transforming-growth-factor-beta and Heart-Diseases

TGFβ superfamily includes the transforming growth factor βs (TGFβs), bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and Activin/Inhibin families of ligands. Among the 33 members of TGFβ superfamily ligands, many act on multiple types of cells within the heart, including cardiomyocytes, cardiac fibroblasts/myofibroblasts, coronary endothelial cells, smooth muscle cells, and immune cells (e.g. monocytes/macrophages and neutrophils). In this review, we highlight recent discoveries on TGFβs, BMPs, and GDFs in different cardiac residential cellular components, in association with functional impacts in heart development, injury repair, and dysfunction. Specifically, we will review the roles of TGFβs, BMPs, and GDFs in cardiac hypertrophy, fibrosis, contractility, metabolism, angiogenesis, and regeneration.

Topics: Animals; Bone Morphogenetic Proteins; Cell Survival; Fibroblasts; Growth Differentiation Factors; Heart Diseases; Humans; Hypertrophy; Ligands; Mice; Mice, Knockout; Myocytes, Cardiac; Regeneration; Signal Transduction; Transforming Growth Factor beta

Cardiac fibrosis is referred to as an excessive accumulation of stromal cells and extracellular matrix proteins in the myocardium. Progressive fibrosis causes stiffening of the cardiac tissue and affects conduction of electrical impulses, leading to heart failures in a broad range of cardiac conditions. At the cellular level, activation of the cardiac stromal cells and myofibroblast formation are considered as hallmarks of fibrogenesis. At the molecular level, transforming growth factor β (TGF-β) is traditionally considered as a master regulator of the profibrotic processes. More recently, the WNT signalling pathway has also been found to be implicated in the development of myocardial fibrosis. In this review, we summarize current knowledge on the involvement of TGF-β and WNT downstream molecular pathways to cardiac fibrogenesis and describe a crosstalk between these two profibrotic pathways. TGF-β and WNT ligands bind to different receptors and trigger various outputs. However, a growing body of evidence points to cross-regulation between these two pathways. It has been recognized that in cardiac pathologies TGF-β activates WNT/β-catenin signalling, which in turn stabilizes the TGF-β/Smad response. Furthermore both, the non-canonical TGF-β and non-canonical WNT signalling pathways, activate the same mitogen-activated protein kinases (MAPKs): the extracellular signal-regulated kinase (Erk), the c-Jun N-terminal kinases (JNKs) and p38. The crosstalk between TGF-β and WNT pathways seems to play an essential role in switching on the genetic machinery initiating profibrotic changes in the heart. Better understanding of these mechanisms will open new opportunities for development of targeted therapeutic approaches against cardiac fibrosis in the future.

Topics: Animals; Fibrosis; Heart Diseases; Humans; Mitogen-Activated Protein Kinases; Myofibroblasts; Protein Binding; Signal Transduction; Transforming Growth Factor beta; Wnt Proteins

Almost 30 years ago, the protein, atrial natriuretic peptide, was identified as a heart-secreted hormone that provides a peripheral signal from the myocardium that communicates to the rest of the organism to modify blood pressure and volume under conditions of heart failure. Since then, additional peripheral factors secreted by the heart, termed cardiokines, have been identified and shown to coordinate this interorgan cross talk. In addition to this interorgan communication, cardiokines also act in an autocrine/paracrine manner to play a role in intercellular communication within the myocardium. This review focuses on the roles of newly emerging cardiokines that are mainly increased in stress-induced cardiac diseases. The potential of these cardiokines as clinical biomarkers for diagnosis and prognosis of cardiac disorders is also discussed.

Topics: Activins; Animals; Biomarkers; Fibroblast Growth Factors; Follistatin; Follistatin-Related Proteins; Growth Differentiation Factor 15; Heart Diseases; Humans; Inflammation; Interleukin-33; Myocardium; Myostatin; Paracrine Communication; Stress, Physiological; Transforming Growth Factor beta

Elastin microfibril interface-located protein 1 (EMILIN1), a glycoprotein, is associated with elastin in the extracellular matrix (ECM) of arteries, lymph vasculature, and other tissues. EMILIN1 particularly has a niche role in elastin fiber biogenesis (elastogenesis) by aiding with the fusion of elastin fibers, rendering them more ordered. In addition to elastogenesis, EMILIN1 has been shown to have roles in maintenance of vascular cell morphology, smooth muscle cell adhesion to elastic fibers, and transforming growth factor (TGFβ) regulation, by inhibiting TGFβ activation via blocking the proteolytic production of the latency-associated peptide/active TGFβ complex. The increased TGFβ signaling induced during EMILIN1 deficiency alters TGFβ activity, resulting in vascular smooth muscle cell growth and vascular remodeling. The increasing systemic blood pressure associated with TGFβ signaling may be closely linked to the activity of other mediators that affect cardiovascular homeostasis, such as angiotensin II. The increase in prevalence of hypertension and other cardiovascular diseases in other disease states likely involve a complex activation of TGFβ signaling and ECM dysfunction. Thus, the interaction of TGFβ and ECM components appears to be integrative involving both structural alterations to vessels through EMILIN1 and changes in TGFβ signaling processes. This review summarizes the current knowledge on the EMILIN1-TGFβ relationship; the specific roles of EMILIN1 and TGFβ in blood pressure regulation, their synergistic interaction, and in particular the role of TGFβ (in conjunction with ECM proteins) in other disease states altering cardiovascular homeostasis.

Topics: Blood Pressure; Blood Vessels; Extracellular Matrix; Heart Diseases; Humans; Hypertension; Membrane Glycoproteins; Myocytes, Smooth Muscle; Peptides; Polymorphism, Single Nucleotide; Protein Precursors; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Hey bHLH transcription factors are direct targets of canonical Notch signaling. The three mammalian Hey proteins are closely related to Hes proteins and they primarily repress target genes by either directly binding to core promoters or by inhibiting other transcriptional activators. Individual candidate gene approaches and systematic screens identified a number of Hey target genes, which often encode other transcription factors involved in various developmental processes. Here, we review data on interaction partners and target genes and conclude with a model for Hey target gene regulation. Furthermore, we discuss how expression of Hey proteins affects processes like cell fate decisions and differentiation, e.g., in cardiovascular, skeletal, and neural development or oncogenesis and how this relates to the observed developmental defects and phenotypes observed in various knockout mice.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular System; Cell Cycle Proteins; Cell Differentiation; COUP Transcription Factor II; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Heart Diseases; Humans; Mice, Knockout; Muscle Development; Muscle, Smooth, Vascular; Neoplasms; Nuclear Receptor Coactivator 2; Receptors, Notch; Repressor Proteins; Transforming Growth Factor beta

There are a variety of pathophysiologic conditions that are known to induce skeletal muscle atrophy. However, muscle wasting can occur through multiple distinct signaling pathways with differential sensitivity between selective skeletal muscle fiber subtypes. This review summarizes some of the underlying molecular mechanisms responsible for fiber-specific muscle mass regulation.. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha protects slow-twitch oxidative fibers from denervation/immobilization (disuse)-induced muscle atrophies. Nutrient-related muscle atrophies, such as those induced by cancer cachexia, sepsis, chronic heart failure, or diabetes, are largely restricted to fast-twitch glycolytic fibers, of which the underlying mechanism is usually related to abnormality of protein degradation, including proteasomal and lysosomal pathways. In contrast, nuclear factor kappaB activation apparently serves a dual function by inducing both fast-twitch fiber atrophy and slow-twitch fiber degeneration.. Fast-twitch glycolytic fibers are more vulnerable than slow-twitch oxidative fibers under a variety of atrophic conditions related to signaling transduction of Forkhead box O family, autophagy inhibition, transforming growth factor beta family, and nuclear factor-kappaB. The resistance of oxidative fibers may result from the protection of peroxisome proliferator-activated receptor gamma coactivator 1-alpha.

Topics: Animals; Cachexia; Chronic Disease; Diabetes Mellitus; Disease Models, Animal; Forkhead Box Protein O1; Forkhead Transcription Factors; Glycolysis; Heart Diseases; Humans; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscular Atrophy; Muscular Diseases; NF-kappa B; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Sepsis; Signal Transduction; Transcription Factors; Transforming Growth Factor beta

Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, "activated" fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)beta, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFbeta, endothelin-1, Ang II, CCN2, and PDGF and to fibroblast activation in tissue repair and fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of cardiac fibrosis.

