transforming-growth-factor-beta and Aortic-Dissection

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

Aortic structure and function are controlled by the coordinated actions of different aortic cells and the extracellular matrix. Several pathways have been identified that control the aortic wall in a cell-type-specific manner and play diverse roles in various phases of aortic injury, repair, and remodeling. This complexity of signaling in the aortic wall poses challenges to the development of therapeutic strategies for treating aortic aneurysms and dissections. Here, in part II of this Recent Highlights series on aortic aneurysms and dissections, we will summarize recent studies published in

Topics: Aortic Aneurysm; Aortic Dissection; Extracellular Matrix; Humans; Mutation; Receptors, Angiotensin; Signal Transduction; Transforming Growth Factor beta

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

Thoracic aortic aneurysms that progress to acute aortic dissections are often fatal. Thoracic aneurysms have been managed with treatment with β-adrenergic blocking agents (β-blockers) and routine surveillance imaging, followed by surgical repair of the aneurysm when the risk of dissection exceeds the risk for repair. Thus, there is a window to initiate therapies to slow aortic enlargement and delay or ideally negate the need for surgical repair of the aneurysm to prevent a dissection. Mouse models of Marfan syndrome-a monogenic disorder predisposing to thoracic aortic disease-have been used extensively to identify such therapies. The initial finding that TGFβ (transformation growth factor-β) signaling was increased in the aortic media of a Marfan syndrome mouse model and that its inhibition via TGFβ neutralization or At1r (Ang II [angiotensin II] type I receptor) antagonism prevented aneurysm development was generally viewed as a groundbreaking discovery that could be translated into the first cure of thoracic aortic disease. However, several large randomized trials of pediatric and adult patients with Marfan syndrome have subsequently yielded no evidence that At1r antagonism by losartan slows aortic enlargement more effectively than conventional treatment with β-blockers. Subsequent studies in mouse models have begun to resolve the complex molecular pathophysiology underlying onset and progression of aortic disease and have emphasized the need to preserve TGFβ signaling to prevent aneurysm formation. This review describes critical experiments that have influenced the evolution of our understanding of thoracic aortic disease, in addition to discussing old controversies and identifying new therapeutic opportunities.

Topics: Acute Disease; Angiotensin II; Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Losartan; Mice; Signal Transduction; Transforming Growth Factor beta

Recent advances in DNA sequencing technology have identified several causative genes for hereditary thoracic aortic aneurysms and dissections (TAADs), including Marfan syndrome (MFS), Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial non-syndromic TAADs. Syndromic TAADs are typically caused by pathogenic variants in the transforming growth factor-β signal and extracellular matrix-related genes (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2, and COL3A1). On the other hand, approximately 20% of the non-syndromic hereditary TAADs result from altered components of the contractile apparatus of vascular smooth muscle cells, which are encoded by ACTA2, MYH11, MYLK, and PRKG1 genes; however, the remaining 80% cannot be explained by previously reported candidate genes. Moreover, the relationship between the genotype and phenotype of TAADs has extensively been reported to investigate better methods for risk stratification and further personalized treatment strategies. With regard to MFS-causing FBN1, recent reports have shown significantly increased risk of aortic events in patients carrying a truncating variant or a variant exhibiting a haploinsufficient-type effect, typically comprising nonsense or small insertions/deletions resulting in out-of-frame effects, compared to those carrying a variant with dominant negative-type effect, typically comprising missense variants. Therefore, cardiologists are required to have sufficient knowledge regarding the genetics of hereditary TAADs for providing the best clinical management, with an appropriate genetic counseling. In the current review, we present current advances in the genetics of hereditary TAADs and discuss the benefits and limitations with respect to the use of this genetic understanding in clinical settings.

Topics: Actins; Aortic Aneurysm, Thoracic; Aortic Dissection; Calcium-Binding Proteins; Collagen Type III; Cyclic GMP-Dependent Protein Kinase Type I; Female; Fibrillin-1; Humans; Male; Muscle, Smooth, Vascular; Myosin Heavy Chains; Myosin-Light-Chain Kinase; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta2

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

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

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

This review discusses the role of biomarkers for both diagnoses and disease monitoring before, during, and after treatment of aortic dissection.

