy were both stiffer than their respective controls.. In Marfan VSMC, both in tissue and in culture, there are variable TGF-β-dependent phenotypic changes affecting contractile proteins and collagen I, leading to greater cellular and extracellular matrix stiffness. Altogether, these alterations may contribute to the known aortic rigidity that precedes or accompanies Marfan's syndrome aneurysm formation.

Topics: Actins; Aorta; Aortic Aneurysm; Biomarkers; Calcium-Binding Proteins; Calponins; Case-Control Studies; Cell Differentiation; Cell Line, Tumor; Collagen Type I; Cytoskeletal Proteins; Dilatation, Pathologic; Focal Adhesions; Humans; Marfan Syndrome; Microfilament Proteins; Muscle Proteins; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nuclear Proteins; Phenotype; rhoA GTP-Binding Protein; Signal Transduction; Stress Fibers; Trans-Activators; Transforming Growth Factor beta; Vascular Remodeling

Studies of mice with mild Marfan syndrome (MFS) have correlated the development of thoracic aortic aneurysm (TAA) with improper stimulation of noncanonical (Erk-mediated) TGFβ signaling by the angiotensin type I receptor (AT1r). This correlation was largely based on comparable TAA modifications by either systemic TGFβ neutralization or AT1r antagonism. However, subsequent investigations have called into question some key aspects of this mechanism of arterial disease in MFS. To resolve these controversial points, here we made a head-to-head comparison of the therapeutic benefits of TGFβ neutralization and AT1r antagonism in mice with progressively severe MFS (Fbn1(mgR/mgR) mice).. Aneurysm growth, media degeneration, aortic levels of phosphorylated Erk and Smad proteins and the average survival of Fbn1(mgR/mgR) mice were compared after a ≈3-month-long treatment with placebo and either the AT1r antagonist losartan or the TGFβ-neutralizing antibody 1D11. In contrast to the beneficial effect of losartan, TGFβ neutralization either exacerbated or mitigated TAA formation depending on whether treatment was initiated before (postnatal day 16; P16) or after (P45) aneurysm formation, respectively. Biochemical evidence-related aneurysm growth with Erk-mediated AT1r signaling, and medial degeneration with TGFβ hyperactivity that was in part AT1r dependent. Importantly, P16-initiated treatment with losartan combined with P45-initiated administration of 1D11 prevented death of Fbn1(mgR/mgR) mice from ruptured TAA.. By demonstrating that promiscuous AT1r and TGFβ drive partially overlapping processes of arterial disease in MFS mice, our study argues for a therapeutic strategy against TAA that targets both signaling pathways although sparing the early protective role of TGFβ.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies, Neutralizing; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Rupture; Disease Models, Animal; Disease Progression; Fibrillin-1; Fibrillins; Humans; Losartan; Marfan Syndrome; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Microfilament Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Phosphorylation; Receptor, Angiotensin, Type 1; Signal Transduction; Smad2 Protein; Time Factors; Transforming Growth Factor beta

mua-3 is a Caenorhabditis elegans homolog of the mammalian fibrillin1, a monogenic cause of Marfan syndrome. We identified a new mutation of mua-3 that carries an in-frame deletion of 131 amino acids in the extracellular domain, which allows the mutants to survive in a temperature-dependent manner; at the permissive temperature, the mutants grow normally without obvious phenotypes, but at the nonpermissive temperature, more than 90% die during the L4 molt due to internal organ detachment. Using the temperature-sensitive lethality, we performed unbiased genetic screens to isolate suppressors to find genetic interactors of MUA-3. From two independent screens, we isolated mutations in dpy-17 as a suppressor. RNAi of dpy-17 in mua-3 rescued the lethality, confirming dpy-17 is a suppressor. dpy-17 encodes a collagen known to genetically interact with dpy-31, a BMP-1/Tolloid-like metalloprotease required for TGFβ activation in mammals. Human fibrillin1 mutants fail to sequester TGFβ2 leading to excess TGFβ signaling, which in turn contributes to Marfan syndrome or Marfan-related syndrome. Consistent with that, RNAi of dbl-1, a TGFβ homolog, modestly rescued the lethality of mua-3 mutants, suggesting a potentially conserved interaction between MUA-3 and a TGFβ pathway in C. elegans. Our work provides genetic evidence of the interaction between TGFβ and a fibrillin homolog, and thus provides a simple yet powerful genetic model to study TGFβ function in development of Marfan pathology.

Topics: Alleles; Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Adhesion Molecules; Connective Tissue; Disease Models, Animal; Genes, Lethal; Humans; Marfan Syndrome; Neuropeptides; Non-Fibrillar Collagens; Phenotype; Polymorphism, Single Nucleotide; RNA Interference; Signal Transduction; Temperature; Transforming Growth Factor beta

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

Topics: Analysis of Variance; Animals; Aortic Aneurysm, Thoracic; DNA, Complementary; Fibrillin-1; Fibrillins; Immunohistochemistry; Latent TGF-beta Binding Proteins; Marfan Syndrome; Mice; Microfilament Proteins; Multiprotein Complexes; Muscle, Smooth, Vascular; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of renal failure that is due to mutations in two genes, PKD1 and PKD2. Vascular complications, including aneurysms, are a well recognized feature of ADPKD, and a subgroup of families exhibits traits reminiscent of Marfan syndrome (MFS). MFS is caused by mutations in fibrillin-1 (FBN1), which encodes an extracellular matrix protein with homology to latent TGF-β binding proteins. It was recently demonstrated that fibrillin-1 deficiency is associated with upregulation of TGF-β signaling. We investigated the overlap between ADPKD and MFS by breeding mice with targeted mutations in Pkd1 and Fbn1. Double heterozygotes displayed an exacerbation of the typical Fbn1 heterozygous aortic phenotype. We show that the basis of this genetic interaction results from further upregulation of TGF-β signaling caused by Pkd1 haploinsufficiency. In addition, we demonstrate that loss of PKD1 alone is sufficient to induce a heightened responsiveness to TGF-β. Our data link the interaction of two important diseases to a fundamental signaling pathway.

Topics: Animals; Disease Models, Animal; Epistasis, Genetic; Female; Fibrillin-1; Fibrillins; Genetic Association Studies; Haploinsufficiency; Heterozygote; Humans; Male; Marfan Syndrome; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; Microfilament Proteins; Mutation; Polycystic Kidney, Autosomal Dominant; Signal Transduction; Transforming Growth Factor beta; TRPP Cation Channels; Vascular Diseases

Colobomata are etiologically heterogeneous and may occur as an isolated defect or as a feature of a variety of single-gene disorders, chromosomal syndromes, or malformation syndromes. Although not classically associated with Marfan syndrome, colobomata have been described in several reports of Marfan syndrome, typically involving the lens and rarely involving other ocular structures. While colobomata of the lens have been described in Marfan syndrome, there are very few reports of coloboma involving other ocular structures. We report a newborn boy presenting with coloboma of the iris, lens, retina, and optic disk who was subsequently diagnosed with Marfan syndrome. Marfan syndrome is a disorder of increased TGFβ signaling, and recent work in the mouse model suggests a role for TGFβ signaling in eye development and coloboma formation, suggesting a causal association between Marfan syndrome and coloboma.

Topics: Adult; Arachnodactyly; Coloboma; DNA Mutational Analysis; Female; Fibrillins; Gestational Age; Humans; Infant, Newborn; Iris; Lens, Crystalline; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Optic Disk; Retina; Signal Transduction; Transforming Growth Factor beta

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Awards and Prizes; Fibrillins; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mice; Microfilament Proteins; Scleroderma, Systemic; Signal Transduction; Societies, Medical; Transforming Growth Factor beta; Translational Research, Biomedical; United States

In Marfan Syndrome (MFS), development of thoracic aortic aneurysms (TAAs) is characterized by degeneration of the medial layer of the aorta, including fragmentation and loss of elastic fibers, phenotypic changes in the smooth muscle cells, and an increase in the active form of transforming growth factor-β (TGFβ), which is thought to play a major role in development and progression of the aneurysm. We hypothesized that regional difference in elastic fiber fragmentation contributes to TGFβ activation and hence the localization of aneurysm formation. The fibrillin-1-deficient mgR/mgR mouse model of MFS was used to investigate regional changes in elastin fiber fragmentation, TGFβ activation and changes in gene expression as compared to wild-type littermates. Knockdown of Smad 2 and Smad 3 with shRNA was used to determine the role of the specific transcription factors in gene regulation in aortic smooth muscle cells. We show increased elastin fiber fragmentation in the regions associated with aneurysm formation and altered TGFβ signaling in these regions. Differential effects of Smad 2 and Smad 3 were observed in cultured smooth muscle cells by shRNA-mediated knockdown of expression of these transcription factors. Differential signaling through Smad 2 and Smad 3 in regions of active vascular remodeling likely contribute to aneurysm formation in the mgR/mgR model of MFS. Increased elastin fiber fragmentation in these regions is associated with these changes as compared to other regions of the thoracic aorta and may contribute to the changes in TGFβ signaling in these regions.