Topics: Angiotensin II; Animals; Cardiovascular Agents; Connective Tissue Growth Factor; Drug Design; Endothelin-1; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Heart Diseases; Humans; Myocardium; Platelet-Derived Growth Factor; Signal Transduction; Transforming Growth Factor beta

Diabetes mellitus is characterized by a lack of insulin causing elevated blood glucose, often with associated insulin resistance. Over time, especially in genetically susceptible individuals, such chronic hyperglycemia can cause tissue injury. One pathological response to tissue injury is the development of fibrosis, which involves predominant extracellular matrix (ECM) accumulation. The main factors that regulate ECM in diabetes are thought to be pro-sclerotic cytokines and protease/anti-protease systems. This review will examine the key markers and regulators of tissue fibrosis in diabetes and whether their levels in biological fluids may have clinical utility.

Topics: Animals; Basement Membrane; Biomarkers; Cardiomyopathies; Connective Tissue Growth Factor; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Endothelium, Vascular; Extracellular Matrix; Fatty Liver; Fibrosis; Glycation End Products, Advanced; Heart Diseases; Heart Failure; Humans; Hyperglycemia; Immediate-Early Proteins; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Liver Cirrhosis; Metalloproteases; Peptide Fragments; Procollagen; Renin-Angiotensin System; Transforming Growth Factor beta; Tunica Intima; Up-Regulation

The type beta transforming growth factors (TGF-betas) are involved in a number of human diseases, including heart failure and myocardial arrhythmias. In fact, during the last 20 years numerous studies have demonstrated that TGF-beta affects the architecture of the heart under both normal and pathological conditions. Moreover, TGF-beta signaling is currently under investigation, with the aim of discovering potential therapeutic roles in human disease. In contrast, only few studies have investigated whether TGF-beta affects electrophysiological properties of the heart. This fact is surprising since electrical remodeling represents an important substrate for cardiac disease. This review discusses the potential role of TGF-beta on cardiac excitation-contraction (EC) coupling, action potentials, and ion channels. We also discuss the effects of TGF-beta on cardiac development and disease from structural and electrophysiological points of view.

Topics: Action Potentials; Animals; Fibrosis; Heart; Heart Atria; Heart Conduction System; Heart Diseases; Heart Ventricles; Humans; Ion Channels; Myocardial Contraction; Myocardium; Signal Transduction; Transforming Growth Factor beta; Ventricular Remodeling

Topics: Active Transport, Cell Nucleus; Animals; Atrial Natriuretic Factor; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Heart Diseases; Humans; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) participates in the pathogenesis of multiple cardiovascular diseases, including hypertension, restenosis, atherosclerosis, cardiac hypertrophy and heart failure. TGF-beta exerts pleiotropic effects on cardiovascular cells, regulating cell growth, fibrosis and inflammation. TGF-beta has long been believed to be the most important extracellular matrix regulator. We review the complex mechanisms involved in TGF-beta-mediated vascular fibrosis that includes the Smad signaling pathway, activation of protein kinases and crosstalk between these pathways. TGF-beta blockade diminishes fibrosis in experimental models, however better antifibrotic targets are needed for an effective therapy in human fibrotic diseases. A good candidate is connective tissue growth factor (CTGF), a downstream mediator of TGF-beta-induced fibrosis. Among the different factors involved in vascular fibrosis, Angiotensin II (AngII) has special interest. AngII can activate the Smad pathway independent of TGF-beta and shares with TGF-beta many intracellular signals implicated in fibrosis. Blockers of AngII have demonstrated beneficial effects on many cardiovascular diseases and are now one of the best options to block TGF-beta fibrotic responses. A better knowledge of the intracellular signals of TGF-beta can provide novel therapeutic approaches for fibrotic diseases.

Topics: Animals; Fibrosis; Heart Diseases; Humans; Muscle, Smooth, Vascular; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

The importance of fibrosis in organ pathology and dysfunction appears to be increasingly relevant to a variety of distinct diseases. In particular, a number of different cardiac pathologies seem to be caused by a common fibrotic process. Within the heart, this fibrosis is thought to be partially mediated by transforming growth factor-beta1 (TGF-beta1), a potent stimulator of collagen-producing cardiac fibroblasts. Previously, TGF-beta1 had been implicated solely as a modulator of the myocardial remodelling seen after infarction. However, recent studies indicate that dilated, ischaemic and hypertrophic cardiomyopathies are all associated with raised levels of TGF-beta1. In fact, the pathogenic effects of TGF-beta1 have now been suggested to play a major role in valvular disease and arrhythmia, particularly atrial fibrillation. Thus far, medical therapy targeting TGF-beta1 has shown promise in a multitude of heart diseases. These therapies provide great hope, not only for treatment of symptoms but also for prevention of cardiac pathology as well. As is stated in the introduction, most reviews have focused on the effects of cytokines in remodelling after myocardial infarction. This article attempts to underline the significance of TGF-beta1 not only in the post-ischaemic setting, but also in dilated and hypertrophic cardiomyopathies, valvular diseases and arrhythmias (focusing on atrial fibrillation). It also aims to show that TGF-beta1 is an appropriate target for therapy in a variety of cardiovascular diseases.

Topics: Arrhythmias, Cardiac; Cardiomyopathies; Fibrosis; Heart Diseases; Heart Valve Diseases; Humans; Matrix Metalloproteinases; Myocardium; Transforming Growth Factor beta; Transforming Growth Factor beta1

Recent guidelines define chronic obstructive pulmonary disease (COPD) as a preventable and treatable disease characterized by airflow limitation and systemic consequences. Airflow limitation in COPD worsens over years as assessed by the forced expiratory volume in one second (FEV(1)). Regardless, while it is likely that cardiovascular and other systemic components also worsen as COPD progresses, there are no accepted or validated outcomes to measure such pathophysiologic changes as they relate to COPD disease progression. It is clear that health status in COPD is more closely related to levels of patients' physical functional capacity than it is to changes in FEV(1). Furthermore, the relative contributions of pathoanatomic changes such as small airways fibrosis and pulmonary emphysema to declining airflow remain unknown. These features may even progress at different rates in the same individuals. Although stopping smoking is the only intervention shown to alter the relentless progression of COPD, the resultant slowing of FEV(1) decline takes several years to evince and requires at least 1,000 subjects to demonstrate annual therapeutic benefits of as little as 20 ml. The FEV(1) cannot distinguish between peribronchiolar fibrosis and emphysema and it is feasible that, as techniques are developed and validated, lung imaging methodologies may become important and sensitive outcomes measures of time- and age-dependent lung structural changes in COPD. The development of biomarkers of lung damage, pulmonary inflammation, and systemic disease will be essential to our further understanding of the natural history of COPD and the discovery of new, effective treatments for its progression.

Topics: Animals; Biomarkers; Comorbidity; Disease Progression; Forced Expiratory Volume; Heart Diseases; Humans; Magnetic Resonance Imaging; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Respiratory Mechanics; Smoking; Smoking Cessation; Transforming Growth Factor beta; Treatment Outcome

Transforming growth factor (TGF-beta) is a multifunctional peptide growth factor that has an important role in the regulation of cell growth, differentiation, and repair in a variety of tissues. In mammals, the cytokine has three isoforms, TGF-beta1, TGF-beta2, and TGF-beta3. TGF- beta1 is up-regulated by Ang II and induction of TGF-beta1 causes cardiac fibrosis. The stimulus that triggers the expression of TGF-beta1 may be repeated causing continual injury, which is associated with an increase in the activity of Ang II in heart tissue. The interplay between Ang II and TGF-beta1 causes continued activation that may result in chronic hypertension and progressive myocardial fibrosis, leading to heart failure. The regulation of TGF-beta1 secretion and action involves complex transcriptional events. Overproduction of TGF-beta1 underlies tissue fibrosis. Understanding the actions and signaling transduction of TGF-beta could lead to the development of therapeutic options that may be effective in inhibiting myocardial fibrosis triggered by TGF-beta1 in heart failure.