Topics: Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Calcium-Binding Proteins; Calponins; Elastin; Endothelin-1; Fibrin Fibrinogen Degradation Products; Humans; Microfilament Proteins; Natriuretic Peptide, Brain; Peptide Fragments; Peptidyl-Dipeptidase A; Receptors, Notch; Smooth Muscle Myosins; Transforming Growth Factor beta

Thoracic aortic aneurysm and dissection in young and middle aged patients is increasingly recognised as due to genetic aortopathy. Mutations in multiple genes affecting proteins in the extracellular matrix, microfibrillar structure, the endothelium and cell signalling pathways have been associated with thoracic aortic disease. The TGFß signalling pathway appears to play a key role in mediating abnormal aortic growth and aneurysm formation. A challenge remains in understanding how the many different gene mutations can result in deranged TGFß signalling. This review examines the functional relationships between key structural and signalling proteins, with reference to the need for maintenance of homeostasis in mechanotransduction within the aortic wall. A mechanism, through which perturbations in mechanotransduction, arising from different gene mutations, results in altered TGFß signalling is described.

Topics: Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Mechanotransduction, Cellular; Mutation; Transforming Growth Factor beta

Heritable connective tissue diseases comprise a heterogeneous group of multisystemic disorders that are characterized by significant morbidity and mortality. These disorders do not merely result from defects in the amount or structure of one of the components of the extracellular matrix, as the extracellular matrix also serves other functions, including sequestration of cytokines, such as transforming growth factor beta (TGFβ). Indeed, disturbed TGFβ signaling was demonstrated in several heritable connective tissue diseases, including syndromic forms such as Marfan or Loeys-Dietz syndrome and non-syndromic presentations of thoracic aortic aneurysm/dissection. Because of these findings, new therapeutic targets have been unveiled, leading to the initiation of large clinical trials with angiotensin II type 1 receptor antagonists that also have an inhibiting effect on TGFβ signaling. Here, we present an overview of the clinical characteristics, the molecular findings, and the therapeutic strategies for the currently known syndromic and non-syndromic forms of thoracic aortic aneurysm/dissection.

Topics: Angiotensin II Type 1 Receptor Blockers; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Transforming Growth Factor beta

Four distinguishing histopathological characteristics of thoracic aortic aneurysms and dissections (TAADs) are the fragmentation or degradation of elastic fibers, loss of smooth muscle, pooling of glycosaminoglycans, and remodeling of fibrillar collagens. Of these, pooling of glycosaminoglycans appears to be unique to these lesions.. This review acknowledges the importance of dysregulated transforming growth factor-β (TGF-β) in TAADs and offers a complementary hypothesis that increased TGF-β could contribute to the accumulation of glycosaminoglycans in the media of the proximal thoracic aorta. Regardless, observed pools of glycosaminoglycans could decrease tensile strength, cause stress concentrations, and increase intralamellar swelling pressure, all of which could initiate local delaminations that could subsequently propagate as dissections and result in a false lumen or rupture.. There is a pressing need to investigate potential mechanical as well as biological consequences of accumulated glycosaminoglycans in TAADs and to elucidate responsible signaling pathways, with particular attention to synthetic cells of nonmesodermal lineage. Such research could provide insight into the mechanisms of dissection and the seemingly paradoxical role of the over-expression of a cytokine that is typically associated with fibrosis but is implicated in a degenerative disease of the aorta that can result in a catastrophic mechanical failure.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Biomechanical Phenomena; Glycosaminoglycans; Humans; Signal Transduction; Tensile Strength; Transforming Growth Factor beta

Arterial dissection (AD) is defined as the longitudinal splitting up of the arterial wall caused by intramural bleeding. It can occur as a spontaneous event in all large and medium sized arteries. The histological hallmark of AD is medial degeneration. Histological investigations, gene expression profiling and proteome studies of affected arteries reveal disturbances in many different biological processes including inflammation, proteolytic activity, cell proliferation, apoptosis and smooth muscle cell (SMC) contractile function. Medial degeneration can be caused by various rare dominant Mendelian disorders. Genetic linkage analysis lead to the identification of mutations in different disease-causing genes involved in the biosynthesis of the extracellular matrix (FBN1, COL3A1), in transforming growth factor (TGF) beta signaling (FBN1, TGFBR1, TGFBR2) and in the SMC contractile system (ACTA2, MYH11). Genome wide association studies suggest that the CDKN2A/CDKN2B locus plays a role in the etiology AD and other arterial diseases.