Topics: Animals; Aorta; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Disease Models, Animal; Disease Progression; Elastic Tissue; Gene Expression Regulation; Gene Knockdown Techniques; Marfan Syndrome; Mice, 129 Strain; Mice, Inbred C57BL; Organ Specificity; Phosphorylation; RNA, Small Interfering; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Patients with Marfan syndrome (MFS) are at risk for cardiovascular disease. Marfan associated mutations in the FBN1 gene lead to increased transforming growth factor-β (TGF-β) activation. The aim of this study was to investigate the role of plasma TGF-β as a biomarker for progressive aortic root dilatation and dissection.. Plasma TGF-β level and aortic root diameter by means of echocardiography were assessed in 99 MFS patients. After 38 months of follow-up measurement of the aortic root was repeated and individual aortic root growth curves were constructed. Clinical events were evaluated. The primary composite endpoint was defined as aortic dissection and prophylactic aortic root replacement.. TGF-β levels were higher in MFS patients as compared to healthy controls (109 pg/ml versus 54 pg/ml, p<0.001). Higher plasma TGF-β levels correlated with larger aortic root dimensions (r=0.26, p=0.027), previous aortic root surgery (161 pg/ml versus 88 pg/ml, p=0.007) and faster aortic root growth rate (r=0.42, p<0.001). During 38 months of follow-up, 17 events were observed (four type B dissections and 13 aortic root replacements). Patients with TGF-β levels above 140 pg/ml had a 6.5 times higher risk of experiencing the composite endpoint compared to patients with TGF-β levels below 140 pg/ml (95% CI: 2.1 to 20.1, p=0.001) with 65% sensitivity and 78% specificity.. Elevated TGF-β level in patients with Marfan syndrome is correlated with larger aortic root diameters and faster aortic root growth. Level of plasma TGF-β predicts cardiovascular events and might serve as a prognostic biomarker in MFS.

Topics: Adolescent; Adult; Aortic Diseases; Biomarkers; Disease Progression; Female; Follow-Up Studies; Humans; Male; Marfan Syndrome; Middle Aged; Prognosis; Transforming Growth Factor beta; Young Adult

We previously found that a subset of patients with pulmonary non-tuberculous mycobacterial (pNTM) disease were taller, leaner, and had a higher prevalence of pectus excavatum and scoliosis than uninfected controls. Additionally, whole blood of pNTM patients stimulated ex vivo with live Mycobacterium intracellulare produced significantly less interferon-gamma (IFNγ) compared to that of uninfected controls. Since IFNγ production can be suppressed by transforming growth factor-beta (TGFβ), an immunosuppressive cytokine, we measured basal and M. intracellulare-stimulated blood levels of TGFβ in a group of 20 pNTM patients and 20 uninfected controls. In contrast to the IFNγ findings, we found that stimulated blood from pNTM patients produced significantly higher levels of TGFβ compared to controls. Since pNTM patients frequently possess body features that overlap with Marfan syndrome (MFS), and increased TGFβ expression is important in the pathogenesis of MFS, we posit that a yet-to-be-identified syndrome related to MFS predisposes certain individuals to develop pNTM disease.

Topics: Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Fibrillins; Humans; Lung Diseases; Marfan Syndrome; Microfilament Proteins; Mycobacterium avium Complex; Mycobacterium Infections, Nontuberculous; Transforming Growth Factor beta

Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-β activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-β in cells from affected individuals, the latter being consistent with available data on the role of TGF-β in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-β signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes.

Topics: Adolescent; Animals; Cathepsin H; Child; Child, Preschool; Female; Gene Expression; Genetic Predisposition to Disease; Homozygote; Humans; Infant; LDL-Receptor Related Protein-Associated Protein; Low Density Lipoprotein Receptor-Related Protein-1; Male; Marfan Syndrome; Mice; Mutation; Myopia; Pedigree; Phenotype; Sclera; Severity of Illness Index; Transforming Growth Factor beta

Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fibrillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-β) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP). In this work, we test the hypothesis that antagonism of GxxPG fragments can suppress disease progression in the Marfan aorta. Fibrillin-1 underexpressing mgR/mgR Marfan mice were treated with weekly intraperitoneal (i.p.) injections of an antibody directed against GxxPG fragments. The treatment was started at 3 weeks of age and continued for 8 weeks. The treatment significantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage infiltration in the aorta of the mgR/mgR mice. Additionally, airspace enlargement and increased pSmad2 activity in the lungs of mgR/mgR animals were prevented by the treatment. Our findings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced inflammatory activity in the pathogenesis of thoracic aortic aneurysm (TAA) in mgR/mgR mice. Moreover, the results of the current study suggest that antagonism of the effects of GxxPG fragments may be a fruitful therapeutic strategy in MFS.

Topics: Amino Acid Motifs; Animals; Antibodies, Monoclonal; Aortic Aneurysm, Thoracic; Aortic Diseases; Blotting, Western; Disease Models, Animal; Elastin; Enzyme-Linked Immunosorbent Assay; Fibrillin-1; Fibrillins; Immunohistochemistry; Latent TGF-beta Binding Proteins; Macrophages; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Microfilament Proteins; Mutation; Peptides; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation

Marfan syndrome is an autosomal dominant disease characterized by aneurysm and dilatation of the aortic root, tall stature, and ectopia lentis. These manifestations reflect excessive signaling of transforming growth factor beta (TGF-β). Moreover, cases are frequently associated with severe periodontitis, which is a chronic inflammation of the gingiva, periodontal ligament, and alveolar bone. Recently, angiotensin II receptor blockers (ARBs) were discovered to be an effective drug class that can prevent aortic aneurysm and dilation in Marfan syndrome by inhibiting TGF-β signaling. To investigate the effect of ARB on the progression of periodontitis, the application of a potent ARB, telmisartan, was examined in a mouse model of Marfan syndrome (MgΔ). Six-week-old male heterozygous MgΔ and wild-type mice were challenged with Porphyromonas gingivalis, which causes chronic periodontitis, with and without telmisartan application. After infection, alveolar bone resorption was measured by micro-computed tomography (μCT), and inflammatory cytokine levels were examined. Infection of Porphyromonas gingivalis induced alveolar bone resorption in both MgΔ and wild-type mice. The amount of resorption was significantly larger in the former than the latter. Immunoarray and enzyme-linked immunosorbent assay (ELISA) analyses demonstrated that interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α) levels were significantly higher in infected MgΔ mice than infected wild-type mice. Telmisartan treatment significantly suppressed the alveolar bone resorption of infected MgΔ mice. Telmisartan also significantly decreased levels of TGF-β, IL-17, and TNF-α in infected MgΔ mice to levels seen in infected wild-type mice. This study suggests that ARB can prevent the severe periodontitis frequently seen in Marfan syndrome.