Topics: Angiotensin II; Animals; Cardiac Output, Low; Chronic Disease; Disease Progression; Heart Diseases; Humans; Myocardium; Signal Transduction; Transforming Growth Factor beta; Ventricular Remodeling

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

Topics: Animals; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression Regulation; Genetic Therapy; Heart Diseases; Humans; Matrix Metalloproteinases; Muscle, Smooth, Vascular; Myocardium; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Ventricular Remodeling

Topics: Angiotensin II; Heart Diseases; Humans; Kidney Diseases; Models, Biological; Signal Transduction; Transforming Growth Factor beta

1. Transforming growth factors-beta (TGF-beta) are multifunctional proteins that regulate cell growth, differentiation, migration and extracellular matrix production and have an important role in embryonic development and tissue remodelling. 2. The diverse biological actions of TGF-beta are elicited following their interaction with type I and type II TGF-beta receptors, both of which are transmembrane serine/threonine kinases, suggesting an important role for protein phosphorylation in the mechanism of action of these cytokines on the growth of cells and their extracellular environment. 3. Alterations in TGF-beta gene expression and action in various cell types associated with the cardiovascular system may contribute to the pathophysiology of a number of diseases, such as hypertension, atherosclerosis and restenosis, as well as the development of cardiac abnormalities.

Topics: Animals; Arteriosclerosis; Cardiovascular System; ErbB Receptors; Heart Diseases; Humans; Hypertension; Receptors, Transforming Growth Factor beta; Second Messenger Systems; Transforming Growth Factor beta

To better understand the formation of the cardiovascular system and its disease states, models amenable to manipulation must be developed. In this article we present two models. One is a small animal model for an inflammatory disorder that can lead to heart failure. Production of this model is based on the ability of blastocyst-derived embryonic stem cells, which can be genetically altered in vitro by a technique called gene targeting, to reconstitute an entire animal when reintroduced into a blastocyst and allowed to colonize the germ line of the resulting chimeric embryo. The other model is based on the capacity of embryonic stem cells to differentiate in culture into embryo-like structures called embryoid bodies. Embryoid bodies contain angioblasts, or prevascular endothelial cells, which can be induced to undergo aspects of vascular development by manipulation of culture conditions.

Topics: Animals; Blood Vessels; Cell Differentiation; Disease Models, Animal; Embryo, Mammalian; Embryo, Nonmammalian; Embryonic and Fetal Development; Genetic Engineering; Heart Diseases; Myocarditis; Stem Cells; Transforming Growth Factor beta

Cardiac fibrosis increases with age. Fibroblast activation plays an essential role in cardiac fibrosis. Histone modifications are involved in various chromatin-dependent processes. Attenuation of the histone H3 trimethylation on lysine 27 demethylase UTX by RNA interference or heterozygous mutation extends lifespan in worm. The objective of this study was to explore whether epigenetic silencing of UTX mitigates aging-associated cardiac fibrosis.. Middle-aged mice (15 months old) were used and started to receive adeno-associated virus-scrambled-small hairpin RNA and adeno-associated virus-UTX-small hairpin RNA every 3 months from 15 months to 21 months, respectively. The mice were euthanized at 24 months of age (length of the study).. Adeno-associated virus-UTX-small hairpin RNA delivery significantly attenu-ated aging-associated increase in blood pressure, especially in diastolic blood pressure, indicating silencing of UTX rescued aging-associated cardiac dysfunction. Aging-associated cardiac fibrosis is characterized by fibroblast activation and abundant extracellular matrix deposition, including collagen deposition and alpha smooth muscle actin activation. Silencing of UTX abolished collagen deposition and alpha smooth muscle actin activation, decreased serum transforming growth factor β, blocked cardiac fibro blast s-to- myofi brobl asts trans-differentiation by elevation of cardiac resident mature fibroblast markers, TCF21, and platelet-derived growth factor receptor alpha, which are important proteins for maintaining cardiac fibroblast physiological function. In the mechanistic study, adeno-associated virus-UTX-small hairpin RNA blocked transforming growth factor β-induced cardiac fibro blast s-to- myofi brobl asts trans-differentiation in isolated fibroblasts from 24-month-old mouse heart. The same results demonstrated as the in vivo study.. Silencing of UTX attenuates aging-associated cardiac fibrosis via blocking cardiac fibroblasts-to-myofibroblasts transdifferentiation and consequently attenuates aging-associated cardiac dysfunction and cardiac fibrosis.

Topics: Actins; Aging; Animals; Cardiomyopathies; Cell Transdifferentiation; Cells, Cultured; Collagen; Fibroblasts; Fibrosis; Heart Diseases; Mice; Myocardium; Myofibroblasts; RNA, Small Interfering; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

An inappropriate accumulation of fibrillar collagen is a common pathologic feature of early aged hypertensive heart disease, but little information regarding the effects of exercise training on cardiac fibrosis in hypertension is available. The purpose of this study was to evaluate the effects of exercise training on cardiac fibrotic pathways in early aged hypertensive rats.. Masson's trichrome staining and Western blotting were performed on the excised left ventricle from twenty male spontaneously hypertensive rats at age of 48 weeks, which were randomly divided into either a sedentary hypertensive group (SHR) or exercise hypertensive group (SHR-EX, running on a treadmill running occurred 5 days/week for 60 min/day, for 12 weeks), and from age-matched male Wistar-Kyoto normotensive controls (WKY).. Exercise training suppresses early aged hypertensive heart-induced LOX-2/TGF-β-mediated fibrotic pathways associated with decreasing AT

Topics: Animals; Exercise Therapy; Fibrosis; Heart Diseases; Hypertension; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

Rapid eye movement (REM) sleep deprivation triggers mania and induces cardiac fibrosis. Beyond neuroprotection, lithium has cardioprotective potential and antifibrotic activity. This study investigated whether lithium improved REM sleep deprivation-induced cardiac dysfunction and evaluated the potential mechanisms. Transthoracic echocardiography, histopathological analysis, and Western blot analysis were performed in control and REM sleep-deprived rats with or without lithium treatment (LiCl of 1 mmol/kg/day administered by oral gavage for 4 weeks) in vivo and in isolated ventricular preparations. The results revealed that REM sleep-deprived rats exhibited impaired contractility and greater fibrosis than control and lithium-treated REM sleep-deprived rats. Western blot analysis showed that REM sleep-deprived hearts had higher expression levels of transforming growth factor beta (TGF-β), phosphorylated Smad 2/3, and alpha-smooth muscle actin than lithium-treated REM sleep-deprived and control hearts. Moreover, lithium-treated REM sleep-deprived hearts had lower expression of angiotensin II type 1 receptor, phosphorylated nuclear factor kappa B p65, calcium release-activated calcium channel protein 1, transient receptor potential canonical (TRPC) 1, and TRPC3 than REM sleep-deprived hearts. The findings suggest that lithium attenuates REM sleep deprivation-induced cardiac fibrogenesis and dysfunction possibly through the downregulation of TGF-β, angiotensin II, and Ca

Topics: Actins; Angiotensin II; Animals; Heart Diseases; Lithium; Lithium Compounds; NF-kappa B; ORAI1 Protein; Rats; Receptor, Angiotensin, Type 1; Sleep Deprivation; Sleep, REM; Transforming Growth Factor beta

Sudden unexpected death in epilepsy (SUDEP) is a major outcome of cardiac dysfunction in patients with epilepsy. In continuation of our previous work, the present study was envisaged to explore the key regulators responsible for cardiac damage associated with chronic seizures using whole transcriptome and proteome analysis in a rat model of temporal lobe epilepsy.. A standard lithium-pilocarpine protocol was used to induce recurrent seizures in rats. The isolated rat heart tissue was subjected to transcriptomic and proteomic analysis. An integrated approach of RNA-Seq, proteomics, and system biology analysis was used to identify key regulators involved in seizure-linked cardiac changes. The analyzed differential expression patterns and network interactions were supported by gene and protein expression studies.. Altogether, 1157 differentially expressed genes and 1264 proteins were identified in the cardiac tissue of epileptic animals through RNA-Seq and liquid chromatography with tandem mass spectrometry-based proteomic analysis, respectively. The network analysis revealed seven critical genes-STAT3, Myc, Fos, Erbb2, Erbb3, Notch1, and Mapk8-that could play a role in seizure-mediated cardiac changes. The LC-MS/MS analysis supported the activation of the transforming growth factor β (TGF-β) pathway in the heart of epileptic animals. Furthermore, our gene and protein expression studies established a key role of STAT3, Erbb, and Mapk8 to develop cardiac changes linked with recurrent seizures.. The present multi-omics study identified STAT3, Mapk8, and Erbb as key regulators involved in seizure-associated cardiac changes. It provided a deeper understanding of molecular, cellular, and network-level operations of the identified regulators that lead to cardiac changes in epilepsy.

