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Immunology. May 2006; 118(1): 10–24.
PMCID: PMC1782267

Fibrosis in heart disease: understanding the role of transforming growth factor-β1 in cardiomyopathy, valvular disease and arrhythmia


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-β1 (TGF-β1), a potent stimulator of collagen-producing cardiac fibroblasts. Previously, TGF-β1 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-β1. In fact, the pathogenic effects of TGF-β1 have now been suggested to play a major role in valvular disease and arrhythmia, particularly atrial fibrillation. Thus far, medical therapy targeting TGF-β1 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-β1 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-β1 is an appropriate target for therapy in a variety of cardiovascular diseases.

Keywords: anti-fibrotic treatment, atrial fibrillation, remodelling, Smad, transforming growth factor-β1


Transforming growth factor-β1 (TGF-β1) is a profibrotic cytokine that stimulates the production of extracellular matrix proteins in a number of different organ systems. However, overexpression of TGF-β1 results in tissue fibrosis and organ dysfunction. TGF-β1 has been implicated in the development of diabetic nephropathy, ulcerative colitis, hepatic fibrosis and congenital disease.14

Similarly, in the heart, TGF-β1 appears to be one of several factors that cause disease by inducing cardiac fibrosis, as evidenced by overexpression and knockout models.58 The increased presence of extracellular matrix proteins within the myocardium results in an alteration of ventricular properties that causes both systolic and diastolic dysfunction.9 TGF-β1-associated fibrosis also results in an inhomogeneous milieu for electrical propagation. This environment impedes anisotropic or linear conduction leading to the development of arrhythmia.10 Similarly, excessive production of extracellular proteins within heart valves results in leaflet thickening and impaired motion with associated valvular dysfunction.11

The significant pathology correlated with TGF-β1 overexpression has led to an increasing amount of research examining treatment for TGF-β1-induced fibrosis. Thus far, TGF-β1 inhibition has been shown to reverse the fibrotic effects of the cytokine in animal models.12 In addition, the promise of gene therapy used to promote the expression of TGF-β inhibitors offers hope for preventing fibrosis rather than merely treating it.13

Until recently most reviews have focused on the effects of TGF-β1 in postmyocardial infarction remodelling. However, this study attempts to create a new paradigm emphasizing the significance of TGF-β1 in a variety of heart diseases.

Examining TGF-β1 and its physiological role

In mammals, TGF-β is found in three isoforms: TGF-β1, TGF-β2 and TGF-β3. TGF-β1 is expressed in myofibroblasts, vascular smooth muscle cells, endothelial cells and macrophages.14 The human TGF-β1 gene is found on chromosome 19, and can be transcribed and translated to form a 390 amino acid propeptide. This propeptide is cleaved intracellularly, producing two identical 112 amino acid peptide subunits joined together by a disulphide bond.15 TGF-β1 is secreted initially as a biologically inactive molecule bound to latent associated peptides.16 Latent TGF-β1 is then activated by cell–cell interaction, acidification, and enzymatic cleavage.15

TGF-β1 plays a significant physiological role within the body. In the brain, TGF-β1 acts synergistically with glial-derived neurotrophic factor in promoting the survival of both peripheral and central nervous system neurons.17 TGF-β1 acts primarily as a powerful immunosuppressant, inhibiting lymphocyte proliferation in the presence of interleukin-2, as well as modulating differentiation and apoptosis of T cells.18,19 Studies have also suggested that TGF-β1 may be important in the stabilization of atherosclerotic plaques through inhibition of local inflammation.20,21 Finally, TGF-β1 is released at wound sites initially stimulating the migration of neutrophils, monocytes and fibroblasts to injury zones. It subsequently enhances expression of extracellular matrix proteins from fibroblasts.22

Unfortunately, the overexpression of TGF-β1 is thought to result in increased extracellular matrix protein synthesis. It is this excess of extracellular matrix proteins that defines fibrosis.

Molecular mechanisms of TGF-β1 action

Up-regulation of TGF-β1 via angiotensin II

The link between angiotensin II and TGF-β1 was first noted in the kidney. Angiotensin II was shown to raise TGF-β1 levels in the kidney, resulting in the development and progression of nephritic glomerular disease.23 Similarly, Fukuda established that angiotensin II stimulated the expression of TGF-β1 in vascular smooth muscle cells and led to cellular proliferation.24

Regarding the heart, there have been a number of in vitro and in vivo studies which have indicated that TGF-β1 is up-regulated by angiotensin II in myofibroblasts and cardiac fibroblasts.25,26 Administration of angiotensin II to cardiocytes has been shown to be associated with increased TGF-β1 expression.27 Using human atrial myocardial tissue, Kupfahl et al. noted that angiotensin II did not directly stimulate collagen expression, but rather caused TGF-β1 up-regulation, which then altered collagen production.28 Kim et al. found that angiotensin II antagonists inhibited the expression of the TGF-β1 gene in cardiac and vascular tissue in rats.29 Similarly, in hypertensive rat models, the use of angiotensin II receptor blockers has been shown to suppress the induction of TGF-β1 and prevent myocardial fibrosis. Finally, Schultz et al. demonstrated that angiotensin II could not induce hypertrophy in mice lacking the TGF-β1 gene.8

In clinical trials, a number of studies have indicated that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists may decrease production of TGF-β1.30,31 In patients with cardiorenal damage and associated increased angiotensin II serum levels, Laviades et al. noted elevated serum concentrations of TGF-β1and C-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) when compared to controls.32 Administration of losartan reduced serum levels of TGF-β1 and C-terminal propeptide of procollagen type I.

The ameliorative effects of ACE inhibitors and angiotensin II receptor blockers on the heart are partially attributable to the inhibition of extracellular protein production. Both animal and clinical studies indicate that these effects are most likely mediated through antagonism of TGF-β1 and its downstream proteins.

Following the TGF-β1–Smad pathway

After synthesis and release into the extracellular space, TGF-β1 binds to a dimerized complex, which is comprised of two serine-threonine kinase receptors known as TGF-β1 receptor 1 and 2.33 Ligand-receptor binding eventually leads to phosphorylation of Smad proteins, conserved transcriptional proteins that act as second messengers for the TGF-β1 superfamily, and the formation of a heteromeric complex that regulates expression of DNA. Smad proteins can be categorized into three groups: receptor-activated Smads (Smad1, Smad2, Smad3, Smad5 and Smad8), co-mediator Smads (Smad4 and Smad10) and inhibitory Smads (Smad6 and Smad7).34

In the heart, it has been postulated that the effects of TGF-β1 are primarily mediated through Smad2 phosphorylation.35 Once phosphorylated, Smad2 forms a complex with Smad3 and Smad4. This complex then translocates into the nucleus and binds to Smad-binding oligonucleotides present in the regulatory regions of specific genes, resulting in the alteration of gene expression levels.36 Smad6 and Smad7 inhibit the action of TGF-β1 by preventing Smad2 phosphorylation and disrupting Smad complex formation, respectively (Fig. 1).37

Figure 1
The TGF-β1–Smad pathway. (1) Initiation of the pathway begins after TGF-β1 is up-regulated by angiotensin II. (2) Once in the extracellular space, TGF-β1 binds to a dimerized receptor, consisting of TGF-β1receptor ...

The TGF-β1–Smad pathway appears to be involved in the activation of collagen-gene promoter sites, primarily enhancing DNA translation of collagen type I. Evidence from transfected mesangial cell lines indicates that COL1A1 (encoding one component of collagen type I) is a primary site for Smad binding.38 Verrecchia et al. found that the TGF-β1–Smad pathway in dermal fibroblasts caused the induction of COL1A1, along with COL1A2 (encoding a second component of collagen type I), COL3A1 (encoding a component of collagen type 3), COL6A1 (encoding a component of collagen type VI) and COL6A3 (encoding another component of collagen type VI).39

Alternative pathways for TGF-β1-induced fibrosis

Recently, an alternative pathway for TGF-β1-induced fibrosis involving TGF-β-activated kinase (TAK1) has been suggested. TAK1, a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is thought to be a significant downstream modulator for the TGF-β1 superfamily.40 Zhang et al. found that the administration of TGF-β1 to cardiac fibroblasts resulted in a 200–400% increase in TAK1.41 The study also noted that constitutive TAK1 activity in transgenic mice led to a 46% increase in cardiac mass, with significant worsening of both systolic and diastolic cardiac functioning. Histological specimens of the myocardium in these mice revealed increased interstitial fibrosis and myocyte hypertrophy.