Topics: Alveolar Bone Loss; Angiotensin Receptor Antagonists; Animals; Bacteroidaceae Infections; Benzimidazoles; Benzoates; Bone Resorption; Disease Models, Animal; Inflammation; Interleukin-17; Male; Marfan Syndrome; Mice; Osteoclasts; Periodontitis; Porphyromonas gingivalis; Telmisartan; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Dilation or aneurysm of the ascending aorta can progress to acute aortic dissection (Thoracic Aortic Aneurysms and Aortic Dissections, TAAD). Mutations in genes encoding TGF-β-related proteins (TGFBR1, TGFBR2, FBN1, and SMAD3) cause syndromic and inherited TAAD. SMAD4 mutations are associated with juvenile polyposis syndrome (JPS) and a combined JPS-hereditary hemorrhagic telangiectasia (HHT) known as JPS-HHT. A family with JPS-HHT was reported to have aortic root dilation and mitral valve abnormalities. We report on two patients with JPS-HHT with SMAD4 mutations associated with thoracic aortic disease. The first patient, an 11-year-old boy without Marfan syndrome features, had JPS and an apparently de novo SMAD4 mutation (c.1340_1367dup28). Echocardiography showed mild dilation of the aortic annulus and aortic root, and mild dilation of the sinotubular junction and ascending aorta. Computed tomography confirmed aortic dilation and showed small pulmonary arteriovenous malformations (PAVM). The second patient, a 34-year-old woman with colonic polyposis, HHT, and features of Marfan syndrome, had a SMAD4 mutation (c.1245_1248delCAGA). Echocardiography showed mild aortic root dilation. She also had PAVM and hepatic focal nodular hyperplasia. Her family history was significant for polyposis, HHT, thoracic aortic aneurysm, and dissection and skeletal features of Marfan syndrome in her father. These two cases confirm the association of thoracic aortic disease with JPS-HHT resulting from SMAD4 mutations. We propose that the thoracic aorta should be screened in patients with SMAD4 mutations to prevent untimely death from dissection. This report also confirms that SMAD4 mutations predispose to TAAD.

Topics: Adult; Aorta; Aortic Aneurysm, Thoracic; Child; Echocardiography; Female; Fibrillin-1; Fibrillins; Humans; Intestinal Polyposis; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad3 Protein; Smad4 Protein; Telangiectasia, Hereditary Hemorrhagic; Transforming Growth Factor beta

Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined.. We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.. Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/+)) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/+) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/+) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/+) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/+) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.. We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

Topics: Age Factors; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Aortic Aneurysm; Apoptosis; Apoptosis Regulatory Proteins; Cells, Cultured; Disease Models, Animal; Elastin; Female; Fibrillin-1; Fibrillins; Genetic Therapy; Losartan; Male; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfilament Proteins; MicroRNAs; NF-kappa B; Oligonucleotides, Antisense; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Up-Regulation

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the gene coding for FIBRILLIN-1 (FBN1), an extracellular matrix protein. MFS is inherited as an autosomal dominant trait and displays major manifestations in the ocular, skeletal, and cardiovascular systems. Here we report molecular and phenotypic profiles of skeletogenesis in tissues differentiated from human embryonic stem cells and induced pluripotent stem cells that carry a heritable mutation in FBN1. We demonstrate that, as a biological consequence of the activation of TGF-β signaling, osteogenic differentiation of embryonic stem cells with a FBN1 mutation is inhibited; osteogenesis is rescued by inhibition of TGF-β signaling. In contrast, chondrogenesis is not perturbated and occurs in a TGF-β cell-autonomous fashion. Importantly, skeletal phenotypes observed in human embryonic stem cells carrying the monogenic FBN1 mutation (MFS cells) are faithfully phenocopied by cells differentiated from induced pluripotent-stem cells derived independently from MFS patient fibroblasts. Results indicate a unique phenotype uncovered by examination of mutant pluripotent stem cells and further demonstrate the faithful alignment of phenotypes in differentiated cells obtained from both human embryonic stem cells and induced pluripotent-stem cells, providing complementary and powerful tools to gain further insights into human molecular pathogenesis, especially of MFS.

Topics: Base Sequence; Bone and Bones; Cell Differentiation; Chondrogenesis; Embryonic Stem Cells; Fibrillin-1; Fibrillins; Humans; Induced Pluripotent Stem Cells; Marfan Syndrome; Microfilament Proteins; Molecular Sequence Data; Osteogenesis; Phenotype; Signal Transduction; Transforming Growth Factor beta

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Marfan Syndrome; Mice; Transforming Growth Factor beta; Treatment Outcome

Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. A role for fibrillin-1 in specifying tissue microenvironments has not been elucidated, even though the concept that fibrillin-1 provides extracellular control of growth factor signaling is currently appreciated. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes.

Topics: ADAMTS Proteins; Adolescent; Adult; Animals; Binding Sites; Cellular Microenvironment; Exons; Extracellular Matrix; Extracellular Matrix Proteins; Female; Fibrillin-1; Fibrillins; Humans; Latent TGF-beta Binding Proteins; Male; Marfan Syndrome; Mice; Mice, Transgenic; Microfibrils; Microfilament Proteins; Peptide Hydrolases; Sequence Deletion; Signal Transduction; Skin Abnormalities; Transforming Growth Factor beta; Weill-Marchesani Syndrome

To assess the effect of Loeys-Dietz syndrome (LDS) mutations affecting TGFΒR1 a selection of seven disease-associated amino acid substitutions were introduced into wild type TGFβR1 and constitutively active TGFβR1(T204D). Receptor function was tested by co-transfection with a luciferase reporter or EGFP-tagged SMAD2 in HEK293 cells. All of the mutations were found to be inactivating for canonical TGF-β signaling. Differences in residual activity were not found to correlate with disease subtype. In co-transfection experiments with equal amounts wild-type receptor, the LDS mutations were found to confer a modest dominant negative effect. These results are discussed in relation to LDS and the related Marfan syndrome.

Topics: Aortic Aneurysm; Genes, Dominant; HEK293 Cells; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mutation; Phenotype; Phosphorylation; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad Proteins; Transfection; Transforming Growth Factor beta

Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far.. Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients.. In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Topics: Adolescent; Adult; Aorta; Cluster Analysis; Cytokines; Dilatation, Pathologic; Female; Gene Expression Profiling; Humans; Inflammation; Male; Marfan Syndrome; Middle Aged; Oligonucleotide Array Sequence Analysis; Severity of Illness Index; Transcriptome; Transforming Growth Factor beta; Young Adult

The nature and cause of President Abraham Lincoln's unusual physical features have long been debated, with the greatest attention directed at two monogenic disorders of the transforming growth factor β system: Marfan syndrome and multiple endocrine neoplasia type 2B. The present report examines newly discovered phenotypic information about Lincoln's biological mother, Nancy Hanks Lincoln, and concludes that (a) Lincoln's mother was skeletally marfanoid, (b) the President and his mother were highly concordant for the presence of numerous facial features found in various transforming growth factor β disorders, and (c) Lincoln's mother, like her son, had hypotonic skeletal muscles, resulting in myopathic facies and 'pseudodepression'. These conclusions establish that mother and son had the same monogenic autosomal dominant marfanoid disorder. A description of Nancy Hanks Lincoln as coarse-featured, and a little-known statement that a wasting disease contributed to her death at age 34, lends support to the multiple endocrine neoplasia type 2B hypothesis.

Topics: Famous Persons; Female; History, 19th Century; Humans; Male; Marfan Syndrome; Multiple Endocrine Neoplasia Type 2b; Muscle Hypotonia; Phenotype; Transforming Growth Factor beta; United States

Aneurysm and dissection of the ascending thoracic aorta are the main cardiovascular complications of Marfan syndrome (MFS) resulting in premature death. Studies using mouse models of MFS have shown that activation of transforming growth factor-beta (TGF-β) and the concomitant upregulation of matrix metalloproteinases (MMPs) contribute to aneurysm development. Our previous study showed that doxycycline delayed aneurysm rupture in a mouse model of MFS, Fbn1(mgR/mgR). Losartan has been shown to prevent aneurysms in another mouse model of MFS, Fbn1(C1039G/+), through inhibition of the Erk1/2 pathway. However, the role of MMP-2 in MFS and effect of losartan on the lifespan of MFS mice remain unknown.. We investigated the role of MMP-2 in MFS and compared the effects of losartan and doxycycline on aortic dilatation and survival in Fbn1(mgR/mgR) mice.. By life table analysis, we found that losartan and doxycycline improved the survival of Fbn1(mgR/mgR) mice. Gelatin zymography and Western blot data showed that only doxycycline inhibited MMP-2 expression, whereas both drugs decreased Erk1/2 phosphorylation. When combined, only one of nine mice died within the 30-week study; aortic histology and diameter were normalized and the effects on Smad2 phosphorylation was additive. To further explore the role of MMP-2 in MFS, we created MMP-2-deficient Fbn1(mgR/mgR) mice. MMP-2 deletion inhibited activation of TGF-β and phosphorylation of Erk1/2 and Smad2 and prolonged the lifespan of the mice.. These studies demonstrated that inhibition of MMP-2 by doxycycline delayed the manifestations of MFS, in part, through its ability to decrease active TGF-β and the noncanonical signaling cascade downstream of TGF-β. This study further suggested that targeting TGF-β signaling at different points might be a more effective strategy for inhibiting disease progression.