Topics: Animals; Chromatography, Liquid; Disease Models, Animal; Epilepsy; Gene Expression Profiling; Gene Regulatory Networks; Heart Diseases; Lithium Chloride; Mitogen-Activated Protein Kinase 8; Muscarinic Agonists; Myocardium; Pilocarpine; Proteome; Proteomics; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-myc; Rats; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2; Receptor, ErbB-3; Receptor, Notch1; RNA-Seq; Signal Transduction; STAT3 Transcription Factor; Tandem Mass Spectrometry; Time Factors; Transforming Growth Factor beta

In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear

Topics: Animals; Chromatin; Enhancer Elements, Genetic; Epigenomics; Fibroblasts; Gene Expression Regulation; Heart Diseases; Homeodomain Proteins; Humans; Mice; Proteins; Single-Cell Analysis; Transcription Factors; Transcriptome; Transforming Growth Factor beta

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

Topics: Adolescent; Adult; Aged; Animals; Cardiomyopathies; Extracellular Matrix Proteins; Female; Fibrosis; Gene Expression Regulation; Gene Regulatory Networks; Genetic Predisposition to Disease; Heart Diseases; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Protein Isoforms; Smad2 Protein; Transforming Growth Factor beta; Ubiquitin-Protein Ligases; Young Adult

Consumption of high fat diet (HFD) is associated with increased cardiovascular risk factors among elderly people. Aging and obesity induced-cardiac remodeling includes hypertrophy and fibrosis. Gelsolin (GSN) induces cardiac hypertrophy and TGF-β, a key cytokine, which induces fibrosis. The relationship between TGF-β and GSN in aging induced cardiac remodeling is still unknown. We evaluated the expressions of TGF-β and GSN in HFD fed 22 months old aging SD rats, followed by the administration of either probucol or alcalase potato protein hydrolysate (APPH). Western blotting and Masson trichrome staining showed that APPH (45 and 75 mg/kg/day) and probucol (500 mg/kg/day) treatments significantly reduced the aging and HFD-induced hypertrophy and fibrosis. Echocardiograph showed that the performance of the hearts was improved in APPH, and probucol treated HFD aging rats. Serum from all rats was collected and H9c2 cells were cultured with collected serums separately. The GSN dependent hypertrophy was inhibited with an exogenous TGF-β in H9c2 cells cultured in HFD+ APPH treated serum. Thus, we propose that along with its role in cardiac fibrosis, TGF-β also acts as an upstream activator of GSN dependent hypertrophy. Hence, TGF-β in serum could be a promising therapeutic target for cardiac remodeling in aging and/or obese subjects.

Topics: Administration, Oral; Aging; Animals; Cells, Cultured; Diet, High-Fat; Gelsolin; Heart Diseases; Myocardium; Obesity; Protein Hydrolysates; Rats; Rats, Sprague-Dawley; Signal Transduction; Solanum tuberosum; Subtilisins; Transforming Growth Factor beta

Transforming growth factor-β (TGF-β) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF-β1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF-β1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac fibroblasts (NMCFs), we found that exogenous TGF-β1 induced the upregulation of TGF-β1 itself in a time- and dose-dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML-NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF-β signal or Pin1 with LY364947 (3 μM) or Juglone (3 μM), the TGF-β1-induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF-β1 and Pin1. To verify the cellular function of PML by means of gain- or loss-of-function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF-β-Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF-β1/PML SUMOylation/Pin1 leading to myocardial fibrosis.

Topics: Animals; Feedback, Physiological; Fibrosis; Heart; Heart Diseases; Mice; Myocardium; NIMA-Interacting Peptidylprolyl Isomerase; Promyelocytic Leukemia Protein; Sumoylation; Transforming Growth Factor beta

It is well known that obesity contributes to the development of systemic inflammatory responses, which in turn may be involved in the process of interstitial fibrosis and left ventricular (LV) remodelling. Activation of pro-inflammatory factors such as transforming growth factor β (TGF-β) can directly stimulate mitogen-activated protein kinase (MAPK) p38 and JNK. The aim of the study was to evaluate the level of TGF-β and MAPK p38 and JNK in the LV in Sprague Dawley (SPRD) rats maintained on a high fat diet (HFD). The SPRD rats from 4 weeks of age were on a normal fat diet (NFD) or a HFD for 12 weeks (NFD-16-week-old rats, NFD 16-wk; or HFD-16-week-old rats, HFD 16-wk) or 16 weeks (NFD-20-week-old rats, NFD 20-wk; or HFD-20-week-old rats, HFD 20-wk). At the end of the experiment, blood and LV were collected from all rats for further analysis (biochemical, Real Time PCR and immunohistochemical analysis). TGF-β mRNA expression did not differ between the study groups of rats. However, p38 MAPK mRNA expression was significantly lower in the HFD 20-wk rats than in both the HFD 16-wk rats and the NFD 20-wk rats. c-jun mRNA expression was significantly higher in the HFD 16-wk rats than in the NFD 16-wk rats. There was significantly lower expression of c-jun mRNA in the HFD 20-wk rats and in the NFD 20-wk rats than in the HFD 16-wk rats and in the NFD 16-wk rats, respectively. TGF-β type II receptor (TβRII) protein demonstrated only cytoplasmic reactivity, while p38 MAPK protein and c-jun protein showed both nuclear and cytoplasmic reactivity. The results suggest that a high fat diet and in two time intervals significantly influence the expression of p38 MAPK and JNK in the LV. However, demonstrating their potential involvement in the processes of interstitial myocardial fibrosis and left ventricular remodeling requires further research.

Topics: Animals; Diet, High-Fat; Fibrosis; Heart Diseases; Heart Ventricles; Male; Myocardium; Obesity; p38 Mitogen-Activated Protein Kinases; Rats; Transforming Growth Factor beta

AMP-activated protein kinase (AMPK) is a central regulator of multiple metabolic pathways. It has been shown that activation of AMPK could inhibit fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby suppressing cardiac fibrosis. Baicalin, the major component found in skullcap, possesses multiple protective effects on the cardiovascular system. However, little is known about the effect of baicalin on cardiac fibrosis and the molecular mechanism by which baicalin exerts its anti-fibrotic effects has not been investigated. In this study, we revealed that baicalin could inhibit cell proliferation, collagen synthesis, fibronectin (FN) and Connective tissue growth factor (CTGF) protein expression in cardiac fibroblasts induced by angiotensin Ⅱ (Ang Ⅱ). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, baicalin inhibited transforming growth factor-β (TGF-β)/Smads signaling pathway stimulated with Ang Ⅱ through activating AMPK. Subsequently, we also demonstrated that baicalin attenuated Ang Ⅱ-induced Smad3 nuclear translocation, and interaction with transcriptional coactivator p300, but promoted the interaction of p300 and AMPK. Taken together, these results provide the first evidence that the effect of baicalin against cardiac fibrosis may be attributed to its regulation on AMPK/TGF-β/Smads signaling, suggesting the therapeutic potential of baicalin on the prevention of cardiac fibrosis and heart failure.

Topics: Angiotensin II; Animals; Cells, Cultured; Collagen; Connective Tissue Growth Factor; Dose-Response Relationship, Drug; Fibronectins; Fibrosis; Flavonoids; Heart Diseases; Myocardium; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Background Transforming growth factor beta ( TGF -β) is an important cytokine in mediating the cardiac fibrosis that often accompanies pathogenic cardiac remodeling. Cardiomyocyte-specific expression of a mutant αB-crystallin (Cry AB

Topics: alpha-Crystallin B Chain; Analysis of Variance; Animals; Cardiomyopathies; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Heart Diseases; Male; Mice, Transgenic; Muscular Dystrophies; Myocardium; Myocytes, Cardiac; Myofibroblasts; Receptor, Transforming Growth Factor-beta Type II; Signal Transduction; Transforming Growth Factor beta

The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β-Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload-induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload-induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast-specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β-Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.