Topics: Animals; Aortic Dissection; Female; Gene Expression Profiling; Genetic Predisposition to Disease; Humans; Male; Models, Cardiovascular; Mutation; Myocytes, Smooth Muscle; Peptide Hydrolases; Phenotype; 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

The lethality of acute aortic dissection is well recognized. Successful treatment and prevention of aortic dissection is going to be dependent upon an improved understanding of the molecular and physiologic events which predispose to dissection development and propagation. In this review, we will focus on the elastic fiber, one of the critical elements of the aortic wall matrix. Mechanical or functional failure of the elastin in the wall of the aorta likely predisposes to dissection as well as the post-dissection aortic degeneration with aneurysm formation. Insight into the role of the elastin and the elastic fiber in aortic dissection has recently been accelerated by research into the molecular mechanisms associated with hereditary propensity for aortic dissection, such as Marfan syndrome. These studies have implicated both structural and metabolic contributions of alterations in the scaffolding proteins in matrix elastic fibers. In particular, increased transforming growth factor-β (TGF-β) activity may play a prominent role in predisposing the aortic wall to dissection. The events which predispose to post-dissection aortic degeneration are somewhat less well defined. However, the loss of the structural integrity of the remaining elastic fibers leaves the wall weaker and prone to dilatation and rupture. It appears likely that the upregulation of several potent proteases, particularly those of the matrix metalloproteinase (MMP) family such as MMP-9, are participating in the subsequent matrix damage. Novel medical treatments based on this pathologic data have been proposed and in some cases have made it to clinical trials. The ongoing study evaluating whether therapeutic inhibition of TGF-β may be useful in reducing the risk of aortic dissection in patients at high risk represents one promising new strategy in the treatment of this deadly disease.

Topics: Acute Disease; Aortic Aneurysm; Aortic Dissection; Aortic Rupture; Elastic Tissue; Hemodynamics; Humans; Matrix Metalloproteinases; 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

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

When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD).. We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific. In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-β (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg,. Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.

Topics: Aneurysm; Animals; Aorta; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Cells, Cultured; Chromatin; Collagen; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Smooth Muscle; Proto-Oncogene Proteins c-akt; Transforming Growth Factor beta

To investigate the association of myosin heavy chain protein 11 (MYH11) and transforming growth factor β signaling-related gene polymorphisms with the susceptibility of DeBakey type III aortic dissection (AD) and its clinical outcomes. Four single-nucleotide polymorphism (SNPs) (MYH11 rs115364997, rs117593370, TGFB1 rs1800469, and TGFBR1 rs1626340) were analyzed in patients with DeBakey III AD (173) and healthy participants (335). Gene-gene and gene-environment interactions were evaluated using generalized multifactor dimensionality reduction. The patients were followed up for a median of 55.7 months. MYH11 rs115364997 G or TGFBR1 rs1626340 A carriers had an increased risk of DeBakey type III AD. MYH11, TGFB1, TGFBR1, and environment interactions contributed to the risk of DeBakey type III AD (cross-validation consistency = 10/10, P = 0.001). Dominant models of MYH11 rs115364997 AG + GG genotype (HR = 2.443; 95%CI: 1.096-5.445, P = 0.029), TGFB1 rs1800469 AG + GG (HR = 2.303; 95%CI: 1.069-4.96, P = 0.033) were associated with an increased risk of mortality in DeBakey type III AD. The dominant model of TGFB1 rs1800469 AG + GG genotype was associated with an increased risk of recurrence of chest pain in DeBakey type III AD (HR = 1.566; 95%CI: 1.018-2.378, P = 0.041). In conclusions, G carriers of MYH11 rs115364997 or TGFB1 rs1800469 may be the poor prognostic indicators of mortality and recurrent chest pain in DeBakey type III AD. The interactions of gene-gene and gene-environment are associated with the risk of DeBakey type III AD.