Topics: Animals; Aorta, Thoracic; Disease Progression; Doxycycline; Drug Therapy, Combination; Losartan; MAP Kinase Signaling System; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Phosphorylation; Transforming Growth Factor beta; Vasodilation

Marfan syndrome (MFS) is an autosomal dominant hereditary disorder of connective tissue associated with perturbations in transforming growth factor β (TGF-β) biology, most often due to mutations in FBN1 gene that encodes fibrillin-1. To our knowledge, there is no known association of MFS with thyroid carcinoma. We report a 46-year-old man with known history of MFS who developed an unusual histological variant of papillary thyroid carcinoma. The tumor exhibited a widely invasive florid papillary growth pattern with prominent long villous fronds. Immunohistochemical and molecular analysis revealed a BRAF(V600E) mutation, evidence of aggressive biomarker expression (positivity for HBME-1, cytokeratin 19, galectin-3 and cyclin D1, and loss of p27), and changes associated with TGF-β-related epithelial-to-mesenchymal transition with active phospho-SMAD signaling. We introduce a unique histological pattern of papillary thyroid carcinoma that is associated with MFS. The combination of BRAF(V600E) mutation in the setting of altered TGF-β signaling and weak connective tissue integrity associated with MFS may cooperate and possibly be responsible to form this unique villous morphology with epithelial-to-mesenchymal transition and invasive growth.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Papillary; Cyclin D1; Epithelial-Mesenchymal Transition; Galectin 3; Humans; Keratin-19; Male; Marfan Syndrome; Middle Aged; Mutation; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins B-raf; Signal Transduction; Smad Proteins; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transforming Growth Factor beta

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

Topics: Animals; Aortic Aneurysm; Arachnodactyly; Cells, Cultured; Craniosynostoses; DNA-Binding Proteins; Fibroblasts; Humans; Loeys-Dietz Syndrome; Marfan Syndrome; Mice; Mutation; Phenotype; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Signal Transduction; Transforming Growth Factor beta; Zebrafish

Marfan syndrome (MFS) is a hereditary disease caused by mutations in the gene encoding Fibrillin-1 (FBN1) and characterized by a number of skeletal abnormalities, aortic root dilatation, and sometimes ectopia lentis. Although the molecular pathogenesis of MFS was attributed initially to a structural weakness of the fibrillin-rich microfibrils within the extracellular matrix, more recent results have documented that many of the pathogenic abnormalities in MFS are the result of alterations in TGFβ signaling. Mutations in FBN1 are therefore associated with increased activity and bioavailability of TGF-β1, which is suspected to be the basis for phenotypical similarities of FBN1 mutations in MFS and mutations in the receptors for TGFβ in Marfan syndrome-related diseases. We have previously demonstrated that unique skeletal phenotypes observed in human embryonic stem cells carrying the monogenic FBN1 mutation (MFS cells) are faithfully phenocopied by cells differentiated from induced pluripotent-stem cells (MFSiPS) derived independently from MFS patient fibroblasts. In this study, we aimed to determine further the biochemical features of transducing signaling(s) in MFS stem cells and MFSiPS cells highlighting a crosstalk between TGFβ and BMP signaling. Our results revealed that enhanced activation of TGFβ signaling observed in MFS cells decreased their endogenous BMP signaling. Moreover, exogenous BMP antagonized the enhanced TGFβ signaling in both MFS stem cells and MFSiPS cells therefore, rescuing their ability to undergo osteogenic differentiation. This study advances our understanding of molecular mechanisms underlying the pathogenesis of bone loss/abnormal skeletogenesis in human diseases caused by mutations in FBN1.

Topics: Bone and Bones; Bone Morphogenetic Protein 2; Cell Differentiation; Cell Growth Processes; Embryonic Stem Cells; Fibrillin-1; Fibrillins; Humans; Induced Pluripotent Stem Cells; Marfan Syndrome; Microfilament Proteins; Mutation; Osteogenesis; Recombinant Proteins; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Aortic Aneurysm; Clinical Trials as Topic; Extracellular Signal-Regulated MAP Kinases; Humans; Losartan; MAP Kinase Signaling System; Marfan Syndrome; Mice; Protein Kinase Inhibitors; Signal Transduction; Transforming Growth Factor beta

Transforming growth factor-β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal-regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase-1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.

Topics: Animals; Anthracenes; Aorta; Aortic Aneurysm; Diphenylamine; Disease Models, Animal; Disease Progression; Enzyme Activation; Losartan; MAP Kinase Signaling System; Marfan Syndrome; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase 8; Protein Kinase Inhibitors; Smad2 Protein; Smad4 Protein; Sulfonamides; Transforming Growth Factor beta

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Aortic Aneurysm; Aortic Rupture; Disease Models, Animal; Disease Progression; Enalapril; Losartan; MAP Kinase Signaling System; Marfan Syndrome; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Receptor, Angiotensin, Type 2; Signal Transduction; Transforming Growth Factor beta

Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue that affects the ocular, skeletal and cardiovascular systems, with a wide clinical variability. Although mutations in the FBN1 gene have been recognized as the cause of the disease, more recently other loci have been associated with MFS, indicating the genetic heterogeneity of this disease. We addressed the issue of genetic heterogeneity in MFS by performing linkage analysis of the FBN1 and TGFBR2 genes in 34 families (345 subjects) who met the clinical diagnostic criteria for the disease according to Ghent. Using a total of six microsatellite markers, we found that linkage with the FBN1 gene was observed or not excluded in 70.6% (24/34) of the families, and in 1 family the MFS phenotype segregated with the TGFBR2 gene. Moreover, in 4 families linkage with the FBN1 and TGFBR2 genes was excluded, and no mutations were identified in the coding region of TGFBR1, indicating the existence of other genes involved in MFS. Our results suggest that the genetic heterogeneity of MFS may be greater that previously reported.

Topics: Chi-Square Distribution; Cohort Studies; Female; Fibrillin-1; Fibrillins; Genetic Heterogeneity; Genetic Linkage; Genetic Markers; Humans; Lod Score; Male; Marfan Syndrome; Microfilament Proteins; Mutation Rate; Transforming Growth Factor beta

Topics: Aortic Aneurysm; Aortic Dissection; Biomarkers; Humans; Marfan Syndrome; Transforming Growth Factor beta

Marfan syndrome (MFS) is a systemic disorder of the connective tissues caused by insufficient fibrillin-1 microfibril formation and can cause cardiac complications, emphysema, ocular lens dislocation, and severe periodontal disease. ADAMTSL6β (A disintegrin-like metalloprotease domain with thrombospondin type I motifs-like 6β) is a microfibril-associated extracellular matrix protein expressed in various connective tissues that has been implicated in fibrillin-1 microfibril assembly. We here report that ADAMTSL6β plays an essential role in the development and regeneration of connective tissues. ADAMTSL6β expression rescues microfibril disorder after periodontal ligament injury in an MFS mouse model through the promotion of fibrillin-1 microfibril assembly. In addition, improved fibrillin-1 assembly in MFS mice following the administration of ADAMTSL6β attenuates the overactivation of TGF-β signals associated with the increased release of active TGF-β from disrupted fibrillin-1 microfibrils within periodontal ligaments. Our current data thus demonstrate the essential contribution of ADAMTSL6β to fibrillin-1 microfibril formation. These findings also suggest a new therapeutic strategy for the treatment of MFS through ADAMTSL6β-mediated fibrillin-1 microfibril assembly.