Topics: Animals; Fibrosis; Gene Deletion; Heart Diseases; Male; Mice; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Myofibroblasts; Organ Specificity; 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; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta

Besides environmental risk factors, genetic factors play a crucial role in the pathogenesis of primary hypertension. The current study is to unravel whether hypertensive phenotypes vary in mice with different genetic background.. Hypertension was induced in C57BL/6J (B6), DBA/2J (D2), and 25 BXD strains by administrating angiotensin (Ang)II (2.5 mg/kg/day infused by osmotic minipump) for 4 weeks. Systolic blood pressure was monitored before (baseline) and after 4 weeks of AngII treatment by tail cuff. Cardiac and renal fibrosis was evaluated by picrosirius red staining and collagen volume fraction (CVF) was quantitated using imaging analyzing system; cardiac transforming growth factor (TGF)-β gene expression was monitored by RT-PCR, and inflammatory response was detected by immunohistochemical ED-1 staining.. AngII infusion caused hypertension in all strains. However, blood pressure elevation was more evident in the D2 strain than the B6 group, while it was widely variable among BXD strains. Furthermore, chronic AngII treatment lead to development of hypertensive cardiac and renal diseases. Cardiac and renal CVF levels in the D2 strain was significantly higher than the B6 cohort, whereas these varied vastly across BXD strains. Moreover, cardiac TGF-β mRNA levels were markedly diverse among various mouse strains.. Our study unequivocally demonstrates that in response to AngII, BXDs with different genetic background expressed hypertension phenotypes with varied degree in severity. It implicates that genomics contribute to pathogenesis of primary hypertension. Building upon the genotype and hypertensive phenotypes, the BXD cohort can be further exploited experimentally to identify genes that influence blood pressure.

Topics: Angiotensin II; Animals; Blood Pressure; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Phenotype; Species Specificity; Transforming Growth Factor beta; Vasoconstrictor Agents

Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA-126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR-126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126

Topics: Actins; Animals; Animals, Newborn; Brain; Cells, Cultured; Chemokine CCL2; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation; Heart Diseases; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Myocardium; Myocytes, Cardiac; NADPH Oxidase 2; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Obesity is a major health problem in modern society because their progression is always associated with many health issues. The major among them is developing the cardiovascular disease because as the obesity prolonged it results with cardiac remodelling and finally results in the dysfunction of the cardiac system. Many genes are associated with developing the obesity-linked cardiac dysfunction and it should be evaluated at different pathological stages of obesity.. In the present studies, we analyzed the expression pattern of Smad6 and TGF-β using obesity-induced mice model which are ob/ob-/- deficient. The pathology of disease progression in initial and aggressive stage of cardiac dysfunction are studied together with Smad6 and TGF-β expression.. The mice develop initial stages of cardiac dysfunction on 3rd month and advanced stage of cardiac dysfunction on the 6th month. The results with histology show as the dysfunction progress it shows cellular lesions associated with enlarged cells. Immunochemistry with Smad6 represents that its expression positively regulate and repair the initial lesion but it has no role in the aggressive form of cardiac dysfunction and at that stage their expression downregulated. The results with TGF-β show initial upregulation in repairing the damage but in latter stage its expression many fold increases and it takes part in the inflammatory response.. Overall our results show aberrant expression of Smad6 and TGF-β at different stages of obesity linked cardiac dysfunction.

Topics: Animals; Heart Diseases; Mice; Obesity; Signal Transduction; Smad6 Protein; Transforming Growth Factor beta

Obstructive sleep apnea (OSA) associated with chronic intermittent hypoxia (CIH) increases the morbidity and mortality of ischemic heart disease in patients. Yet, there is a paucity of preventive measures targeting the pathogenesis of CIH-induced myocardial injury. We examined the cardioprotective effect of melatonin against the inflammation, fibrosis and the deteriorated sarcoplasmic reticulum (SR) Ca(2+) homeostasis, and ischemia/reperfusion (I/R)-induced injury exacerbated by CIH. Adult male Sprague Dawley rats that had received a daily injection of melatonin (10 mg/kg) or vehicle were exposed to CIH treatment mimicking a severe OSA condition for 4 wk. Systolic pressure, heart weights, and malondialdehyde were significantly increased in hypoxic rats but not in the melatonin-treated group, when compared with the normoxic control. Levels of the expression of inflammatory cytokines (TNF-α, IL-6, and COX-2) and fibrotic markers (PC1 and TGF-β) were significantly elevated in the hypoxic group but were normalized by melatonin. Additionally, infarct size of isolated hearts with regional I/R was substantial in the hypoxic group treated with vehicle but not in the melatonin-treated group. Moreover, melatonin treatment mitigated the SR-Ca(2+) homeostasis in the cardiomyocyte during I/R with (i) Ca(2+) overloading, (ii) decreased SR-Ca(2+) content, (iii) lowered expression and activity of Ca(2+) -handling proteins (SERCA2a and NCX1),and (iv) decreased expressions of CAMKII and phosphorylated eNOS(ser1177). Furthermore, melatonin ameliorated the level of expression of antioxidant enzymes (CAT and MnSOD) and NADPH oxidase (p22 and NOX2). Results support a prophylactic usage of melatonin in OSA patients, which protects against CIH-induced myocardial inflammation and fibrosis with impaired SR-Ca(2+) handling and exacerbated I/R injury.

Topics: Animals; Antioxidants; Biomarkers; Cardiotonic Agents; Chronic Disease; Cytokines; Gene Expression Regulation; Heart Diseases; Hypoxia; Male; Melatonin; Myocardium; Rats; Sleep Apnea, Obstructive; Transforming Growth Factor beta

Cardiac fibrosis is one of the key structural changes of the hypertrophied left ventricle in hypertensive heart disease. Increased angiotensin II was found to be important in the hypertension related fibrosis, while the underlying mechanism is unknown. In this study, we found that angiotensin II dose-dependently increased the expression of Col1a1, Col3a1 and α-smooth muscle actin, which were blocked by ROS (reactive oxygen species) scavenger N-acetyl cysteine (NAC). Mechanistically, angiotensin II induced robust ROS generation, which in turn induced cytoplasmic translocation of RNA binding protein HuR. Cytoplasmic translocated HuR increased TGFβ pathway activity and subsequent collagen synthesis. In contrast, knockdown of HuR nearly blocked angiotensin II induced TGFβ activation and collagen synthesis. Taken together, we here identified that angiotensin II promotes collagen synthesis in cardiac fibroblast through ROS-HuR-TGFβ pathway.

Topics: Acetylcysteine; Angiotensin II; Animals; Collagen; Cytoplasm; Dose-Response Relationship, Drug; ELAV Proteins; Heart Diseases; Male; Mice; Mice, Inbred C57BL; Protein Transport; Reactive Oxygen Species; Transforming Growth Factor beta

We investigated the association between left ventricular (LV) torsional deformation and vascular dysfunction, fibrosis, neurohumoral activation, and exercise capacity in patients with normal ejection fraction. In 320 newly-diagnosed untreated hypertensive patients and 160 controls, we measured: pulse wave velocity (PWV); coronary flow reserve (CFR) by Doppler echocardiography; global longitudinal strain and strain rate, peak twisting, the percentage changes between peak twisting, and untwisting at mitral valve opening (%dpTw - UtwMVO ), at peak (%dpTw - UtwPEF ), and the end of early LV diastolic filling (%dpTw - UtwEDF ) by speckle tracking imaging; transforming growth factor (TGFb-1), metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloptoteinase-1(TIMP-1), markers of collagen synthesis, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Oxygen consumption (VO2 ), measured by means of cardiopulmonary exercise test, was assessed in a subset of 80 patients. The PWV, CFR, longitudinal strain and strain rate, %dpTw-UtwMVO , %dpTw-UtwPEF , and %dpTw-UtwEDF were impaired in hypertensive patients compared with controls. In multivariable analysis, CFR, PWV, LV mass, and systolic blood pressure were independent determinants of longitudinal strain, strain rate, and untwisting markers (P < 0.05). Increased TGFb-1 was related with increased collagen synthesis markers, TIMP-1 and MMP-9 and these biomarkers were associated with impaired longitudinal systolic strain rate, untwisting markers, CFR and PWV (P < 0.05). Delayed untwisting as assessed by reduced %dpTw - UtwEDF was related with increased NT-proBNP and reduced VO2 (P < 0.05).. Impaired LV untwisting is associated with increased arterial stiffness and coronary microcirculatory dysfunction, and is linked to reduced exercise capacity and neurohumoral activation in hypertensive heart disease. A fibrotic process may be the common link between vascular dysfunction and abnormal myocardial deformation.