Hanafusa et al. also found that TAK1, once activated by TGF-β1, phosphorylated activated transcription factor-2 (ATF-2), which then combined with the Smad proteins 2, 3 and 4 to form a transcription complex (Fig. 2).42 Overexpression of non-phosphorylated ATF-2 resulted in inhibition of TGF-β1 transcriptional activity. The study noted that coexpression of cells with Smad2 and Smad4 along with TAK1 resulted in synergistic activation of promoter sites. Similarly, Sano et al. showed that Smad3/Smad4 complex binding to ATF-2 increased the latter's trans-activating capacity.43 Monzen et al. have also found that Smad proteins and TAK1 work together in cardiomyocyte differentiation.44 Although few studies have quantified the importance of the TAK1 pathway on collagen expression and distribution within the heart, overexpression of TAK1 in articular chondrocytes has been shown to increase cellular collagen type II expression more than threefold, approximating the effects of TGF-β1 stimulation.45

Figure 2
The TGF–TAK1 pathway. (1) Initiation of the pathway begins when TGF- β1 binds to the dimerized TGF- β1 receptor 1 (TGF- β1R1) – TGF- β1 receptor 2 (TGF- β1R2) complex. (2) Ligand-receptor binding ...

TGF-β1 induction of connective tissue growth factor

TGF-β1 is thought to up-regulate pro-fibrotic proteins that further stimulate extracellular matrix protein expression. In particular, TGF-β1 has been shown to increase connective tissue growth factor (CTGF) synthesis within different fibroblast subtypes, including cardiac fibroblasts, most probably by acting on TGF-β1 response elements localized in CTGF promoter site.46,47 Chen et al. found that rises in myocardial CTGF after infarction paralleled elevations in TGF-β1 and collagen expression in rats.48 Furthermore, the use of CTGF antibodies has been shown to partially attenuate TGF-β1-induced collagen synthesis from fibroblasts.49

Interaction between TGF-β1 and matrix metalloproteinases

Until very recently, the extracellular matrix was considered to be a static network of proteins. However, research now indicates that this network is constantly changing in both structure and composition. Proteolytic enzymes, such as matrix metalloproteinases (MMPs), play an integral role in promoting change and remodelling. Examining left ventricular failure in animal models, Spinale et al. showed that MMP expression increased in a time-dependent manner with left ventricular dysfunction and dilatation.50 Activation of the MMPs led to disruption of the extracellular network surrounding myocytes. Kim et al. noted that overexpression of MMP-1 (collagenase) in mice led to compensatory hypertrophy and increased collagen concentration within the myocardium, resulting in eventual ventricular impairment.51 In addition, targeted deletion of MMP-2 prevented early and late left ventricular remodelling in mouse models.52

The roles of TGF-β1 and MMPs in cardiac remodelling may be intertwined. In fact, both proteins may be part of one complex pathway for fibrosis. It has been noted that levels of both MMP-2 and membrane type-MMP (MT-MMP) are higher in terminally failing hearts, in concordance with when TGF-β1 expression is also increased.53 Similarly, Shimizu et al. found that TGF-β1 and MMP-2 concentrations were both elevated in the myocardium of infarcted rats.54

Increasing evidence points towards the possibility that TGF-β1 increases MMP activity within the myocardium. TGF-β1 appears to up-regulate MMP-2 and membrane-bound MT-MMP in fibroblasts.55 Briest et al. found norepinephrine-induced myocardial TGF-β1 expression caused elevations in MMP-2 levels.56 In addition, collagen type I, whose production is regulated by TGF-β1, has been shown to increase MMP-2 activity.57

Stawowy et al. noted that TGF-β1-induced expression of MMP-2 facilitates migration and motility of cardiac fibroblasts.58 This, in turn, allows for the local production of extracellular proteins and increased fibrosis within the myocardium of the heart associated with cardiac remodelling.

Sources for TGF-β1 in the myocardium

In the heart, TGF-β1 is primarily secreted by cardiac fibroblasts. In turn, TGF-β1 induces the differentiation of cardiac fibroblasts to more active connective tissue cells known as myofibroblasts.59 Petrov et al. found that myofibroblasts can produce up to twice as much collagen as their fibroblast precursors.60 TGF-β1 is also involved in raising the production of cellular adhesion molecules, which are thought to increase myofibroblast survival and activity.61

Along with fibroblasts, Riemann et al. showed that macrophages may be another source of TGF-β1 production.62 Macrophages have been shown to colocalize with myofibroblasts in areas of fibrosis within the heart during cardiac hypertrophy.63 It has been proposed that macrophages may serve as an initial or additional source of TGF-β1 in the heart.64 Kagitani et al. noted that administration of anti-inflammatory medication to hypertensive rats led to reduced infiltration of macrophages into the myocardium and prevented collagen accumulation when compared to controls.65

The TGF-β1–Smad pathway appears to be an integral component of fibrosis within the heart. However, the pathway and its regulation have yet to be fully elucidated. Furthermore, more research is required to understand cell-signalling overlap between the TGF-β1–Smad pathway and other extracelullar matrix protein up-regulators, such as osteopontin, to create a global model for pathological fibrosis within the myocardium.

TGF-β1-induced fibrosis as a cause of cardiomyopathy

Alteration of ventricular properties caused by excess extracellular matrix production

For many years the heart was assumed to be a homogeneous organ, consisting solely of muscle cells. However, current evidence suggests that fibroblasts actually outnumber cardiac myocytes within the heart.66 These connective tissue cells help to produce an extracellular matrix which allows for fibrosis within the myocardium.

The function of this fibrosis is still not completely known. Yet, more recently, it has come to be understood that networks of elastic tissue within the heart may allow for maintenance of myocardial architecture. Collagen networks are also thought to be involved in the transmission of force generated in muscle tissue.

Unfortunately, excessive deposition of fibrotic tissue in the heart results in cardiac pathology. Most notably, raised levels of collagen within the myocardium cause reduced ventricular compliance. This change can be attributed to the inherent stiffness of collagen type I which, as measured by Young's modulus of elasticity, is ~ 30-fold greater than that of a cardioctye.67 Concordantly, Jalil et al. noted that passive ventricular stiffness correlated well with collagen volume fraction.68 Generally, a two- to threefold rise in collagen volume fraction causes notable ventricular stiffening.69 Increasing chamber stiffness is accompanied by impaired myocyte relengthening during relaxation. Improper myocyte relaxation results in aberrant ventricular filling and is associated with increased filling pressures. Consequential decreases in stroke volume and increases in myocardial demand for oxygen lead to eventual cardiac dysfunction. While examining the role of fibrosis in cardiac pathology, MacKenna et al. showed that administration of intra-arteriolar bacterial collagenase into the myocardium of rats resulted in local degradation of collagen, which, in turn, caused increased chamber compliance and reduced diastolic dysfunction.70

Systolic dysfunction is also marked by the presence of increased myocardial collagen concentrations. The increased extracellular matrix generally serves as a replacement for necrosed or apoptotic myocytes. Unfortunately, the reduction in muscle tissue associated with this fibrosis results in poor ventricular contraction and reduced cardiac output. In addition, Wu et al. have noted that the increase in collagen concentration causes alterations to ventricular geometry, resulting in impaired sarcomere extension.71 As the force of ventricular contraction is directly related to sarcomere length, the fibrosed heart has a greatly reduced ability to produce adequate pressures for systemic perfusion.

The changes in ventricle size and shape induced by the up-regulation of fibrotic proteins greatly compromise the ability of the heart to function. In fact, studies indicate that fibrosis may contribute greatly to cardiac dysfunction in ischaemic, dilated and hypertrophic cardiomyopathy.