Topics: Animals; Disease Models, Animal; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillin-1; Fibrillins; Gene Expression Regulation, Developmental; Humans; Immunohistochemistry; Marfan Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microfibrils; Microfilament Proteins; Models, Genetic; Recombinant Proteins; Tooth; Transforming Growth Factor beta; Wound Healing

Topics: Aortic Aneurysm; Genetic Markers; Humans; Marfan Syndrome; Transforming Growth Factor beta

A 36-year-old man was admitted to our hospital for investigation of microscopic hematuria. He was very tall and presented arachnodactyly of the fingers and toes. Chest computed tomography and cardiac echography revealed annuloaortic ectasia and aortic regurgitation. Based on these findings, we suspected Marfan syndrome and performed gene analysis of the FBN1 gene, which encodes fibrillin-1. Mutational analysis showed the missence mutation, p. Ile 2585 Thr, present in exon 62 of the FBN1 gene. To investigate the genesis of microscopic and dismorphic hematuria, we performed a renal biopsy. Light microscopic analysis revealed the absence of any apparent histological changes in the glomerulus, small artery and arteriole. Electron microscopic analysis revealed the glomerular basement membrane to be irregularly thickened, however, there was neither any electron dense deposition nor fibrillar material. Marfan syndrome is an inherited disorder of connective tissue based on abnormality of the FBN1 gene. Fibfibrllin-1 acts not only as a component of microfibrils, but also as the regulator of transforming growth factor -beta signal transduction. From these points of view, we speculated that irregular formation of the glomerular basement membrane of our patient was induced by an imbalance in production of the extracellular matrix as the consequence of abnormal fibrillin-1--TGF-beta signaling.

Topics: Adult; Fibrillin-1; Fibrillins; Glomerular Basement Membrane; Hematuria; Humans; Male; Marfan Syndrome; Microfilament Proteins; Mutation, Missense; Signal Transduction; Transforming Growth Factor beta

We have previously shown that the angiotensin-converting enzyme (ACE) inhibitor perindopril reduced aortic diameter by 3-7mm in Marfan syndrome (MFS) patients. Excessive signalling by the transforming growth factor-beta (TGF-beta) has been implicated in the development of aortic dilatation. We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF-beta and matrix metalloproteinase (MMP) levels.. 17 MFS patients (aged 33+/-5 (mean+/-SD)) on standard beta-blocker therapy were randomised to also receive perindopril (n=10) or placebo (n=7) for 24 weeks in a double blind study. Aortic root diameters were assessed at four sites via transthoracic echocardiography. Venous blood samples were analysed for latent and active TGF-beta, MMP-2 and MMP-3 levels.. Perindopril significantly reduced aortic root diameters relative to placebo in both end-systole and end-diastole (by 1.2-3mm/m(2), p<0.001). In addition, compared to placebo perindopril significantly reduced latent TGF-beta levels by 14.0+/-4.5ng/ml (p=0.01), active TGF-beta levels by 4+/-1ng/ml (p=0.02), MMP-2 levels by 22+/-6ng/ml (p<0.001), and MMP-3 levels by 5+/-1ng/ml (p<0.001). There were moderately strong correlations between the pre/post intervention change in aortic diameters and the change in both latent (r=0.49-0.76, p=0.001-0.04) and active TGF-beta (r=0.59-0.73, p=0.002-0.02), MMP-2 (r=0.63-0.75, p=0.001-0.007), and MMP-3 plasma levels (r=0.81-0.83, p<0.0001).. Plasma TGF-beta, MMP-2 and MMP-3 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Aortic Aneurysm; Biomarkers; Female; Humans; Male; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinase Inhibitors; Perindopril; Randomized Controlled Trials as Topic; Transforming Growth Factor beta

TGF-beta regulates many aspects of cellular performance relevant to tissue morphogenesis and homeostasis. Postnatal perturbation of TGF-beta signaling contributes to the pathogenesis of many disease states, as recently exemplified through the study of Marfan syndrome (MFS), including aortic aneurysm and skeletal muscle myopathy. Heterogeneity in the regulation and consequences of TGF-beta signaling, amplified in the context of disease, has engendered confusion and controversy regarding its utility as a therapeutic target. Three studies recently published in the JCI, including one in this issue, underscore the complexity of this subject. Heydemann and colleagues implicate dimorphic variation in latent TGF-beta-binding protein 4 (LTBP4), a regulator of TGF-beta bioavailability and activation, as a modifier of muscular dystrophy in gamma-sarcoglycan-deficient mice. In contrast to experience with ascending aortic aneurysm in MFS, Wang and colleagues show that systemic abrogation of TGF-beta signaling worsens (rather than attenuates) Ang II-induced abdominal aortic aneurysm progression in mice. Tieu and colleagues define alterations in the regulation of vascular inflammation in the pathogenesis of Ang II-induced aneurysm and dissection in mice, which may help shed some light on this apparent paradox.

Topics: Animals; Aortic Aneurysm; Child; Disease Models, Animal; Humans; Latent TGF-beta Binding Proteins; Male; Marfan Syndrome; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Diseases; Muscular Dystrophies; Signal Transduction; Transforming Growth Factor beta

Topics: Genome-Wide Association Study; Genomics; Humans; Marfan Syndrome; Mass Spectrometry; Myocardial Infarction; Sequence Analysis, DNA; Transforming Growth Factor beta

Abnormal fibrillinogenesis is associated with connective tissue disorders (CTDs), including Marfan syndrome (MFS), systemic sclerosis (SSc) and Tight-skin (Tsk) mice. We have previously shown that TGF-beta and Wnt stimulate fibrillin-1 assembly and that fibrillin-1 and the developmental regulator CCN3 are both highly increased in Tsk skin. We investigated the role of CCN3 in abnormal fibrillinogenesis in Tsk mice, MFS, and SSc. Smad3 deletion in Tsk mice decreased CCN3 overexpression, suggesting that TGF-beta mediates at least part of the effect of Tsk fibrillin on CCN3 which is consistent with a synergistic effect of TGF-beta and Wnt in vitro on CCN3 expression. Disruption of fibrillin-1 assembly by MFS fibrillin decreased CCN3 expression and skin from patients with early diffuse SSc showed a strong correlation between increased CCN3 and fibrillin-1 expression, suggesting that CCN3 regulation by fibrillin-1 extends to these CTDs. Diffuse SSc skin and sera also showed evidence of increased Wnt activity, implicating a Wnt stimulus behind this correlation. CCN3 overexpression markedly repressed fibrillin-1 assembly and also blocked other TGFbeta- and Wnt-regulated profibrotic gene expression. Together, these data indicate that CCN3 counter-regulates positive signals from TGF-beta and Wnt for fibrillin fibrillogenesis and profibrotic gene expression.

Topics: Animals; Biopsy; Case-Control Studies; CCN Intercellular Signaling Proteins; Cells, Cultured; Disease Models, Animal; Fibrillin-1; Fibrillins; Humans; Intracellular Signaling Peptides and Proteins; Marfan Syndrome; Mice; Mice, Mutant Strains; Microfilament Proteins; Nephroblastoma Overexpressed Protein; Proto-Oncogene Proteins; Scleroderma, Systemic; Signal Transduction; Skin; Smad3 Protein; Transforming Growth Factor beta; Wnt Proteins

Losartan potassium (INN losartan), an antihypertensive drug, has been shown to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of transforming growth factor beta. Recently we reported that doxycycline, a nonspecific inhibitor of matrix metalloproteinases 2 and 9, normalized aortic vasomotor function and suppressed aneurysm growth. We hypothesized that a combination of losartan potassium and doxycycline would offer better secondary prevention treatment than would single-drug therapy to manage thoracic aortic aneurysm.. A well-characterized mouse model of Marfan syndrome (Fbn1(C1039G/+)) was used. At 4 months of age, when aneurysm had established, mice (n = 15/group) were given doxycycline alone (0.24 g/L), losartan potassium alone (0.6 g/L), or combined (0.12-g/L doxycycline and 0.3-g/L losartan potassium) in drinking water. Littermate Fbn1(+/+) mice served as control. Thoracic aortas at 6 and 9 months were studied.. At 9 months, aortic diameter in untreated group was increased by 40% relative to control. Losartan potassium or doxycycline reduced aortic diameter by 10% to 16% versus untreated aortas. Losartan potassium and doxycycline combined completely prevented thoracic aortic aneurysm and improved elastic fiber organization, also downregulating matrix metalloproteinases 2 and 9 and transforming growth factor beta and normalizing aortic contractile and relaxation functions to control values.. Neither losartan potassium nor doxycycline alone completely restored vascular integrity and cell function when given during delayed treatment, indicating the importance of timed pharmacologic intervention. Combined, however, they synergistically offered better aneurysm-suppressing effects than did single-drug medication in the secondary prevention of thoracic aortic aneurysm.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Disease Models, Animal; Doxycycline; Drug Synergism; Drug Therapy, Combination; Elastic Tissue; Fibrillin-1; Fibrillins; Losartan; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microfilament Proteins; Phosphorylation; Protease Inhibitors; Secondary Prevention; Smad2 Protein; Time Factors; Transforming Growth Factor beta; Vasoconstriction; Vasodilation