Topics: Aortic Dissection; Chest Pain; Genetic Predisposition to Disease; Genotype; Humans; Myosin Heavy Chains; Polymorphism, Single Nucleotide; Receptor, Transforming Growth Factor-beta Type I; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study is aimed at investigating the association of Fibrillin-1 (FBN1) and transforming growth factor β (TGF-β) signaling-related gene polymorphisms with the susceptibility of Stanford type B aortic dissection (AD) and its clinical prognostic outcomes.. Five single-nucleotide polymorphism (SNPs) (FBN1rs 145233125, rs201170905, rs11070646, TGFB1rs1800469, and TGFB2rs900) were analyzed in patients with Stanford type B AD (164) and healthy controls (317). Gene-gene and gene-environment interactions were assessed by generalized multifactor dimensionality reduction. A 4-year follow-up was performed for all AD patients.. G carriers of FBN1 rs201170905 and TGFB1 rs1800469 have an increased risk of Stanford type B AD. The interaction of FBN1, TGFB1, TGFB2 and environmental promoted to the increased risk of type B AD (cross-validation consistency = 10/10, P = 0.001). Dominant models of FBN1rs145233125 TC + CC genotype (P = 0.028), FBN1 rs201170905 AG + GG (P = 0.047) and TGFB1 rs1800469 AG + GG (P = 0.052) were associated with an increased risk of death of Stanford type B AD. The recessive model of FBN1 rs145233125 CC genotype (P < 0.001), FBN1rs201170905 GG (P < 0.001), TGFB1 rs1800469 AG + GG genotype (P = 0.011) was associated with an increased risk of recurrence of chest pain in Stanford type B AD.. The interactions of gene-gene and gene-environment are related with the risk of Stanford type B AD. C carriers of rs145233125, G carriers of rs201170905 and G carriers of rs1800469 may be the poor clinical outcome indicators of mortality and recurrent chest pain in Stanford type B AD.

Topics: Aortic Dissection; Chest Pain; Fibrillin-1; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Prognosis; Transforming Growth Factor beta

Aortic dissection (AD) is a life-threatening emergency, and lumican (LUM) is a potential Biomarker for AD diagnosis. We investigated LUM expression patterns in patients with AD and explored the molecular functions of Lum in AD mice model.. LUM expression patterns were analyzed using aortic tissues of AD patients, and serum soluble LUM (s-LUM) levels were compared between patients with acute AD (AAD) and chronic AD (CAD). Lum-knockout (Lum-/-) mice were challenged with β-aminopropionitrile (BAPN) and angiotensin II (Ang II) to induce AD. The survival rate, AD incidence, and aortic aneurysm (AA) in these mice were compared with those in BAPN-Ang II-challenged wildtype (WT) mice. Tgf-β/Smad2, Mmps, Lum, and Nox expression patterns were examined.. LUM expression was detected in the intima and media of the ascending aorta in patients with AAD. Serum s-LUM levels were significantly higher in patients with AAD than CAD. Furthermore, AD-associated mortality and thoracic aortic rupture incidence were significantly higher in the Lum-/- AD mice than in the WT AD mice. However, no significant pathologic changes in AA were observed in the Lum-/- AD mice compared with the WT AD mice. The BAPN-Ang II-challenged WT and Lum-/- AD mice had higher Tgf-β, p-Smad2, Mmp2, Mmp9, and Nox4 levels than those of non-AD mice. We also found that Lum expression was significantly higher in the BAPN-Ang II-challenged WT in comparison to the unchallenged WT mice.. LUM expression was altered in patients with AD display increased s-LUM in blood, and Lum-/- mice exhibited augmented AD pathogenesis. These findings support the notion that LUM is a biomarker signifying the pathogenesis of injured aorta seen in AAD. The presence of LUM is essential for maintenance of connective tissue integrity. Future studies should elucidate the mechanisms underlying LUM association in aortic changes.