Involvement of TGF-β1 in ventricular remodelling and the development of ischaemic injury

After infarction, the myocardium undergoes a reparative process where necrotic cardiac tissue is replaced by extracellular matrix proteins, in an effort to protect the integrity of the heart wall. This ‘scarred tissue’ is dynamic, constantly producing and resorbing collagen. Functionally, the remainder of the heart makes up for the lost muscle tissue by increasing levels of fibrosis and inducing myocyte hypertrophy, allowing for initial compensation of ventricular function. Based on evidence from animal-based and in vitro studies, TGF-β1 is thought to be responsible for this reparative fibrosis. Deten et al. showed that TGF-β1 expression in rats was increased within the first day after infarct.72 Increased myocardial concentrations of collagen I and collagen III occurred 3 days post-infarction, and coincided with the rise in TGF-β1 expression. In fact, TGF-β1 remained elevated for 82 days after infarction and was proposed to be involved in ongoing, rather than just acute, ventricular remodelling. Similarly, Hao et al. noted that TGF-β1, Smad1, Smad2 and Smad3 were all elevated even 8 weeks postinfarction in rats.73 Wang et al. found that levels of Smad7, an inhibitor in the TGF-β1-Smad pathway, were greatly reduced in rats 2 weeks after myocardial infarction.74 This reduction was associated with a greater amount of fibrosis. Most importantly, the degree of TGF-β1 expression in structural remodelling has been shown to correlate with the degree of fibrosis.75

Up-regulation of TGF-β1 receptors also contributes to increased activity of TGF-β1 signalling. After prolonged ischaemia (4 weeks), TGF-β1 receptor density has been shown to be raised threefold within the left ventricle and twofold within the right ventricle in rat models.76 Sites of receptor up-regulation were associated with increased levels of fibrosis.

There is an increasing body of evidence indicating that higher levels of TGF-β1 are not only produced after an ischaemic myocardial event, but they may also predispose to one as well. Studies, using rabbit models, indicate that TGF-β1 overexpression in vascular smooth muscle may lead to increased extracellular matrix protein production contributing to artery narrowing.77,78 Lindner found that injection of soluble TGF-β1 receptor II, acting as a TGF-β1 inhibitor, into the carotid arteries of rats resulted in a 65% decrease in intimal lesion formation and an 88% increase in luminal size.79 Friedl et al. noted that intimal hyperplasia in the saphenous vein and internal mammary artery may be attributable to TGF-β1, as both hyperplastic vein and artery had greater levels of TGF-β1 expression when compared to patent vessels in patients.80

Genetic studies also indicate that TGF-β1 polymorphisms may predispose individuals to ischaemic heart disease. In their examination of patients with end-stage renal failure, Rao et al. discovered that over 52% of patients with TGF-β1 coding region G→C (915) polymorphisms had associated ischaemic heart disease.81 Similarly, Yokota et al. found that TGF-β1 T→C (29) polymorphisms were correlated with a greater susceptibility to myocardial infarctions.82 Not surprisingly, individuals with such polymorphisms exhibit higher levels of serum TGF-β1.

Single-nucleotide changes in genes encoding downstream proteins in the TGF-β1–Smad pathway have also been correlated with ischaemic disease. Blom et al. have found polymorphisms within the CTGF promoter region that are associated with ischaemic heart disease.83 These genetic variances caused increased CTGF expression and are thought to result in neointimal proliferation within blood vessels. Both Smad3 and Smad4 proteins within the TGF-β1 cascade are thought to be the most important regulators of CTGF promoter activity.84

TGF-β1 appears to play a significant role in the pre- and post-infarction environment, although human studies are currently lacking. In both, TGF stimulates extracellular protein production leading to vascular or ventricular dysfunction. Therefore, understanding the regulation, as well as dysregulation, of the TGF-β1–Smad pathway becomes paramount for prevention of ischaemic heart disease and attenuation of remodelling.

Fibrosis as a pathological process in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is characterized by interventricular septum or left ventricular hypertrophy, interstitial fibrosis and arterial wall thickening.85 The most significant consequence of this hypertrophy is decreased compliance of the ventricles and eventual diastolic dysfunction. Shirani et al. found that the collagen network within the hearts of patients with hypertrophic cardiomyopathy was significantly greater than that seen in the hearts of patients without cardiovascular disease.86 Collagen levels were independent of both structural and clinical disease variables and therefore the increased collagen network size was thought to be the result of a primary pathological process rather than simply serving as a consequence of other factors. In fact, it has been suggested that increased fibrosis, not myocardial hypertrophy, may be the most significant cause of diastolic dysfunction in hypertrophic cardiac disease.86 Mundhenkeet al. noted that increased collagen type I within the myocardium was a predictor of both diastolic and systolic dysfunction during exercise in hypertrophic cardiomyopathic patients who underwent transvalvular myectomy.87

TGF-β1 is thought to be an important trigger of fibrosis in the hypertrophied heart. Expression levels of TGF-β1 in hypertrophic obstructive cardiomyopathy were 2·5 times higher than in non-hypertrophied hearts.88 Li et al. have found that the maximal binding affinity of TGF-β1 to its receptor was higher in individuals with idiopathic hypertrophic cardiomyopathy.89 Di Nardo et al. noted that early embryonic gene expression, rather than severity of haemodynamic overload, was the trigger for structural changes in the myocardium of hamsters with hereditary hypertrophic cardiomyopathy.90 In this study, activation and regulation of embryonic gene expression were thought to be caused by TGF-β1, as a threefold increase in TGF-β1 gene expression was closely associated with a rise in myocardial early embryonic gene expression.

The involvement of fibrosis in the pathogenesis of hypertrophic cardiomyopathy has altered its perception as a disease consisting solely of myocyte disarray and dysfunction. However, efforts must be made to quantify the role of TGF-β1 and fibrosis in this disorder. Should myocardial TGF-β1 levels correlate with heart function (or dysfunction), these proteins may serve as prognostic markers and obvious targets for disease prevention.

Dilated cardiomyopathy as a consequence of TGF-β1 overexpression

Dilated cardiomyopathy is characterized by ventricular dilatation of the heart and is associated with very little hypertrophy. In dilated cardiomyopathy, diffuse myocyte damage may arise as a result of known (infections, drugs, etc.) or unknown causes. In this disorder, muscle fibres are replaced by extracellular matrix proteins, resulting in expansion of heart size. Such fibrotic changes are independent of other cardiovascular disease. Brooks et al. found that the interstitial levels of collagen were increased in dilated left ventricles that failed to display any pathological signs of ischaemia.91 Marijianowski et al. demonstrated that collagen type I and III, as well as the collagen type I/type III ratio, were all elevated in patients with dilated cardiomyopathy.92 The presence of increased fibrosis implies a possible role for TGF-β1 in dilated cardiac pathology.

Sanderson et al. noted that the plasma levels of TGF-β1 were twice as high in patients who had developed idiopathic dilated cardiomyopathy when compared to controls.93 Levels of TGF-β1 were also increased in macrophages present within the myocardial tissue of the dilated heart. This becomes increasingly important as Kuhl et al. have noted that there are an increased number of macrophages in the heart of individuals with dilated cardiomyopathy.94

Thus far, genetic studies have also hinted at the possible involvement of TGF-β1 in dilated cardiomyopathy. Holweg et al. showed that the codon (10) Leu→Pro TGF-β1 gene polymorphism, which correlates with elevated circulating levels of TGF-β1, is associated with dilated cardiomyopathy.95,96 These changes occur within the signal sequence of the TGF-β1 gene, which is extremely important, as protein synthesis and activity are post-translationally regulated by such sequences.

Alterations in downstream modulators of TGF-β1 may also predispose to dilated cardiomyopathy. Dixon et al. have documented that altered Smad2 and Smad4 expression in rats are associated with increased levels of cardiac fibrosis, elevated collagen turnover and the development of dilated cardiomyopathy.97 In patients with HIV, up-regulation of TGF-B1 effector molecules such as ATF-2 have also been shown to cause dilated cardiomyopathy.98

The importance of fibrosis in dilated cardiomyopathy makes TGF-β11 an apt choice for inducing pathogenesis. If causality between TGF-β1 overexpression and cardiomyopathy can be proven, the use of antifibrotics such as TGF-β1 antagonists may provide a means for reversing dilatation of the heart and systolic dysfunction.