Reduced bone mineral density (osteopenia) is a poorly characterized manifestation of pediatric and adult patients afflicted with Marfan syndrome (MFS), a multisystem disorder caused by structural or quantitative defects in fibrillin-1 that perturb tissue integrity and TGFβ bioavailability. Here we report that mice with progressively severe MFS (Fbn1(mgR/mgR) mice) develop osteopenia associated with normal osteoblast differentiation and bone formation. In vivo and ex vivo experiments, respectively, revealed that adult Fbn1(mgR/mgR) mice respond more strongly to locally induced osteolysis and that Fbn1(mgR/mgR) osteoblasts stimulate pre-osteoclast differentiation more than wild-type cells. Greater osteoclastogenic potential of mutant osteoblasts was largely attributed to Rankl up-regulation secondary to improper TGFβ activation and signaling. Losartan treatment, which lowers TGFβ signaling and restores aortic wall integrity in mice with mild MFS, did not mitigate bone loss in Fbn1(mgR/mgR) mice even though it ameliorated vascular disease. Conversely, alendronate treatment, which restricts osteoclast activity, improved bone quality but not aneurysm progression in Fbn1(mgR/mgR) mice. Taken together, our findings shed new light on the pathogenesis of osteopenia in MFS, in addition to arguing for a multifaceted treatment strategy in this congenital disorder of the connective tissue.

Topics: Alendronate; Animals; Aorta; Aortic Aneurysm; Bone Diseases, Metabolic; Bone Morphogenetic Proteins; Bone Resorption; Disease Models, Animal; Fibrillin-1; Fibrillins; Losartan; Marfan Syndrome; Mice; Mice, Inbred C57BL; Microfilament Proteins; Mutation; Osteoblasts; Osteoclasts; Osteogenesis; Spine; Tomography, X-Ray Computed; Transforming Growth Factor beta

Topics: Animals; Biomarkers; Humans; Marfan Syndrome; Transforming Growth Factor beta

Previous studies provided evidence about left ventricular systolic and diastolic dysfunction in adults with Marfan syndrome (MFS). However, in the literature, data on right ventricular and bi-atrial diastolic function are limited. We aimed to investigate whether, in the absence of significant valvular disease, diastolic dysfunction is present not only in both ventricles but also in the atrial cavities.. Seventy-two adult unoperated MFS patients and 73 controls without significant differences in age, sex, and body surface area from the patient group were studied using two-dimensional, pulsed, and colour-Doppler and tissue-Doppler imaging (TDI). Biventricular early filling measurements were significantly decreased in MFS patients when compared with controls (P < 0.001). Pulsed TDI early filling measurements obtained from five mitral annular regions and over the lateral tricuspid valve corner were significantly reduced in the patient group (P < 0.001). Indices reflecting atrial function at the reservoir, conduit and contractile phases were also significantly decreased in MFS patients (P < 0.001).. This study demonstrated significant biventricular diastolic and biatrial systolic and diastolic dysfunction in MFS patients. Our findings suggest that MFS affects diastolic function independently. Diastolic abnormalities could be attributed to fibrillin-1 deficiency and dysregulation of transforming growth factor-beta activity in the cardiac extracellular matrix.

Topics: Adult; Case-Control Studies; Chi-Square Distribution; Diastole; Echocardiography; Echocardiography, Doppler; Female; Fibrillin-1; Fibrillins; Humans; Male; Marfan Syndrome; Microfilament Proteins; Regression Analysis; Systole; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Dysfunction, Right

Loeys-Dietz syndrome is a recently-characterised genetic disorder with an autosomal-dominant inheritance due to mutations in the transforming growth factor beta-receptor Type 1 or Type 2 genes. We present a Chinese female neonate with genetically-confirmed Loeys-Dietz syndrome, cleft palate, hypertelorism, and an early dilatation of the aortic root and ascending aorta. This syndrome is associated with an aggressive arteriopathy, with an increased risk of dissection and rupture. Early diagnosis, close monitoring and early surgery may prolong the life in affected individuals. Losartan is an emerging therapy that may help slow down the rate of arterial dilatation.

Topics: Anti-Arrhythmia Agents; Aortic Aneurysm; Echocardiography; Female; Humans; Infant, Newborn; Loeys-Dietz Syndrome; Losartan; Marfan Syndrome; Risk; Time Factors; Transforming Growth Factor beta

Topics: Angiotensin II Type 1 Receptor Blockers; History, 20th Century; Humans; Losartan; Marfan Syndrome; Transforming Growth Factor beta

Marfan's syndrome is a genetic disorder affecting connective tissues, and it can lead to death due to aortic defects if left untreated. beta-blocker therapy has been used to slow the progression of this disease. Brooke et al. (2008) now report that combining angiotensin II receptor blockade by losartan with beta-blocker treatment is an effective treatment combination therapy for this disorder.

Topics: Angiotensin II Type 1 Receptor Blockers; Child; Disease Progression; Extracellular Matrix; Fibrillins; Genes, Dominant; Humans; Losartan; Marfan Syndrome; Microfilament Proteins; Mutation; Radiography; Signal Transduction; Transforming Growth Factor beta

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Aorta; Humans; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Perindopril; Transforming Growth Factor beta

Topics: Angiotensin II Type 1 Receptor Blockers; Benzamides; Fibrillins; Humans; Imatinib Mesylate; Losartan; Marfan Syndrome; Microfilament Proteins; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Signal Transduction; Transforming Growth Factor beta

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Child; Fibrillins; Humans; Losartan; Marfan Syndrome; Microfilament Proteins; Mutation; Transforming Growth Factor beta

Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies; Fibrillin-1; Fibrillins; Fluorescent Antibody Technique; Histocytochemistry; Losartan; Marfan Syndrome; Mice; Microfilament Proteins; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Mutation; Regeneration; Signal Transduction; Transforming Growth Factor beta

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Losartan; Marfan Syndrome; Mice; Models, Biological; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Regeneration; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Fibrillins; Humans; Marfan Syndrome; Mice; Microfilament Proteins; Mutation; Transforming Growth Factor beta

The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-beta in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFbeta1 and is required for TGFbeta mediated inhibition of cell proliferation.. We show that loss of LRP1 in VSMC (smLRP(-)) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFbeta target genes thrombospondin-1 (TSP1) and PDGFRbeta in the vascular wall. Treatment of smLRP1(-) animals with the PPARgamma agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels.. Our findings are consistent with an activation of TGFbeta signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity.

Topics: Animals; Atherosclerosis; Blotting, Western; Low Density Lipoprotein Receptor-Related Protein-1; Marfan Syndrome; Mice; Mice, Transgenic; Microscopy, Fluorescence; Platelet-Derived Growth Factor; Rosiglitazone; Signal Transduction; Smad Proteins; Thiazolidinediones; Transforming Growth Factor beta; Tunica Intima

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Topics: Adolescent; Adult; Epidermal Growth Factor; Exons; Female; Fibrillin-1; Fibrillins; Humans; Male; Marfan Syndrome; Microfilament Proteins; Mutation; Phenotype; Prognosis; Protein Structure, Tertiary; Severity of Illness Index; Transforming Growth Factor beta

Topics: Animals; Codon, Nonsense; Dystrophin; Gene Expression; Humans; Losartan; Marfan Syndrome; Mice; Muscular Dystrophy, Duchenne; Oxadiazoles; PPAR alpha; Transforming Growth Factor beta

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Aneurysm; Clinical Trials as Topic; Disease Models, Animal; Emphysema; Fibrillins; Humans; Losartan; Marfan Syndrome; Mice; Microfilament Proteins; Mutation; Transforming Growth Factor beta