Topics: Biomarkers; Blood Pressure; Echocardiography; Female; Heart Diseases; Heart Ventricles; Humans; Hypertension; Male; Matrix Metalloproteinase 9; Middle Aged; Mitral Valve; Natriuretic Peptide, Brain; Peptide Fragments; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD), and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD). Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263) probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD)-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day) were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor β (TGF-β) expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease.

Topics: Animals; Cricetinae; Diet, High-Fat; Fatty Liver; Fibrosis; Heart Diseases; Limosilactobacillus reuteri; Male; Obesity; Probiotics; Transforming Growth Factor beta

Aristolochia yunnanensis, known as Nan Mu Xiang in traditional Chinese medicine, has long been used to treat hypertension and chest pain. In this study, the effect of ethyl acetate extract of Nan Mu Xiang (NMX) on cardiac fibrosis was assessed in vitro by cultured adult rat cardiac fibroblasts with angiotensin II (AngII) stimulation, and in vivo by rats with abdominal aorta constriction (AAC). In cultured adult rat cardiac fibroblasts stimulated by AngII, NMX inhibited cardiac fibroblast proliferation, reduced the expression of fibronectin, α-smooth muscle actin (α-SMA), and transforming growth factor β (TGF-β) in a dose-dependent manner; and suppressed AngII-induced phosphorylation of extracellular signal-regulated kinase (ERK)1/2, C- rapidly accelerated fibrosarcoma (C-Raf), and small mother against decapentaplegic (Smad) 2. Similar results were also observed in AAC rats with intraperitoneal injection of NMX, which not only ameliorated myocardial fibrosis, but also improved cardiac function. The therapeutic effect of NMX on myocardial fibrosis is attributed mainly to the inhibition of ERK and the TGF-β/Smad signaling pathways. NMX may be a promising potential drug candidate for myocardial fibrosis.

Topics: Acetates; Animals; Aristolochia; Fibrosis; Heart Diseases; MAP Kinase Signaling System; Plant Extracts; Rats; Signal Transduction; Transforming Growth Factor beta

Nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) is a pattern recognition receptor that is implicated in the pathogenesis of inflammation and chronic diseases. Although much is known regarding the NLRP3 inflammasome that regulates proinflammatory cytokine production in innate immune cells, the role of NLRP3 in non-professional immune cells is unclear. Here we report that NLRP3 is expressed in cardiac fibroblasts and increased during TGFβ stimulation. NLRP3-deficient cardiac fibroblasts displayed impaired differentiation and R-Smad activation in response to TGFβ. Only the central nucleotide binding domain of NLRP3 was required to augment R-Smad signaling because the N-terminal Pyrin or C-terminal leucine-rich repeat domains were dispensable. Interestingly, NLRP3 regulation of myofibroblast differentiation proceeded independently from the inflammasome, IL-1β/IL-18, or caspase 1. Instead, mitochondrially localized NLRP3 potentiated reactive oxygen species to augment R-Smad activation. In vivo, NLRP3-deficient mice were protected against angiotensin II-induced cardiac fibrosis with preserved cardiac architecture and reduced collagen 1. Together, these results support a distinct role for NLRP3 in non-professional immune cells independent from the inflammasome to regulate differential aspects of wound healing and chronic disease.

Topics: Angiotensin II; Animals; Carrier Proteins; Collagen Type I; Fibrosis; Heart Diseases; Inflammasomes; Interleukin-18; Interleukin-1beta; Mice; Mice, Knockout; Mitochondrial Proteins; Myocardium; Myofibroblasts; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Signal Transduction; Smad Proteins, Receptor-Regulated; Transforming Growth Factor beta; Vasoconstrictor Agents

Interaction of doxorubicin DOX with iron and the consequent generation of reactive oxygen species (ROS) is a major player in DOX-induced cardiomyopathy. Accordingly, this study has been initiated to investigate the preventive effect of the iron chelator, desferrioxamine (DFX), against DOX-induced acute cardiotoxicity in rats. Male Wistar albino rats were divided into four groups and were injected intraperitoneally (I.P.) with normal saline, a single dose of DOX (15 mg/kg), a single dose of DFX (250 mg/kg) and a combined treatment with DFX (250 mg/kg) 30 min prior to a single dose of DOX, (15 mg/kg). A single dose of DOX significantly increased mRNA expression of TGF-β, Smad2, Smad4, CDKN2A and p53 and significantly decreased Samd7 and Mdm2 mRNA expression levels. Administration of DFX prior to DOX resulted in a complete reversal of DOX-induced alteration in cardiac enzymes and gene expression to normal levels. Data from this study suggest that (1) DOX induces its acute cardiotoxicity secondary to increasing genes expression of TGF-β/Smad pathway. (2) DOX increases apoptosis through upregulation of CDKN2A and p53 and downregulation of Mdm2 gene expression. (3) The preventive effect of DFX against DOX-induced cardiotoxicity is mediated via the TGF-β1/Smad pathway.

Topics: Animals; Cardiotoxins; Deferoxamine; Disease Models, Animal; Doxorubicin; Gene Expression Regulation; Heart Diseases; Isoenzymes; Male; Rats; Rats, Wistar; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Aging impairs function in the nonischemic heart and is associated with mechanical remodeling. This process includes accumulation of collagen (i.e., fibrosis) and dysregulation of active matrix metalloproteinases (MMPs). Exercise training (ET) improves cardiac function, but the pathways of protection remain poorly understood. Young (3 mo) and old (31 mo) FBNF1 rats were assigned into sedentary and exercise groups, with ET group rats training on a treadmill 45 min/d, 5 d/wk for 12 wk. Nonlinear optical microscopy (NLOM), histology, immunohistochemistry (IHC), and Western blot analyses were performed on the left ventricle and septum. NLOM, IHC, and histological imaging revealed that ET reduced age-associated elevation of collagen type I fibers. Active MMP-1, active MMP-2, and MMP-14 in the ECM fraction of the left ventricle were reduced by aging, an effect abrogated by ET. Tissue inhibitor of MMP (TIMP-1) was elevated with age but protected by ET. Transforming growth factor-β (TGF-β), upstream regulator of TIMP-1, increased with age but was attenuated by ET. Therefore, exercise training could protect the aging heart against dysregulation of MMPs and fibrosis by suppressing elevation of TIMP-1 and TGF-β.

Topics: Aging; Animals; Fibrosis; Heart Diseases; Matrix Metalloproteinase 1; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Matrix Metalloproteinase 3; Matrix Metalloproteinases; Myocardium; Physical Conditioning, Animal; Rats; Rats, Inbred BN; Rats, Inbred F344; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Ventricular Remodeling

Topics: Aldosterone; Biomarkers; Carrier Proteins; Collagen; Connective Tissue Growth Factor; Heart Diseases; Heart Failure; Humans; Matrix Metalloproteinase 1; Myocardium; Myocytes, Cardiac; Peptide Fragments; Procollagen; Stroke Volume; Transforming Growth Factor beta

Elevated levels of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of urokinase plasminogen activator and tissue plasminogen activator, are implicated in the pathogenesis of tissue fibrosis. Paradoxically, lack of PAI-1 in the heart is associated with the development of cardiac fibrosis in aged mice. However, the molecular basis of cardiac fibrosis in aged PAI-1-deficient mice is unknown. Here, we investigated the molecular and cellular bases of myocardial fibrosis.. Histological evaluation of myocardial tissues derived from aged PAI-1-deficient mice revealed myocardial fibrosis resulting from excessive accumulation of collagen. Immunohistochemical characterization revealed that the levels of matrix metalloproteinase-2, matrix metalloproteinase-9, and transforming growth factor-β1/2 and the number of Mac3-positive and fibroblast specific protein-1-positive cells were significantly elevated in aged PAI-1-deficient myocardial tissues compared with controls. Zymographic analysis revealed that matrix metalloproteinase-2 enzymatic activity was elevated in PAI-1-deficient mouse cardiac endothelial cells. Real-time quantitative polymerase chain reaction analyses of RNA from myocardial tissues revealed the upregulation of profibrotic markers in aged PAI-1-deficient mice. The numbers of phosphorylated Smad2-, phosphorylated Smad3-, and phosphorylated ERK1/2 MAPK-, but not pAkt/PKB-, positive cells were significantly increased in PAI-1-deficient myocardial tissues. Western blot and immunocytochemical analysis revealed that PAI-1-deficient mouse cardiac endothelial cells were more susceptible to endothelial-to-mesenchymal transition in response to transforming growth factor-β2.. These results indicate that spontaneous activation of both Smad and non-Smad transforming growth factor-β signaling may contribute to profibrotic responses in aged PAI-1-deficient mice hearts and establish a possible link between endothelial-to-mesenchymal transition and cardiac fibrosis in PAI-1-deficient mice.