Correlation between valvular dysfunction and TGF-β1 expression

TGF-β1 appears to play a significant role in valvular pathogenesis. Valves primarily consist of interstitial cells, which secrete typical extracellular matrix proteins such as collagen.99 These cells are precursors to myofibroblasts, which, as in the myocardium, are known for their ability to produce matrix proteins. The emergence of myofibroblasts in valvular tissue is strongly associated with disease.100 The presence of these cells has been closely correlated to degenerative lesions and fibrosis of valves.101 Walker et al. noted that TGF-β1 is extremely important in inducing the differentiation of valvular interstitial cells to myofibroblasts, similar to what is seen in the ventricle.11

The local concentration of TGF-β1 within cardiac valves may also be important because TGF-β1appears to directly stimulate extracellular matrix protein expression from valvular interstitial cells even before their differentiation.102 Surrounding ventricular biopsies of patients with both aortic stenosis and regurgitation showed a 1·5- to 2-fold increase in TGF-β1 levels as compared with controls.103 Increased valvular expression of TGF-β1 has been noted in patients with carcinoid syndrome and it has been correlated with greater collagen deposition, extracellular matrix disorganization and calcification of valves in this population.104

The remodelling paradigm created for ischaemic cardiomyopathy may be apt for valvular disease as well. Initial damage to cardiac valves appears to raise local TGF-β1 expression in a manner similar to that seen in the myocardium after infarction. This overexpression of TGF-β1, in turn, could result in pathological repair of diseased areas. Inappropriate repair to initial injury may lead to progressive malfunctioning of the valves.

The role of TGF-β1 in valvular disease is not limited to its overexpression in response to injury. As in ischaemic cardiomyopathy, TGF-β1 polymorphisms may predispose to valvular disease. Chou et al. found that patients with rheumatic heart disease have a lower frequency of TGF-β1 C→T (509) genotype and a higher frequency of the T→C (869) allele.105 The inherent raised TGF-β1 expression associated with the latter polymorphism may allow for increased fibrosis in patients with leaflet infection, creating a link between disease and valvular dysfunction.

In looking at animal models of connective tissue disease, Ng et al. found that mice with Marfan syndrome had increased activation of TGF-β1.106 This increased activity was associated with raised endothelial cell proliferation and myxomatous changes surrounding the aortic valve. Administration of TGF-β1 antibodies prevented any such changes from occurring. Although a clear link between Marfan syndrome and TGF-β1 does not exist, TGF-β1 is known to play an integral part in the development of endovascular cushions, the embryonic precursors to cardiac valves. Expression of TGF-β1 within this tissue is usually limited to the fetal development period. However, persistent expression of TGF-β1 in this tissue at even a minute level could predispose individuals to valvular disease. This process may occur in Marfan patients because fibrillin, the protein generally deficient in the syndrome, is thought to suppress TGF-β1 activity.106

Although, cardiac surgery is the most common treatment for valvular dysfunction, medical therapy directed at limiting the effects of TGF-β1 appears to be a viable alternative. Limiting myxomatous changes seen prior to valvular dysfunction will hopefully lessen the need for surgical intervention. This is of particular importance in the elderly where numerous comorbidities often make valvular surgery impossible.

Electrical conduction disturbances associated with TGF-β1 overexpression

Research involving atrial fibrillation has shown that myocardial fibrosis plays an important role in predisposing to arrhythmia.107 In fact, the arrhythmogenic activity of the pulmonary veins is partially attributed to the fact that myocardial tissue within these vessels is significantly fibrotic (Fig. 3).108 Fibrosis is thought to disturb anisotropic conduction and thereby induce slowing of electrical conduction velocities, allowing for the generation of re-entry circuits. In addition, impaired anisotropic conduction leads to chaotic rather than linear electrical propagation which also promotes arrhythmia.109 Nakajima et al. noted that mice with constitutive expression of TGF-β1 developed selective fibrosis within the atria and not in the ventricles, suggesting that atrial fibroblasts may be particularly sensitive to the actions of TGF-β1.6 In a similar study, mice with increased expression of TGF-β1 were prone to atrial fibrillation development as a result of raised levels of atrial fibrosis.10 Hanna et al. noted that TGF-β1 levels were increased in the atria after the development of congestive heart failure in dogs.110 This correlation may help to explain the presence of arrhythmia seen after the onset of ventricular dysfunction. TGF-β1 polymorphisms are also thought to be involved in inducing congenital heart block as a result of fibrosis, leading to the predisposition of atrial fibrillation.111,112 The aim of new research should be to determine which TGF-β1 polymorphisms (if any) enhance the likelihood of atrial fibrillation development. In addition, expression levels of TGF-β1 in the pulmonary veins must be studied as a possible explanation for the arrhythmogenicity of these vessels.

Figure 3
A histological section of the pulmonary veins at the region of the ostium. Disorganized bundles of the myocardial sleeve extending from the left atrium are surrounded by fibrotic connective tissue. Provided by courtesy of Ivana Kholova, MD.

Regarding treatment, the use of antifibrotics as a preventive measure for atrial fibrillation is intriguing. Using canine models, Shi et al. noted that ACE inhibitors prevented the fibrosis that normally arose after heart failure, leading to the reduced development of atrial fibrillation.113 Similarly, clinical trials show increasing benefits in using ACE and angiotensin II receptor inhibitors for atrial fibrillation in patients with and without underlying cardiopathologies.114117 The inhibition of TGF-β1 may produce similar antiarrhythmic effects.

Treatment directed at TGF-β1-induced fibrosis

There are a number of strategies that have aimed to reduce fibrosis in cardiovascular pathology. Most recent research has focused on the effectiveness of ACE inhibitors and angiotensin II receptor antagonists in attenuating extracellular matrix production within the heart. However, in a recent clinical trial, Hallberg et al. compared the benefits of irbesartan treatment on the ventricular properties of hypertensive groups with two separate TGF-β1 polymorphisms. Patients with the GG genotype, associated with greater TGF-β1 expression, were shown to have a greater left ventricular mass index when compared to patients with the GC genotype.118 This suggests that drugs inhibiting angiotensin may not be able to fully impede the cardiopathological effects of TGF-β1. It also implies that targeting the TGF-β1–Smad pathway directly may be more effective in attenuating fibrosis and hypertrophy in the heart.

Thus far, most research has used animal models to examine the effects of TGF-β1 antagonism. Kuwahara et al. were able to induce increased TGF-β1 expression within the rat heart resulting in progressive myocardial fibrosis and eventual diastolic dysfunction (gauged by immunohistochemistry and echocardiography).12 Administration of TGF-β1 monoclonal antibodies to rats, similarly overexpressing TGF-β1, prevented both fibrosis and diastolic dysfunction. More specifically, these antibodies did not allow for left ventricular hypertrophy and subsequent raised left ventricular end-diastolic pressure, which normally precedes dysfunction. Koyanagi et al. found that TGF-β1 antagonism blocks the migration of rat monocytes and the production of local myofibroblasts, two cell types that serve as the primary sources for TGF-β1 production within the myocardium.119 Tomita et al. noted that TGF-β1 neutralization via polyclonal antibodies resulted in the down-regulation of extracellular matrix gene expression in rats.5 Tranilast, a novel drug already sold in Japan, serves to inhibit transcription of TGF-β1.120 It has been shown to reduce the secretion of TGF-β1 in fibroblast cell cultures. Much like TGF-β1 antibodies, tranilast prevents the migration of monocytes to myocardial tissue in hypertensive mice.65 In addition, it serves to attenuate left ventricular fibrosis in rats with renovascular hypertension.121 Martin et al. have recently shown that tranilast lowers the deposition of cardiac matrix proteins in diabetic rats despite the presence of persistent hyperglycaemia and hypertension.122 The ongoing PRESTO PCI clinical study is attempting to use an oral regimen of tranilast to reduce restenosis of coronary arteries postintervention.123

Regulation of inherent TGF-β1 inhibitors within the body may also help to prevent fibrosis in the heart. For example, Mujumdar and Tyagi noted that levels of one such physiological inhibitor, decorin, are reduced during the transition of the heart from compensated to decompensated failure in hypertensive rats.124 In addition, in early myocardial ischaemia, gene expression of decorin is reduced prior to remodelling.125 Decorin gene transfer to skeletal muscle results in its overexpression. This overexpression is associated with reduced fibrosis levels in many tissues, primarily via a decrease in extracellular matrix protein production through TGF-β1 inhibition.126 Another protein, betaglycan, often referred to as TGF-β1 receptor III, is thought to be a molecule that modulates the binding of TGF-β1to TGF-β1 receptor II in the cardiomyocyte membrane. However, soluble betaglycan, like decorin, has been shown to be a potent physiological inhibitor of TGF-β1.127 Administration of betaglycan has been noted to reduce hepatic fibrosis in chronic liver injury.128 The effects of betaglycan on cardiac fibrosis have not yet been studied.