Aortic aneurysm and dissection are manifestations of Marfan syndrome (MFS), a disorder caused by mutations in the gene that encodes fibrillin-1. Selected manifestations of MFS reflect excessive signaling by the transforming growth factor-beta (TGF-beta) family of cytokines. We show that aortic aneurysm in a mouse model of MFS is associated with increased TGF-beta signaling and can be prevented by TGF-beta antagonists such as TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor (AT1) blocker, losartan. AT1 antagonism also partially reversed noncardiovascular manifestations of MFS, including impaired alveolar septation. These data suggest that losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with MFS and has the potential to prevent the major life-threatening manifestation of this disorder.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies; Aorta; Aortic Aneurysm; Disease Models, Animal; Elastic Tissue; Female; Fibrillin-1; Fibrillins; Losartan; Lung; Lung Diseases; Marfan Syndrome; Mice; Microfilament Proteins; Mutation; Neutralization Tests; Pregnancy; Pregnancy Complications; Propranolol; Pulmonary Alveoli; Receptor, Angiotensin, Type 1; Signal Transduction; Transforming Growth Factor beta

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Fibrillins; Humans; Losartan; Marfan Syndrome; Microfilament Proteins; Transforming Growth Factor beta

Marfan syndrome (MFS), a condition caused by fibrillin-1 gene mutation is associated with aortic aneurysm that shows elastic lamellae disruption, accumulation of glycosaminoglycans, and vascular smooth muscle cell (VSMC) apoptosis with minimal inflammatory response. We examined aneurysm tissue and cultured cells for expression of transforming growth factor-beta1 to -beta3 (TGFbeta1 to 3), hyaluronan content, apoptosis, markers of cell migration, and infiltration of vascular progenitor cells (CD34).. MFS aortic aneurysm (6 males, 5 females; age 8 to 78 years) and normal aorta (5 males, 3 females; age 22 to 56 years) were used. Immunohistochemistry showed increased expression of TGFbeta1 to 3, hyaluronan, and CD34-positive microcapillaries in MFS aneurysm compared with control. There was increased expression of TGFbeta1 to 3 and hyaluronan in MFS cultured VSMCs, adventitial fibroblasts (AF), and skin fibroblasts (SF). Apoptosis was increased in MFS (VSMC: mean cell loss in MFS 29%, n of subjects=5, versus control 8%, n=3, P<0.05; AF: 28%, n=5 versus 7%, n=5, P<0.05; SF: 29%, n=3 versus 4%, n=3, not significant). In MFS, there was a 2-fold increase in adventitial microcapillaries containing CD34-positive cells compared with control tissue. Scratch wound assay showed absence of CD44, MT1-MMP, and beta-3 integrin at the leading edge of migration in MFS indicating altered directional migration. Western blot showed increased expression of TGFbeta1 to 3 in MFS but no change in expression of CD44, MT1-MMP, or beta-3 integrin compared with controls.. There was overexpression of TGF-beta in MFS associated with altered hyaluronan synthesis, increased apoptosis, impaired progenitor cell recruitment, and abnormal directional migration. These factors limit tissue repair and are likely to contribute to aneurysm development.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Dissection; Apoptosis; Blood Vessel Prosthesis Implantation; Cells, Cultured; Child; Elective Surgical Procedures; Female; Fibroblasts; Gene Expression Regulation; Humans; Hyaluronan Receptors; Hyaluronic Acid; Integrin beta3; Male; Marfan Syndrome; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Middle Aged; Muscle Cells; Muscle, Smooth, Vascular; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3

Marfan syndrome (MFS) is known to cause ascending thoracic aortic aneurysms (ATAAs). Transforming growth factor beta (TGF-beta) has recently been implicated in this process. Imbalances between the matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) have also been shown to contribute to aneurysm formation. Whether and to what degree MMP, TIMP, and TGF-beta signaling profiles are altered in ATAAs in MFS compared with non-MFS patients remains unknown.. ATAA samples taken during aortic replacement from age-matched MFS (n=9) and non-MFS (n=18) patients were assessed for representative subtypes of all MMP classes, all 4 known TIMPs, and type 2 TGF-beta receptors (TGFBR2). Results were expressed as a percentage (mean+/-SEM) of reference control samples (100%; n=18) obtained from patients without ATAA. In MFS, decreased MMP-2 (76+/-7; P<0.05 versus control), increased MMP-12 (161+/-27% versus control; P<0.05), and increased MT1-MMP (248+/-64% versus 91+/-21 non-MFS and control; P<0.05) were observed. TIMP-3 (74+/-23%) was reduced compared with control values (P<0.05) and TIMP-2 was elevated (128+/-31%) compared with non-MFS (73+/-19%; P<0.05). In non-MFS samples, MMP-1 (70+/-16%), MMP-3 (77+/-18%), MMP-8 (75+/-11%), MMP-9 (69+/-14%), and MMP-12 (85+/-15%) were decreased compared with control (P<0.05). TIMPs 1 to 3 were reduced in non-MFS compared with control values (P<0.05). TGFBR2 were increased in MFS (193+/-32%) compared with non-MFS (95+/-16%) and controls (P<0.05).. A unique MMP and TIMP portfolio was observed in ATAAs from MFS compared with non-MFS patients. In addition, MFS samples showed evidence of increased TGF-beta signaling. These differences suggest disparate mechanisms of extracellular matrix remodeling between these 2 groups of patients.

Topics: Adult; Aorta; Aortic Aneurysm, Thoracic; Aortic Dissection; Blood Vessel Prosthesis Implantation; Disease Susceptibility; Female; Fibrillins; Gene Expression Profiling; Gene Expression Regulation; Humans; Male; Marfan Syndrome; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Microfilament Proteins; Middle Aged; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta

Light microscopy study of the lumbar spinal meninges of a murine model of Marfan syndrome.. Characterize the pathology of the lumbosacral meninges in Marfan syndrome, seeking clues to the pathophysiology behind dural ectasia.. Dural ectasia is common in Marfan syndrome. The etiology of dural ectasia is unknown, but is conjectured to be related to constitutionally weak spinal dura. The morphology of the lumbar dura in Marfan syndrome has not been described, as it has in other tissues affected by Marfan syndrome.. The lumbosacral dura were removed from three 4-month-old mice, 1 homozygote (mgR/mgR) expressing the murine Marfan phenotype, 1 heterozygote expressing wild-type phenotype, and 1 homozygote wildtype. Hematoxylin and eosin, elastochrome, and immunohistochemical stains against activated transforming growth factor beta, gelatinase A (matrix metalloproteinase-2), and gelatinase-B (matrix metalloproteinase-9) were used for light microscopic evaluation.. No difference was noted between the heterozygous and wild-type mice in dural connective tissue morphology. The homozygote (mgR/mgR) had a marked attenuation of the dura overall, in addition to elastic fiber disorganization. The homozygote dura also stained for increased presence of activated transforming growth factor beta and matrix metalloproteinase-2, but not matrix metalloproteinase-9.. These morphologic findings in the Marfan phenotype mouse mimic the findings of disordered elastic-fibers in other Marfan tissues and demonstrate gross attenuation of the tissue architecture, corroborating the theory that dural ectasia in Marfan syndrome results from hydrostatic pressure on weakened dura. These changes may be due in part to transforming growth factor beta overactivation and gelatinase-A-mediated elastolysis and collagen breakdown.

Topics: Animals; Biomarkers; Cauda Equina; Dilatation, Pathologic; Disease Models, Animal; Dura Mater; Fibrillins; Lumbosacral Region; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Microfilament Proteins; Transforming Growth Factor beta

Marfan syndrome (MFS) is a heritable disorder of the connective tissue which has been linked to mutations in the FBN (fibrillin-1) gene. Murine knockouts of the FBN gene show increased interstitial fibrosis and TGF-beta (tumor growth factor-beta) gene activation. Abnormal TGF-beta expression has previously been linked to radiation-induced fibrosis, suggesting a possible link between MFS and increased late effects following radiotherapy. Herein we report two cases in which MFS patients treated with radical radiotherapy without undue acute or late radiotherapy toxicity suggesting that radiotherapy should not be withheld from MFS patients. MFS patients may provide a unique clinico-translational setting to test associations between FBN mutations, TGF-beta activation and the risk of tissue fibrosis.