Topics: Acute Disease; Aminopropionitrile; Angiotensin II; Animals; Aorta; Aortic Dissection; Aortic Rupture; Biomarkers; Chronic Disease; Disease Models, Animal; Humans; Incidence; Kaplan-Meier Estimate; Lumican; Mice; Mice, Inbred C57BL; Mice, Knockout; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation

Stanford type A aortic dissection (TAAD) is one of the most dangerous cardiovascular diseases. MicroRNAs (miRNAs) have been considered as potential therapeutic targets for TAAD. In this present study, we aimed to investigate the functional role and regulatory mechanism of miR-26b in TAAD development.. MiR-26b mRNA expression was detected by real-time polymerase chain reaction (RT-PCR) and protein levels were measured by Western blot. Verifying the direct target of miR-26b was used by dual luciferase assay, RT-PCR, and Western blot. Cell Counting Kit-8 (CCK-8) and TUNEL staining assays were applied for detecting rat aortic vascular smooth muscle cells (VSMCs) viability and apoptosis, respectively.. We found that miR-26b was under-expressed in TAAD patients and closely associated with the poor prognosis of TAAD patients. Re-expression of miR-26b facilitated while knockdown of miR-26b inhibited VSMC proliferation. However, miR-26b showed the opposite effect on cell apoptosis. More importantly, high-mobility group AT-hook 2 (HMGA2) was verified as the direct target of miR-26b. Furthermore, transforming growth factor beta (TGF-β)/Smad3 signaling pathway was involved in the development of TAAD modulated by miR-26b.. miR-26b impeded TAAD development by regulating HMGA2 and TGF-β/Smad3 signaling pathway, which provided a potential biomarker for TAAD treatment.

Topics: Adult; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Apoptosis; Cells, Cultured; Female; Gene Expression Regulation; HMGA2 Protein; Humans; Male; MicroRNAs; Middle Aged; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Rats; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

The pathogenesis of aortic dissection (AD) is unclear. The aim of this study was to explore the relationship between osteopontin (OPN) and AD. Fifty AD patients were enrolled; 29 had hypertension with AD (H-AD) and 21 no hypertension with HD (NH-AD). Twenty-five healthy controls (NH-C) and 14 patients with hypertension (H-C) were also enrolled. Serum and aortic wall OPN levels were determined. Human vascular muscle cells (HVSMC) were stimulated by both low (1 μg/mL) and high (5 μg/mL) concentrations of OPN and cell proliferation as well as apoptosis was measured. Transforming growth factor-β (TGF-β), matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, TIMP-1, and TIMP-2 gene expressions by HVSMC were measured and Akt, IκB, Smad1/5/8 and Erk1/2 signaling pathways were detected. Our results showed that AD patients demonstrated significantly higher levels of serum and local OPN expressions compared to healthy controls. In those with hypertension, the serum concentrations of OPN were increased compared to those without hypertension. In in vitro culture, a high dose of OPN stimulation promoted the proliferation of HVSMC but did not affect cell apoptosis. Both concentrations of OPN enhanced MMP-2 gene expression and its activity in HVSMC. Moreover, Akt and IκB signaling pathways were significantly activated after OPN stimulation while the Smad1/5/8 and Erk1/2 signaling pathways were not changed. The addition of an IκB inhibitor significantly abrogated MMP-2 gene expression. Our data show that OPN may participate in the pathogenesis of AD by the enhancement of MMP-2 expression.