Recent trends in endocrinology indicate that hormones play a prominent role in the regulation of collagen levels within the heart. Hsu et al. report that both ventricular and atrial cells possess receptors for relaxin, a peptide hormone with antifibrotic properties.129 Du et al. noted that relaxin-deficient mice have increased levels of myocardial collagen and develop subsequent ventricular diastolic dysfunction.130 Dschietzig et al. found that plasma concentration and myocardial expression of relaxin was associated with the preservation of cardiac function in patients with heart failure.131 Samuel et al. showed that relaxin, through a currently unknown mechanism, inhibited fibroblast activation and collagen synthesis in cultured cell lines treated with TGF-β1.132 Therefore, relaxin holds promise as an important therapeutic tool for patients with heart disease.

Finally, the role of genetics in the development of cardiac remodelling seems to be ever increasing. For this reason, the potential for gene therapy as a means for preventing fibrosis is great. Thus far, very little gene therapy research has focused on the treatment of cardiopathology. However, in a recent animal model study, Okada et al. showed that TGF-β1 receptor II gene therapy begun 3 days after infarction (subacute stage) resulted in the attenuation of remodelling in rats, with marked reduction in cardiac fibrosis and prevention of left ventricular enlargement noted after 4 weeks (chronic stage).133 Importantly, at this time, left ventricular function and survival were also found to be significantly greater than in non-treated controls. These findings offer great hope for obtaining similar results with TGF-β1 inhibition in the human heart.

The initial hesitancy to use TGF-β1antagonists in the post-infarct state was based on the cardioprotective effects of fibrosis immediately following myocardial necrosis. However, currently, evidence from in vivo and animal studies indicates that inhibiting the actions of TGF-β1 after the acute phase of infarction may prevent or attenuate remodelling and therefore it must be a target for future therapies. These benefits may not be limited to ventricular remodelling, as mechanisms of pathogenesis in the post-infarct state appear to overlap with those seen in arrhythmia and valvular disease.

Potential adverse consequences of TGF-β1 inhibition

The use of TGF-β1 antagonists to combat myocardial fibrosis does not come without risks. Knockout model studies have helped to outline the potential dangers of TGF-β1 inhibition. Most obviously, knockout mice lacking TGF-β1 are usually unable to survive beyond a few weeks because of aberrant immune regulation, primarily manifested as lethal cardiac and pulmonary inflammation.134 Deletion of the TGF-β1 gene is associated with exacerbation of asthma pathology, with notable eisonophil infiltration and mucus secretion.135137 Knockout models have also shown the importance of TGF-β1 in hair follicle, pulmonary and bone development.138140

TGF-β1 appears to be able to both suppress and stimulate the proliferation of cells, further complicating treatment regimens aimed at TGF-β1 inhibition. TGF-β1 is thought to mediate growth arrest by up-regulating cyclin-dependent kinase inhibitors and down-regulating c-myc and cell division cycle 25A.141 Reduced expression or mutational inactivation of the TGF-β1–Smad pathway is associated with uncontrolled cellular growth, particularly in endothelial cell lines.142 Studies indicate that TGF-β1 heterozygous null mice have increased hepatocyte and mammary epithelial cell proliferation potential, as well as decreased levels of apoptosis within the lung and liver.143 Additionally, loss of TGF-β1 receptor function has been associated with progression of malignancy and increased tumour growth.144,145

Cells whose growth is no longer inhibited by TGF-β1, but where the TGF-β1–Smad pathway is still maintained, show increased migration and invasion in response to TGF-β1 administration.146 In addition, the increased expression of TGF-β1 is associated with increased tumour potential. Massaguéet al. have proposed that TGF-β1 enhances tumour progression through suppression of the immune system, as well as promotion of angiogenesis.141

TGF-β1 is also thought to cause the proliferation of mesenchymal cells such as fibroblasts, necessary for stroma formation in many organs.147 Rosenbaum et al. noted that administration of TGF-β1 produces a dose and time-dependent increase in the proliferation of human liver fibroblasts.148 Although the signalling pathways for these effects are not well known, TGF-β1 may down-regulate expression of cyclin-dependent kinase inhibitors, facilitating cellular entry into the S-phase of its cycle.149 Other theories have proposed the TGF-β1-induced up-regulation of platelet-derived growth factor and fibroblast growth factor are responsible for cellular proliferation.150153

The potential consequences of TGF-β1 inhibition must be looked at carefully before its clinical use. In particular, the important physiological roles of TGF-β1 in organ development, immune system regulation and cellular proliferation suggest the possibility of serious side-effects for treatments targeting the actions of TGF-β1. Further study examining TGF-β1 inhibition would help to identify patient groups at risk for adverse consequences. In addition, efforts must be made to localize TGF-β1 inhibition within the heart to prevent systemic side-effects.


Fibrosis appears to be an integral component of most cardiac pathologies. In fibrosis, the excess production of extracellular matrix proteins alters the structure, architecture and shape of the heart. Such changes have marked effects on ventricular contractility, valvular functioning and electrical conduction. In particular, TGF-β1 has been implicated in the pathogenesis of each of these three facets of cardiac functioning. Although TGF-β1 is known to promote local collagen production, many details regarding the mechanisms of TGF-β1-induced fibrosis remain unclear. For example, circulating levels of ACE and angiotensin II are not elevated in valvular disease as they are after infarction. Rather, ACE levels are raised solely within the valvular tissue itself.154 This may imply that a ‘local remodelling’ process occurs within the endocardium of valves rather than the diffuse myocardial changes that arise in the post-ischaemic state.

The concept of remodelling can be applied to the atrium as well. Generally, this remodelling refers to changes in ion current flow following persistent atrial fibrillation.155 However, structural alterations have also been reported with recurrent atrial tachycardias. Patients with chronic atrial fibrillation were shown to have higher levels of myocardial interstitial fibrosis as compared to controls, particularly within the region of the pulmonary veins, which are known to be arrhythmogenic.156158 An effort must be made to understand whether TGF-β1 plays a prominent role within the ‘atrial fibrillation begets atrial fibrillation’ remodelling paradigm.

As TGF-β1 appears to be involved in different cardiopathological processes, it is an apt target for future therapy. Thus far, animal studies have shown that inhibiting the actions of TGF-β1 may attenuate fibrosis in the heart. Also, with increasing evidence indicating that TGF-β1 gene polymorphism and dysregulation predisposes to heart conditions, drug regimens and gene therapy may act to prevent rather than merely treat disease.

At this time the potential for therapy targeting TGF-β1 seems unlimited. However, before TGF-β1 inhibition can be used in a clinical setting, more in vivo and animal-based studies are required to understand the potential side-effects of treatment, as well as to provide more than the circumstantial correlation between TGF-β1 and cardiac fibrosis that exists currently.


I would like to thank Sapna Rawal for her patience and support.


angiotensin-converting enzyme
activated transcription factor-2
connective tissue growth factor
mitogen-activated protein kinase kinase kinase
matrix metalloproteinases
membrane type-MMP
transforming growth factor-β-activated kinase
transforming growth factor-β1


1. Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest. 2004;34:785–96. [PubMed]
2. Vallance BA, Gunawan MI, Hewlett B, et al. TGF-β1 gene transfer to the mouse colon leads to intestinal fibrosis. Am J Physiol Gastrointest Liver Physiol. 2005 [Epub ahead of print] [PubMed]
3. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–18. [PMC free article] [PubMed]
4. Yang Y, Zhou X, Gao H, Ji SJ, Wang C. The expression of epidermal growth factor and transforming growth factor-beta1 in the stenotic tissue of congenital pelvi-ureteric junction obstruction in children. J Pediatr Surg. 2003;38:1656–60. [PubMed]
5. Tomita H, Egashira K, Ohara Y, et al. Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension. 1998;32:273–9. [PubMed]
6. Nakajima H, Nakajima HO, Salcher O, Dittie AS, Dembowsky K, Jing S, Field LJ. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-beta(1) transgene in the heart. Circ Res. 2000;86:571–9. [PubMed]
7. Rosenkranz S, Flesch M, Amann K, Haeuseler C, Kilter H, Seeland U, Schluter KD, Bohm M. Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta(1) Am J Physiol Heart Circ Physiol. 2002;283:H1253–62. [PubMed]
8. Schultz Jel J, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest. 2002;109:787–96. [PMC free article] [PubMed]
9. Klein G, Schaefer A, Hilfiker-Kleiner D, et al. Increased collagen deposition and diastolic dysfunction but preserved myocardial hypertrophy following pressure overload in mice lacking PKCε Circ Res. 2005 [Epub ahead of print] [PubMed]
10. Verheule S, Sato T, Everett T, 4th, et al. Increased vulnerability to atrial fibrillation in transgenic mice with selective atrial fibrosis caused by overexpression of TGF-β1. Circ Res. 2004;94:1458–65. [PMC free article] [PubMed]
11. Walker GA, Masters KS, Shah DN, Anseth KS, Leinwand LA. Valvular myofibroblast activation by transforming growth factor-beta: implications for pathological extracellular matrix remodeling in heart valve disease. Circ Res. 2004;95:253–60. [PubMed]
12. Kuwahara F, Kai H, Tokuda K, Kai M, Takeshita A, Egashira K, Imaizumi T. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation. 2002;106:130–5. [PubMed]
13. Isaka Y, Tsujie M, Ando Y, Nakamura H, Kaneda Y, Imai E, Hori M. Transforming growth factor-beta 1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral ureteral obstruction. Kidney Int. 2000;58:1885–92. [PubMed]
14. Agrotis A, Kalinina N, Bobik A. Transforming growth factor-beta, cell signaling and cardiovascular disorders. Curr Vasc Pharmacol. 2005;3:55–61. [PubMed]
15. Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta(1) Mol Genet Metab. 2000;71:418–35. [PubMed]
16. Pedrozo HA, Schwartz Z, Gomez R, et al. Growth plate chondrocytes store latent transforming growth factor (TGF)-beta 1 in their matrix through latent TGF-beta 1 binding protein-1. J Cell Physiol. 1998;177:343–54. [PubMed]
17. Krieglstein K, Henheik P, Farkas L, Jaszai J, Galter D, Krohn K, Unsicker K. Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons. J Neurosci. 1998;18:9822–34. [PubMed]
18. Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS. Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med. 1986;163:1037–50. [PMC free article] [PubMed]
19. Luethviksson BR, Gunnlaugsdottir B. Transforming growth factor-beta as a regulator of site-specific T-cell inflammatory response. Scand J Immunol. 2003;58:129–38. [PubMed]
20. Jiang X, Zeng HS, Guo Y, Zhou ZB, Tang BS, Li FK. The expression of matrix metalloproteinases-9, transforming growth factor-beta1 and transforming growth factor-beta receptor I in human atherosclerotic plaque and their relationship with plaque stability. Chin Med J (Engl) 2004;117:1825–9. [PubMed]
21. Cipollone F, Fazia M, Mincione G, et al. Increased expression of transforming growth factor-beta1 as a stabilizing factor in human atherosclerotic plaques. Stroke. 2004;35:2253–7. [PubMed]
22. Roberts AB, Sporn MB. The transforming growth factors-β In: Sporn MB, Roberts AB, editors. Handbook of Experimental Pharmacology. Peptide Growth Factors and Their Receptors. New York: Springer-Verlag; 1990. pp. 419–72.
23. Wolf G. Link between angiotensin II and TGF-beta in the kidney. Miner Electrolyte Metab. 1998;24:174–80. [PubMed]
24. Fukuda N. Molecular mechanisms of the exaggerated growth of vascular smooth muscle cells in hypertension. J Atheroscler Thromb. 1997;4:65–72. [PubMed]
25. Lee AA, Dillmann WH, McCulloch AD, Villarreal FJ. Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol. 1995;27:2347–57. [PubMed]
26. Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol. 1997;29:1947–58. [PubMed]
27. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H. Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats. Hypertension. 1995;25:1252–9. [PubMed]
28. Kupfahl C, Pink D, Friedrich K, et al. Angiotensin II directly increases transforming growth factor beta 1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res. 2000;46:463–75. [PubMed]
29. Kim S, Ohta K, Hamaguchi A, et al. Angiotensin II type I receptor antagonist inhibits the gene expression of TGF-1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther. 1995;273:509–15. [PubMed]
30. el-Agroudy AE, Hassan NA, Foda MA, Ismail AM, el-Sawy EA, Mousa O, Ghoneim MA. Effect of angiotensin II receptor blocker on plasma levels of TGF-beta 1 and interstitial fibrosis in hypertensive kidney transplant patients. Am J Nephrol. 2003;23:300–6. [PubMed]
31. Agarwal R, Siva S, Dunn SR, Sharma K. Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels. Am J Kidney Dis. 2002;39:486–92. [PubMed]
32. Laviades C, Varo N, Diez J. Transforming growth factor beta in hypertensives with cardiorenal damage. Hypertension. 2000;36:517–22. [PubMed]
33. Rosenkranz S. TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res. 2004;63:423–32. [PubMed]
34. Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation. consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci. 2004;35:83–92. [PubMed]
35. Pokharel S, Rasoul S, Roks AJ, et al. N-acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2 in cardiac fibroblasts. Hypertension. 2002;40:155–61. [PubMed]
36. Greene RM, Nugent P, Mukhopadhyay P, Warner DR, Pisano MM. Intracellular dynamics of Smad-mediated TGFbeta signaling. J Cell Physiol. 2003;197:261–71. [PubMed]
37. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14:627–44. [PubMed]
38. Tsuchida K, Zhu Y, Siva S, Dunn SR, Sharma K. Role of Smad4 on TGF-beta-induced extracellular matrix stimulation in mesangial cells. Kidney Int. 2003;63:2000–9. [PubMed]
39. Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001;276:17058–62. [PubMed]
40. Yamaguchi K, Shirakabe K, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transduction. Science. 1995;270:2008–11. [PubMed]
41. Zhang D, Gaussin V, Taffet GE, et al. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med. 2000;6:556–63. [PubMed]
42. Hanafusa H, Ninomiya-Tsuji J, Masuyama N, Nishita M, Fujisawa J, Shibuya H, Matsumoto K, Nishida E. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem. 1999;274:27161–7. [PubMed]
43. Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S. ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling. J Biol Chem. 1999;274:8949–57. [PubMed]
44. Monzen K, Shiojima I, Hiroi Y, et al. Bone morphogenetic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA-4. Mol Cell Biol. 1999;19:7096–105. [PMC free article] [PubMed]
45. Qiao B, Padilla SR, Benya PD. Transforming growth factor (TGF) -beta-activated kinase 1 mimics and mediates TGF-beta-induced stimulation of type II collagen synthesis in chondrocytes independent of Col2a1 transcription and Smad3 signaling. J Biol Chem. 2005;280:17562–71. [PubMed]
46. Moussad EE, Brigstock DR. Connective tissue growth factor: what's in a name? Mol Genet Metab. 2000;71:276–92. [PubMed]
47. Grotendorst GR. Connective tissue growth factor. a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev. 1997;8:171–9. [PubMed]
48. Chen MM, Lam A, Abraham JA, Schreiner GF, Joly AH. CTGF expression is induced by TGF-beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis. J Mol Cell Cardiol. 2000;32:1805–19. [PubMed]
49. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J. 1999;13:1774–86. [PubMed]
50. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure. Relation to ventricular and myocyte function. Circ Res. 1998;82:482–95. [PubMed]
51. Kim HE, Dalal SS, Young E, Legato MJ, Weisfeldt ML, D'Armiento J. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest. 2000;106:857–66. [PMC free article] [PubMed]
52. Hayashidani S, Tsutsui H, Ikeuchi M, et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. Am J Physiol Heart Circ Physiol. 2003;285:H1229–35. [PubMed]
53. Hein S, Arnon E, Kostin S, et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation. 2003;107:984–91. [PubMed]
54. Shimizu N, Yoshiyama M, Takeuchi K, Hanatani A, Kim S, Omura T, Iwao H, Yoshikawa J. Doppler echocardiographic assessment and cardiac gene expression analysis of the left ventricle in myocardial infarcted rats. Jpn Circ J. 1998;62:436–42. [PubMed]
55. Overall CM, Wrana JL, Sodek J. Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem. 1991;266:14064–71. [PubMed]
56. Briest W, Homagk L, Rassler B, et al. Norepinephrine-induced changes in cardiac transforming growth factor-beta isoform expression pattern of female and male rats. Hypertension. 2004;44:410–18. [PubMed]
57. Zigrino P, Drescher C, Mauch C. Collagen-induced proMMP-2 activation by MT1-MMP in human dermal fibroblasts and the possible role of alpha2beta1 integrins. Eur J Cell Biol. 2001;80:68–77. [PubMed]
58. Stawowy P, Margeta C, Kallisch H, Seidah NG, Chretien M, Fleck E, Graf K. Regulation of matrix metalloproteinase MT1-MMP/MMP-2 in cardiac fibroblasts by TGF-beta1 involves furin-convertase. Cardiovasc Res. 2004;63:87–97. [PubMed]
59. Lijnen P, Petrov V. Transforming growth factor-beta 1-induced collagen production in cultures of cardiac fibroblasts is the result of the appearance of myofibroblasts. Meth Find Exp Clin Pharmacol. 2002;24:333–44. [PubMed]
60. Petrov VV, Fagard RH, Lijnen PJ. Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension. 2002;39:258–63. [PubMed]
61. Vaughan MB, Howard EW, Tomasek JJ. Transforming growth factor-beta1 promotes the morphological and functional differentiation of the myofibroblast. Exp Cell Res. 2000;257:180–9. [PubMed]
62. Riemann D, Wollert HG, Menschikowski J, Mittenzwei S, Langner J. Immunophenotype of lymphocytes in pericardial fluid from patients with different forms of heart disease. Int Arch Allergy Immunol. 1994;104:48–56. [PubMed]
63. Hinglais N, Heudes D, Nicoletti A, Mandet C, Laurent M, Bariety J, Michel JB. Colocalization of myocardial fibrosis and inflammatory cells in rats. Lab Invest. 1994;70:286–94. [PubMed]
64. Kuwahara F, Kai H, Tokuda K, Takeya M, Takeshita A, Egashira K, Imaizumi T. Hypertensive myocardial fibrosis and diastolic dysfunction. another model of inflammation? Hypertension. 2004;43:739–45. [PubMed]
65. Kagitani S, Ueno H, Hirade S, Takahashi T, Takata M, Inoue H. Tranilast attenuates myocardial fibrosis in association with suppression of monocyte/macrophage infiltration in DOCA/salt hypertensive rats. J Hypertens. 2004;22:1007–15. [PubMed]
66. Nag AC. Study of non-muscle cells of the adult mammalian heart. A fine structural analysis and distribution. Cytobios. 1980;28:41–61. [PubMed]
67. MacKenna DA, Vaplon SM, McCulloch AD. Microstructural model of perimysial collagen fibers for resting myocardial mechanics during ventricular filling. Am J Physiol. 1997;273:H1576–86. [PubMed]
68. Jalil JE, Doering CW, Janicki JS, Pick R, Shroff SG, Weber KT. Fibrillar collagen and myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res. 1989;64:1041–50. [PubMed]
69. Covell JW. Factors influencing diastolic function: possible role of the extracellular matrix. Circulation. 1990;81:III-115–III-158. [PubMed]
70. MacKenna DA, Omens JH, McCulloch AD, Covell JW. Contribution of collagen matrix to passive left ventricular mechanics in isolated rat hearts. Am J Physiol. 1994;266:H1007–18. [PubMed]
71. Wu Y, Tobias AH, Bell K, et al. Cellular and molecular mechanisms of systolic and diastolic dysfunction in an avian model of dilated cardiomyopathy. J Mol Cell Cardiol. 2004;37:111–19. [PubMed]
72. Deten A, Holzl A, Leicht M, Barth W, Zimmer HG. Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. J Mol Cell Cardiol. 2001;33:1191–207. [PubMed]
73. Hao J, Ju H, Zhao S, Junaid A, Scammell-La Fleur T, Dixon IM. Elevation of expression of Smads 2, 3 and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J Mol Cell Cardiol. 1999;31:667–78. [PubMed]
74. Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol. 2002;282:H1685–96. [PubMed]
75. Maekawa Y, Anzai T, Yoshikawa T, Sugano Y, Mahara K, Kohno T, Takahashi T, Ogawa S. Effect of granulocyte-macrophage colony-stimulating factor inducer on left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2004;44:1510–20. [PubMed]
76. Sun Y, Zhang JQ, Zhang J, Ramires FJ. Angiotensin II, transforming growth factor-beta1 and repair in the infarcted heart. J Mol Cell Cardiol. 1998;30:1559–69. [PubMed]
77. Kanzaki T, Tamura K, Takahashi K, et al. In vivo effect of TGF-beta 1. Enhanced intimal thickening by administration of TGF-beta 1 in rabbit arteries injured with a balloon catheter. Arterioscler Thromb Vasc Biol. 1995;15:1951–7. [PubMed]
78. Chen X, Ren S, Ma MG, Dharmalingam S, Lu L, Xue M, Ducas J, Shen GX. Hirulog-like peptide reduces restenosis and expression of tissue factor and transforming growth factor-beta in carotid artery of atherosclerotic rabbits. Atherosclerosis. 2003;169:31–40. [PubMed]
79. Lindner V. Vascular repair processes mediated by transforming growth factor-beta. Z Kardiol. 2001;90:17–22. [PubMed]
80. Friedl R, Li J, Schumacher B, Hanke H, Waltenberger J, Hannekum A, Stracke S. Intimal hyperplasia and expression of transforming growth factor-beta1 in saphenous veins and internal mammary arteries before coronary artery surgery. Ann Thorac Surg. 2004;78:1312–18. [PubMed]
81. Rao M, Guo D, Jaber BL, Tighiouart H, Pereira BJ, Balakrishnan VS. HEMO Study Group. Transforming growth factor-beta 1 gene polymorphisms and cardiovascular disease in hemodialysis patients. Kidney Int. 2004;66:419–27. [PubMed]
82. Yokota M, Ichihara S, Lin TL, Nakashima N, Yamada Y. Association of a T29 → C polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to myocardial infarction in Japanese. Circulation. 2000;101:2783–7. [PubMed]
83. Blom IE, van Dijk AJ, de Weger RA, Tilanus MG, Goldschmeding R. Identification of human ccn2 (connective tissue growth factor) promoter polymorphisms. Mol Pathol. 2001;54:192–6. [PMC free article] [PubMed]
84. Holmes A, Abraham DJSaS, Shiwen X, Black CM, Leask A. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem. 2001;276:10594–601. [PubMed]
85. Maron BJ, Bonow RO, Cannon RO, 3rd, Leon MB, Epstein SE. Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy. N Engl J Med. 1987;316:780–9. [PubMed]
86. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000;35:36–44. [PubMed]
87. Mundhenke M, Schwartzkopff B, Stark P, Schulte HD, Strauer BE. Myocardial collagen type I and impaired left ventricular function under exercise in hypertrophic cardiomyopathy. Thorac Cardiovasc Surg. 2002;50:216–22. [PubMed]
88. Li G, Borger MA, Williams WG, Weisel RD, Mickle DA, Wigle ED, Li RK. Regional overexpression of insulin-like growth factor-I and transforming growth factor-beta1 in the myocardium of patients with hypertrophic obstructive cardiomyopathy. J Thorac Cardiovasc Surg. 2002;123:89–95. [PubMed]
89. Li G, Li RK, Mickle DA, et al. Elevated insulin-like growth factor-I and transforming growth factor-beta 1 and their receptors in patients with idiopathic hypertrophic obstructive cardiomyopathy. A possible mechanism. Circulation. 1998;98:II144–9. [PubMed]
90. Di Nardo P, Fiaccavento R, Natali A, et al. Embryonic gene expression in nonoverloaded ventricles of hereditary hypertrophic cardiomyopathic hamsters. Laboratory Invest. 1997;77:489–502. [PubMed]
91. Brooks A, Schinde V, Bateman AC, Gallagher PJ. Interstitial fibrosis in the dilated non-ischaemic myocardium. Heart. 2003;89:1255–6. [PMC free article] [PubMed]