Topics: Adolescent; Aged; Brain Neoplasms; Female; Fibrillin-1; Fibrillins; Glioma; Humans; Male; Marfan Syndrome; Microfilament Proteins; Prostatic Neoplasms; Radiation Pneumonitis; Transforming Growth Factor beta

Topics: Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Transforming Growth Factor beta

Although it has been known for more than a decade that Marfan syndrome - a dominantly inherited connective tissue disorder characterized by tall stature, arachnodactyly, lens subluxation, and a high risk of aortic aneurysm and dissection - results from mutations in the FBN1 gene, which encodes fibrillin-1, the precise mechanism by which the pleiotropic phenotype is produced has been unclear. A report in this issue now proposes that loss of fibrillin-1 protein by any of several mechanisms and the subsequent effect on the pool of TGF-beta may be more relevant in the development of Marfan syndrome than mechanisms previously proposed in a dominant-negative disease model. The model proposed in this issue demonstrates several strategies for clinical intervention.

Topics: Animals; Chromosomes, Human, Pair 15; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfibrils; Microfilament Proteins; Phenotype; Protein Isoforms; Transforming Growth Factor beta

Mitral valve prolapse (MVP) is a common human phenotype, yet little is known about the pathogenesis of this condition. MVP can occur in the context of genetic syndromes, including Marfan syndrome (MFS), an autosomal-dominant connective tissue disorder caused by mutations in fibrillin-1. Fibrillin-1 contributes to the regulated activation of the cytokine TGF-beta, and enhanced signaling is a consequence of fibrillin-1 deficiency. We thus hypothesized that increased TGF-beta signaling may contribute to the multisystem pathogenesis of MFS, including the development of myxomatous changes of the atrioventricular valves. Mitral valves from fibrillin-1-deficient mice exhibited postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-beta activation and signaling. In addition, TGF-beta antagonism in vivo rescued the valve phenotype, suggesting a cause and effect relationship. Expression analyses identified increased expression of numerous TGF-beta-related genes that regulate cell proliferation and survival and plausibly contribute to myxomatous valve disease. These studies validate a novel, genetically engineered murine model of myxomatous changes of the mitral valve and provide critical insight into the pathogenetic mechanism of such changes in MFS and perhaps more common nonsyndromic variants of mitral valve disease.

Topics: Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Female; Fibrillin-1; Fibrillins; Humans; Male; Marfan Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Mitral Valve; Mitral Valve Prolapse; Phenotype; Pregnancy; Transforming Growth Factor beta

Mitral valve prolapse (MVP), an abnormal displacement into the left atrium of a thickened and redundant mitral valve during systole, is a relatively frequent abnormality in humans and may be associated with serious complications. A recent study implicates fibrillin-1, a component of extracellular matrix microfibrils, in the pathogenesis of a murine model of MVP. This investigation represents an initial step toward understanding the mechanisms involved in human MVP disease and the development of potential treatments.

Topics: Animals; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Mice; Microfilament Proteins; Mitral Valve Prolapse; Transforming Growth Factor beta

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

Topics: Animals; Apoptosis; Disease Models, Animal; Emphysema; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Lung; Marfan Syndrome; Mice; Mice, Knockout; Mice, Transgenic; Microfilament Proteins; Neutralization Tests; Phenotype; Transforming Growth Factor beta

Topics: Animals; Extracellular Matrix; Fibrillins; Humans; Lung; Marfan Syndrome; Mice; Microfilament Proteins; Transforming Growth Factor beta

Topics: Animals; Animals, Genetically Modified; Antigen Presentation; Arthritis, Psoriatic; Arthritis, Reactive; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Crohn Disease; Cystine; Dimerization; Fibrillins; Genetic Predisposition to Disease; Histocompatibility Antigens Class I; HLA-B27 Antigen; Humans; Lung; Lymphocyte Activation; Marfan Syndrome; Mice; Microfilament Proteins; Models, Immunological; Organ Specificity; Protein Conformation; Rats; Sacroiliac Joint; Spondylitis, Ankylosing; Stress, Mechanical; Transforming Growth Factor beta; Uveitis, Anterior

The transforming growth factor beta (TGF-beta) binding protein-like (TB) domain is found principally in proteins localized to extracellular matrix fibrils, including human fibrillin-1, the defective protein in the Marfan syndrome. Analysis of the nuclear magnetic resonance (NMR) data for the sixth TB module from human fibrillin-1 has revealed the existence of two stable conformers that differ in the isomerization states of two proline residues. Unusually, the two isoforms do not readily interconvert and are stable on the time scale of milliseconds. We have computed independent structures of the major and minor conformers of TB6 to assess how the domain fold adjusts to incorporate alternatively cis- or trans-prolines. Based on previous observations, it has been suggested that multiple conformers can only be accommodated in flexible regions of protein structure. In contrast, P22, which exists in trans in the major form and cis in the minor form of TB6, is in a rigid region of the domain, which is confirmed by backbone dynamics measurements. Overall, the structures of the major and minor conformers are similar. However, the secondary structure topologies of the two forms differ as a direct consequence of the changes in proline conformation.

Topics: Fibrillin-1; Fibrillins; Humans; Isomerism; Magnetic Resonance Spectroscopy; Marfan Syndrome; Microfilament Proteins; Models, Molecular; Proline; Protein Conformation; Protein Structure, Secondary; Transforming Growth Factor beta

Here we describe the high resolution nuclear magnetic resonance (NMR) structure of a transforming growth factor beta (TGF-beta)-binding protein-like (TB) domain, which comes from human fibrillin-1, the protein defective in the Marfan syndrome (MFS). This domain is found in fibrillins and latent TGF-beta-binding proteins (LTBPs) which are localized to fibrillar structures in the extracellular matrix. The TB domain manifests a novel fold which is globular and comprises six antiparallel beta-strands and two alpha-helices. An unusual cysteine triplet conserved in the sequences of TB domains is localized to the hydrophobic core, at the C-terminus of an alpha-helix. The structure is stabilized by four disulfide bonds which pair in a 1-3, 2-6, 4-7, 5-8 pattern, two of which are solvent exposed. Analyses of MFS-causing mutations and the fibrillin-1 cell-binding RGD site provide the first clues to the surface specificity of TB domain interactions. Modelling of a homologous TB domain from LTBP-1 (residues 1018-1080) suggests that hydrophobic contacts may play a role in its interaction with the TGF-beta1 latency-associated peptide.

Topics: Amino Acid Sequence; Cell Adhesion; Extracellular Matrix; Fibrillin-1; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Models, Molecular; Molecular Sequence Data; Mutation; Nuclear Magnetic Resonance, Biomolecular; Peptide Fragments; Protein Structure, Secondary; Protein Structure, Tertiary; Recombinant Proteins; Sequence Homology, Amino Acid; Solutions; Transforming Growth Factor beta

Marfan syndrome results from mutations in an extracellular matrix glycoprotein, fibrillin. Previous studies have characterized approximately 6.9-kb of the estimated 10-kb fibrillin transcript. We have now completed the primary structure of fibrillin, elucidated the exon/intron organization of the gene and derived a physical map of the genetic locus. Pre-fibrillin consists of 2,871 amino acids which, excluding the signal peptide, are arranged into five structurally distinct regions. The largest of these regions comprises about 75% of the entire protein and consists of numerous repeated cysteine-rich sequences homologous to the peptide motifs of the epidermal growth factor (EGF) and transforming growth factor-beta binding protein (TGF-bp). Forty-three of the forty-six EGF-like repeats contain a calcium binding consensus sequence (EGF-CB) conceivably mediating protein-protein interactions. Fibrillin exhibits a few additional cysteine-rich modules that are apparently unique to this macromolecule and may represent evolutionary variants of the EGF-CB and TGF-bp motifs. Almost all of the cysteine-rich repeats are encoded by single exons; consequently, the fibrillin gene is relatively large (approximately 110-kb) and highly fragmented (65 exons). This study provides the first comprehensive analysis of the fibrillin gene and relevant information for the full characterization of Marfan syndrome mutations.

Topics: Amino Acid Sequence; Base Sequence; Carrier Proteins; Chromosome Mapping; Chromosomes, Fungal; Cloning, Molecular; Cysteine; DNA; Epidermal Growth Factor; Exons; Fibrillins; Gene Library; Genome, Human; Humans; Intracellular Signaling Peptides and Proteins; Latent TGF-beta Binding Proteins; Marfan Syndrome; Microfilament Proteins; Molecular Sequence Data; Repetitive Sequences, Nucleic Acid; Transforming Growth Factor beta