Topics: Aging; Animals; Cell Differentiation; Collagen; Disease Models, Animal; Endothelium, Vascular; Fibrosis; Heart Diseases; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesoderm; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; S100 Calcium-Binding Protein A4; S100 Proteins; Serpin E2; Serpins; Signal Transduction; Transforming Growth Factor beta

In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-kappaB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-beta), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in deoxycorticosterone acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, heme arginate against histopathological lesions in DOCA-hypertension. Treatment with heme arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 +/- 0.12 vs. 3.19 +/- 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 +/- 0.62 vs. 4.39 +/- 0.63; n = 16, P < 0.01), left ventricular mass (2.48 +/- 0.14 vs. 2.01 +/- 0.09 g/kg body wt; n = 16, P < 0.01) and left-ventricular wall thickness (2.82 +/- 0.16 vs. 1.98 +/- 0.14 mm; n = 16, P < 0.01), whereas the HO inhibitor, chromium mesoporphyrin, exacerbated hypertrophy and cardiac lesions. The suppression of cardiac hypertrophy was accompanied by a robust increase in HO-1, HO activity, cyclic guanosine monophosphate (cGMP), ferritin and the total antioxidant capacity, whereas 8-isoprostane, NF-kappaB, JNK, AP-1, TGF-beta, fibronectin and collagen-I were significantly abated. Correspondingly, histopathological parameters that depict progressive cardiac damage, including fibrosis, interstitial/perivascular collagen deposition, scarring, muscle-fiber thickness, muscular hypertrophy and coronary-arteriolar thickening were abated. Our study suggests that upregulating the HO system lowers blood pressure, potentiates the antioxidant status in tissues, suppresses oxidative stress/mediators such as NF-kappaB, AP-1 and cJNK, and suppresses the mobilization of ECM proteins like TGF-beta, collagen and fibronectin, with corresponding reduction of cardiac histopathological lesion and hypertrophy.

Topics: Animals; Arginine; Cardiomegaly; Desoxycorticosterone; Disease Models, Animal; Heart; Heart Diseases; Heme; Heme Oxygenase (Decyclizing); Hypertension; Hypertrophy, Left Ventricular; Male; MAP Kinase Kinase 4; Mesoporphyrins; Myocardium; NF-kappa B; Rats; Rats, Sprague-Dawley; Transcription Factor AP-1; Transforming Growth Factor beta

Duchenne muscular dystrophy (DMD) is an X-linked, degenerative muscle disease that is exacerbated by secondary inflammation. Here, we characterized the immunological milieu of dystrophic muscle in mdx mice, a model of DMD, to identify potential therapeutic targets. We identified a specific subpopulation of cells expressing the Vbeta8.1/8.2 TCR that is predominant among TCR-beta+ T cells. These cells expressed high levels of osteopontin (OPN), a cytokine that promotes immune cell migration and survival. Elevated OPN levels correlated with the dystrophic process, since OPN was substantially elevated in the serum of mdx mice and muscle biopsies after disease onset. Muscle biopsies from individuals with DMD also had elevated OPN levels. To test the role of OPN in mdx muscle, mice lacking both OPN and dystrophin were generated and termed double-mutant mice (DMM mice). Reduced infiltration of NKT-like cells and neutrophils was observed in the muscle of DMM mice, supporting an immunomodulatory role for OPN in mdx muscle. Concomitantly, an increase in CD4+ and FoxP3+ Tregs was also observed in DMM muscle, which also showed reduced levels of TGF-beta, a known fibrosis mediator. These inflammatory changes correlated with increased strength and reduced diaphragm and cardiac fibrosis. These studies suggest that OPN may be a promising therapeutic target for reducing inflammation and fibrosis in individuals with DMD.

Topics: Aging; Animals; Diaphragm; Fibrosis; Gene Expression Regulation; Heart Diseases; Humans; Immune System Phenomena; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscular Dystrophy, Animal; Mutation; Osteopontin; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocytes; Transforming Growth Factor beta

Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Chronic Disease; Disease Models, Animal; Heart Diseases; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Macrophages; Male; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Transforming Growth Factor beta; Ventricular Remodeling

Recent studies demonstrate the critical role of the extracellular matrix in the organization of parenchymal cells in the heart. Thus, an understanding of the modes of regulation of matrix production by cardiac myofibroblasts is essential. Transforming growth factor beta (TGF-beta) signaling is transduced through the canonical Smad pathway, and the involvement of this pathway in matrix synthesis and other processes requires precise control. Inhibition of Smad signaling may be achieved at the receptor level through the targeting of the TGF-beta type I receptors with an inhibitory Smad7/Smurf2 complex, or at the transcriptional level through c-Ski/receptor-Smad/co-mediator Smad4 interactions. Conversely, Arkadia protein intensifies TGF-beta-induced effects by marking c-Ski and inhibitory Smad7 for destruction. The study of these TGF-beta mediators is essential for future treatment of fibrotic disease, and this review highlights recent relevant findings that may impact our understanding of cardiac fibrosis.

Topics: Animals; Fibroblasts; Fibrosis; Heart; Heart Diseases; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Proto-Oncogene Proteins; Rats; Signal Transduction; Transforming Growth Factor beta; Ubiquitin-Protein Ligases

The genetic factors contributing to the complex disorder of myocardial calcification are largely unknown. Using a mouse model, we fine-mapped the major locus (Dyscalc1) contributing to the dystrophic cardiac calcification (DCC) to an 840-kb interval containing 38 genes. We then identified the causal gene by using an approach integrating genetic segregation and expression array analyses to identify, on a global scale, cis-acting DNA variations that perturb gene expression. By studying two intercrosses, in which the DCC trait segregates, a single candidate gene (encoding the ATP-binding cassette transporter ABCC6) was identified. Transgenic complementation confirmed Abcc6 as the underlying causal gene for Dyscalc1. We demonstrate that in the cross, the expression of Abcc6 is highly correlated with the local mineralization regulatory system and the BMP2-Wnt signaling pathway known to be involved in the systemic regulation of calcification, suggesting potential pathways for the action of Abcc6 in DCC. Our results demonstrate the power of the integrative genomics in discovering causal genes and pathways underlying complex traits.