Topics: Aorta; Aortic Dissection; Apoptosis; Cell Proliferation; Female; Gene Expression Profiling; Humans; Hypertension; I-kappa B Proteins; Male; Matrix Metalloproteinase 2; Myocytes, Smooth Muscle; Osteopontin; Proto-Oncogene Proteins c-akt; Signal Transduction; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta

The aim of this study was to evaluate CD25

Topics: Aged; Aged, 80 and over; Antigens, CD; Aortic Dissection; Carotid Stenosis; Case-Control Studies; Female; Humans; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Interleukin-6; Lymphocyte Activation Gene 3 Protein; Male; Middle Aged; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Thoracic aortic aneurysm and dissection (TAAD) are severe vascular conditions. Dysfunctional transforming growth factor-β (TGF-β) signaling in vascular smooth muscle cells and elevated angiotensin II (AngII) levels are implicated in the development of TAAD. In this study, we investigated whether these 2 factors lead to TAAD in a mouse model and explored the possibility of using microRNA-21 (. TAAD was developed in. Our study demonstrated that

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Extracellular Signal-Regulated MAP Kinases; Genetic Predisposition to Disease; JNK Mitogen-Activated Protein Kinases; Male; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; Phosphorylation; Signal Transduction; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta

Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Case-Control Studies; Cells, Cultured; Dilatation, Pathologic; Disease Models, Animal; Female; Inflammation Mediators; Macrophages; Male; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Polymorphism, Single Nucleotide; Signal Transduction; Smad4 Protein; Transforming Growth Factor beta; Vascular Remodeling

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families.. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed.. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture.. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395.

Topics: Aortic Aneurysm, Thoracic; Aortic Dissection; Biglycan; Cells, Cultured; Female; Genes, X-Linked; Genetic Predisposition to Disease; Humans; Male; Mutation; Pedigree; Sequence Analysis, DNA; Signal Transduction; Transforming Growth Factor beta

To identify differentially expressed proteins from the aortic tissue of thoracic aortic dissection (TAD) with hypertension and normal aorta and to explore the potential molecular pathogenesis of TAD.. Aortic tissue samples were collected from two groups of age- and gender-matched patients with TAD and normal aorta. These samples were subjected to isobaric tags for relative and absolute quantitation analysis to identify the proteins involved in TAD. Signalling pathways were analysed using the Metacore software, and the identified proteins were validated by western blotting.. A total of 36 proteins were identified between two groups, with 19 of them being significantly down-regulated and 17 up-regulated in patients with TAD. Proteins including fibrillin-1, emilin-1, decorin, protein DJ-1 and histone H4 were validated by western blotting. The enrichment analysis performed using the Metacore process networks data showed that cell adhesion_cell-matrix interactions, proteolysis_extracellular matrix (ECM) remodelling and inflammation_interleukin 6 (IL-6) signalling were the main protein interaction networks involved in TAD. We further observed indications of increased transforming growth factor-β (TGF-β) signalling and impaired aortic wall remodelling, both of which may be molecular mechanisms for the pathogenesis of TAD.. The differentially expressed proteins identified in our study are mainly involved in cell-matrix interaction, ECM remodelling and inflammation. These mechanisms, combined with the TGF-β signalling pathway, may play an important role in the pathogenesis of TAD.

Topics: Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Humans; Isotope Labeling; Protein Interaction Maps; Proteome; Proteomics; Signal Transduction; Transforming Growth Factor beta

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Glycosaminoglycans; Humans; Transforming Growth Factor beta

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Glycosaminoglycans; Humans; Transforming Growth Factor beta

Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK).. In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway.. MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling.

Topics: Actins; Adolescent; Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Thoracic; Aortic Dissection; Cohort Studies; Female; Humans; Male; Middle Aged; Mutation; Myosin Heavy Chains; Pedigree; Signal Transduction; Transforming Growth Factor beta; Up-Regulation

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

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Aneurysm, Ruptured; Aortic Dissection; Celiprolol; Ehlers-Danlos Syndrome; Humans; Signal Transduction; Transforming Growth Factor beta; Vascular Diseases

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

Topics: Aged; Aged, 80 and over; Aortic Aneurysm; Aortic Dissection; Biomarkers, Tumor; Carcinoma, Hepatocellular; Fibrillin-1; Fibrillins; Humans; Liver Neoplasms; Male; Microfilament Proteins; Tomography, X-Ray Computed; Transforming Growth Factor beta