Topics: Animals; ATP-Binding Cassette Transporters; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Calcinosis; Gene Expression Regulation; Genomics; Heart Diseases; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Multidrug Resistance-Associated Proteins; Myocardium; Osteopontin; Signal Transduction; Transforming Growth Factor beta; Wnt Proteins

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Cell Differentiation; Embryonic Stem Cells; Heart Diseases; Humans; Myocytes, Cardiac; Rats; Regeneration; Transforming Growth Factor beta

Human chymase activates not only angiotensin II but also transforming growth factor-beta, a major stimulator of myocardial fibrosis, while rat chymase activates transforming growth factor-beta, but not angiotensin II. To clarify the role of chymase-dependent transforming growth factor-beta activation, we evaluated whether chymase inhibition prevents cardiac fibrosis and cardiac dysfunction after myocardial infarction in rats. Myocardial infarction was induced by ligation of the left anterior descending coronary artery. One day after the ligation, rats were randomized into 2 groups: 1) a chymase-treated group that received 10 mg/kg per day of the chymase inhibitor NK3201 orally for 4 weeks; and 2) a vehicle group of non-treated rats with myocardial infarction. We also included a control group who underwent sham-operation and no treatment. Four weeks after ligation, echocardiography revealed that chymase inhibitor treatment reduced the akinetic area and increased fractional area change but did not significantly change left ventricular end-diastolic area. Chymase inhibition significantly reduced left ventricular end-diastolic pressure, increased the maximal end-systolic pressure-volume relationship and decreased the time constant of left ventricular relaxation. Chymase activity in the non-infarcted myocardium was significantly increased in the vehicle group, but it was significantly reduced by chymase inhibitor treatment. The fibrotic area in the cardiac tissues and the mRNA levels of collagen I and collagen III were also significantly lower in the chymase inhibitor-treated group than in the vehicle group. Therefore, the pathway forming chymase-dependent transforming growth factor-beta may play an important role in myocardial fibrosis and cardiac dysfunction rather than left ventricular dilatation after myocardial infarction.

Topics: Acetamides; Algorithms; Animals; Body Weight; Chymases; Collagen Type I; Collagen Type III; Echocardiography; Fibrosis; Heart Diseases; Hemodynamics; Male; Myocardial Infarction; Myocardium; Organ Size; Protease Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Serine Endopeptidases; Transforming Growth Factor beta

Chymase is one of the inflammatory mediators and is released from mast cells, which are closely associated with adhesion formation. Chymase also activates transforming growth factor beta1, which promotes tissue fibrosis. However, the role of chymase in cardiac adhesion formation has not yet been elucidated. We have assessed whether a specific chymase inhibitor, Suc-Val-Pro-Phe(p) (OPh)(2), prevents postoperative cardiac adhesions in hamsters.. In 66 hamsters the epicardium was abraded, and then either chymase inhibitor or placebo was injected into the left thoracic cavity, leaving the pericardium open. Cardiac chymase activity, the level of transforming growth factor beta1 in the pleural fluid, and the density of epicardial mast cells were measured 3 days postoperatively. The degree of adhesion formation was evaluated macroscopically and histologically 2 weeks postoperatively by using a grading score ranging from 0 (no adhesions) to 4 (severe adhesions).. The cardiac chymase activity and level of transforming growth factor beta1 were lower in the chymase inhibitor-treated group compared with in the placebo-treated group (45.8 +/- 18.7 vs 79.7 +/- 13.7 microU/mg protein [P <.025] and 15.6 +/- 6.5 vs 33.2 +/- 9.8 microg/mL [P <.01], respectively). The density of mast cells was higher in the placebo-treated group, and there was suppression to 60% of this value in the chymase inhibitor-treated group. The adhesion scores were lower in the chymase inhibitor-treated group compared with in the placebo-treated group (1.3 +/- 1.3 vs 3.0 +/- 1.1, P <.01).. Use of a chymase inhibitor suppresses not only cardiac chymase activity but also the level of transforming growth factor beta1, and this results in a reduction in postoperative cardiac adhesion.

Topics: Animals; Biopsy, Needle; Cardiac Surgical Procedures; Chymases; Cricetinae; Disease Models, Animal; Heart Diseases; Immunohistochemistry; Male; Postoperative Complications; Probability; Random Allocation; Reference Values; Sensitivity and Specificity; Serine Endopeptidases; Serine Proteinase Inhibitors; Tissue Adhesions; Transforming Growth Factor beta

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR subfamily comprises of three members, PPAR-alpha, PPAR-beta and PPAR-gamma. There is good evidence that ligands of PPAR-gamma, including certain thiazolinediones, reduce myocardial tissue injury and infarct size. The use of PPAR-gamma agonists in the treatment of heart failure is, however, controversial.

Topics: Animals; Chemokine CCL2; Diabetes Mellitus, Type 2; Disease Models, Animal; Heart Diseases; Humans; Hypoglycemic Agents; Ligands; Mice; Myocardial Infarction; Pioglitazone; PPAR gamma; Rats; Thiazolidinediones; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha

A number of cytokines have been implicated in the pathophysiology of congestive heart failure. Genetic polymorphisms of several cytokine genes are known to result in altered gene expression, enabling us to characterize patients as "high" or "low" producers of specific cytokines. We speculate that the cytokine genotypes for a population of children who underwent heart transplantation for end-stage ventricular failure due to cardiomyopathy or congenital heart disease would be enriched for "high producers" of pro-inflammatory cytokines and "low producers" of anti-inflammatory cytokines.. Cytokine genotyping was performed for the following cytokines on 94 transplanted children using polymerase chain reaction-sequence specific technique: tumor necrosis factor-alpha (-308), interleukin 10 (-1082, -819, -592), interleukin 6 (-174), transforming growth factor-beta1 (codons 10 & 25), and interferon-gamma (+874). Patients with ventricular failure after transplantation for dilated cardiomyopathy, numbering 37, or for congenital heart disease, numbering 34, were compared to 15 children transplanted for structural disease, such as hypoplastic left heart syndrome, without ventricular failure, and to data from healthy children. An additional 8 children with restrictive or hypertrophic cardiomyopathy were also studied.. No differences in genotypic distribution were seen between the groups, and all patients were comparable to genotypic distributions as assessed from published normal data.. No evidence is found to support the hypothesis that these polymorphisms for cytokine genes influence progression to end-stage heart failure in children undergoing transplantation because of cardiomyopathy or congenital heart disease.

Topics: Child; Cytokines; Disease Progression; Genotype; Heart Diseases; Humans; Interferon-gamma; Interleukin-10; Interleukin-6; Polymorphism, Genetic; Prognosis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Extracellular Matrix; Heart Diseases; Humans; Metalloendopeptidases; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Transforming Growth Factor beta1

Involvement of oxidative stress is implicated in the progression of complication of diabetes mellitus. With respect to heart diseases, we have studied role of oxidative stress/antioxidants using rats treated with streptozotocin to induce diabetes (DM). Hemodynamic and echocardiographic measurements showed thickening of the wall and an increase in the internal dimension of the left ventricle (LV) in DM rats at 8th week. Decrease in diastolic posterior wall velocity and rate of LV pressure change, and increase in LV end diastolic pressures also proved cardiac dysfunction. These changes were further developed in DM rats after 12 weeks. Utilizing rat hearts at 8th and 12th weeks, the following estimations were performed. There was a decrease in the activity of Mn-superoxide dismutase (SOD), suggesting abnormal mitochondrial metabolism of reactive oxygen species. The level of glutathione (GSH) decreased concomitant with a decrease in the expression of gamma-glutamylcysteine synthetase (gamma-GCS). The expression of transforming growth factor-beta1 (TGF-beta1), known as a growth factor and a suppressor of GSH synthesis, elevated in DM rat hearts. Immunohistochemical estimation showed an increase in type IV collagen in DM hearts. Collectively, it was suggested a linkage between mitochondrial damage to generate reactive oxygen species and inactivation of Mn-SOD and elevation of the expression of TGF-beta1 to lead suppression of GSH synthesis and induction of fibrous change for the consequent cardiac dysfunction in DM.

Topics: Animals; Antioxidants; Collagen; Diabetes Mellitus, Experimental; Electrocardiography; Glutamate-Cysteine Ligase; Glutathione; Heart Diseases; Heart Ventricles; Hemodynamics; Male; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Transforming Growth Factor beta; Transforming Growth Factor beta1

Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF- beta) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF- beta is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF- beta induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF- beta induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF- beta induced CTGF expression. Furthermore, we found that both TGF- beta and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF- beta signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.

Topics: Adult; Aged; Animals; Animals, Newborn; Biomarkers; Blotting, Northern; Cells, Cultured; Colforsin; Collagen; Connective Tissue Growth Factor; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Female; Fibroblasts; Fibronectins; Fibrosis; Flavonoids; Genes, Reporter; Growth Substances; Heart Diseases; Heart Ventricles; Humans; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Luciferases; Male; MAP Kinase Signaling System; Middle Aged; Myocardial Infarction; Myocardium; Plasminogen Activator Inhibitor 1; Promoter Regions, Genetic; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Tissue Distribution; Transforming Growth Factor beta; Up-Regulation