92. Marijianowski MM, Teeling P, Mann J, Becker AE. Dilated cardiomyopathy is associated with an increase in the type I/type III collagen ratio: a quantitative assessment. J Am Coll Cardiol. 1995;25:1263–72. [PubMed]
93. Sanderson JE, Lai KB, Shum IO, Wei S, Chow LT. Transforming growth factor-beta (1) expression in dilated cardiomyopathy. Heart. 2001;86:701–8. [PMC free article] [PubMed]
94. Kuhl U, Noutsias M, Schultheiss HP. Immunohistochemistry in dilated cardiomyopathy. Eur Heart J. 1995;16:100–6. [PubMed]
95. Holweg CT, Baan CC, Niesters HG, Vantrimpont PJ, Mulder PG, Maat AP, Weimar W, Balk AH. TGF-beta1 gene polymorphisms in patients with end-stage heart failure. J Heart Lung Transplant. 2001;20:979–84. [PubMed]
96. Yamada Y, Miyauchi A, Takagi Y, Tanaka M, Mizuno M, Harada A. Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res. 1998;13:1569–76. [PubMed]
97. Dixon IM, Hao J, Reid NL, Roth JC. Effect of chronic AT (1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters. Cardiovasc Res. 2000;46:286–97. [PubMed]
98. Kan H, Xie Z, Finkel MS. p38 MAP kinase-mediated negative inotropic effect of HIV gp120 on cardiac myocytes. Am J Physiol Cell Physiol. 2004;286:C1–7. [PubMed]
99. Taylor PM, Batten P, Brand NJ, Thomas PS, Yacoub MH. The cardiac valve interstitial cell. Int J Biochem Cell Biol. 2003;35:113–18. [PubMed]
100. Olsson M, Rosenqvist M, Nilsson J. Expression of HLA-DR antigen and smooth muscle cell differentiation markers by valvular fibroblasts in degenerative aortic stenosis. J Am Coll Cardiol. 1994;24:1664–71. [PubMed]
101. Rabkin E, Aikawa M, Stone JR, Fukumoto Y, Libby P, Schoen FJ. Activated interstitial myofibroblasts express catabolic enzymes and mediate matrix remodeling in myxomatous heart valves. Circulation. 2001;104:2525–32. [PubMed]
102. Jian B, Narula N, Li QY, Mohler ER, III, Levy RJ. Progression of aortic valve stenosis: TGF-beta1 is present in calcified aortic valve cuSPS and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg. 2003;75:457–65. [PubMed]
103. Fielitz J, Hein S, Mitrovic V, et al. Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol. 2001;37:1443–9. [PubMed]
104. Jian B, Xu J, Connolly J, Savani RC, Narula N, Liang B, Levy RJ. Serotonin mechanisms in heart valve disease I. serotonin-induced up-regulation of transforming growth factor-beta1 via G-protein signal transduction in aortic valve interstitial cells. Am J Pathol. 2002;161:2111–21. [PMC free article] [PubMed]
105. Chou HT, Chen CH, Tsai CH, Tsai FJ. Association between transforming growth factor-beta1 gene C-509T and T869C polymorphisms and rheumatic heart disease. Am Heart J. 2004;148:181–6. [PubMed]
106. Ng CM, Cheng A, Myers LA, et al. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest. 2004;114:1586–92. [PMC free article] [PubMed]
107. Nattel S, Shiroshita-Takeshita A, Cardin S, Pelletier P. Mechanisms of atrial remodeling and clinical relevance. Curr Opin Cardiol. 2005;20:21–5. [PubMed]
108. Hassink RJ, Aretz HT, Ruskin J, Keane D. Morphology of atrial myocardium in human pulmonary veins: a postmortem analysis in patients with and without atrial fibrillation. J Am Coll Cardiol. 2003;42:1108–14. [PubMed]
109. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of repolarization with anisotropic propagation in dog atria. A mechanism for both preventing and initiating reentry. Circ Res. 1989;65:1612–31. [PubMed]
110. Hanna N, Cardin S, Leung TK, Nattel S. Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure. Cardiovasc Res. 2004;63:236–44. [PubMed]
111. Clancy RM, Backer CB, Yin X, Kapur RP, Molad Y, Buyon JP. Cytokine polymorphisms and histologic expression in autopsy studies. contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block. J Immunol. 2003;171:3253–61. [PubMed]
112. Neuberger HR, Schotten U, Verheule S, Eijsbouts S, Blaauw Y, van Hunnik A, Allessie M. Development of a substrate of atrial fibrillation during chronic atrioventricular block in the goat. Circulation. 2005;111:30–7. [PubMed]
113. Shi Y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res. 2002;54:456–61. [PubMed]
114. Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999;100:376–80. [PubMed]
115. L'Allier PL, Ducharme A, Keller PF, Yu H, Guertin MC, Tardif JC. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol. 2004;44:159–64. [PubMed]
116. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:712–19. [PubMed]
117. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation. 2002;106:331–6. [PubMed]
118. Hallberg P, Lind L, Billberger K, et al. Transforming growth factor beta1 genotype and change in left ventricular mass during antihypertensive treatment – results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) Clin Cardiol. 2004;27:169–73. [PubMed]
119. Koyanagi M, Egashira K, Kubo-Inoue M, Usui M, Kitamoto S, Tomita H, Shimokawa H, Takeshita A. Role of transforming growth factor-beta1 in cardiovascular inflammatory changes induced by chronic inhibition of nitric oxide synthesis. Hypertension. 2000;35:86–90. [PubMed]
120. Ikeda H, Inao M, Fujiwara K. Inhibitory effect of tranilast on activation and transforming growth factor beta 1 expression in cultured rat stellate cells. Biochem Biophys Res Commun. 1996;227:322–7. [PubMed]
121. Hocher B, Godes M, Olivier J, et al. Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension. J Hypertens. 2002;20:745–51. [PubMed]
122. Martin J, Kelly DJ, Mifsud SA, et al. Tranilast attenuates cardiac matrix deposition in experimental diabetes: role of transforming growth factor-beta. Cardiovasc Res. 2005;65:694–701. [PubMed]
123. Holmes D, Fitzgerald P, Goldberg S, et al. The PRESTO (Prevention of restenosis with tranilast and its outcomes) protocol: a double-blind, placebo-controlled trial. Am Heart J. 2000;139:23–31. [PubMed]
124. Mujumdar VS, Tyagi SC. Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure. J Hypertens. 1999;17:261–70. [PubMed]
125. Simkhovich BZ, Marjoram P, Poizat C, Kedes L, Kloner RA. Age-related changes of cardiac gene expression following myocardial ischemia/reperfusion. Arch Biochem Biophys. 2003;420:268–78. [PubMed]
126. Costacurta A, Priante G, D'Angelo A, Chieco-Bianchi L, Cantaro S. Decorin transfection in human mesangial cells downregulates genes playing a role in the progression of fibrosis. J Clin Laboratory Anal. 2002;16:178–86. [PubMed]
127. Lopez-Casillas F, Payne HM, Andres JL, Massague J. Betaglycan can act as a dual modulator of TGF-beta access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol. 1994;124:557–68. [PMC free article] [PubMed]
128. Ezquerro IJ, Lasarte JJ, Dotor J, et al. A synthetic peptide from transforming growth factor beta type III receptor inhibits liver fibrogenesis in rats with carbon tetrachloride liver injury. Cytokine. 2003;22:12–20. [PubMed]
129. Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ. Activation of orphan receptors by the hormone relaxin. Science. 2002;295:671–4. [PubMed]
130. Du XJ, Samuel CS, Gao XM, Zhao L, Parry LJ, Tregear GW. Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype. Cardiovasc Res. 2003;57:395–404. [PubMed]
131. Dschietzig T, Richter C, Bartsch C, Laule M, Armbruster FP, Baumann G, Stangl K. The pregnancy hormone relaxin is a player in human heart failure. FASEB J. 2001;15:2187–95. [PubMed]
132. Samuel CS, Unemori EN, Mookerjee I, Bathgate RA, Layfield SL, Mak J, Tregear GW, Du XJ. Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology. 2004;145:4125–33. [PubMed]
133. Okada H, Takemura G, Kosai K, et al. Postinfarction gene therapy against transforming growth factor-beta signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation. 2005;111:2430–7. [PubMed]
134. Chen W, Wahl SM. TGF-beta: receptors. Current Directions Autoimmunity. 2002;5:62–91. [PubMed]
135. Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993;90:770–4. [PMC free article] [PubMed]
136. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–9. [PMC free article] [PubMed]
137. Scherf W, Burdach S, Hansen G. Reduced expression of transforming growth factor beta 1 exacerbates pathology in an experimental asthma model. Eur J Immunol. 2005;35:198–206. [PubMed]
138. Foitzik K, Lindner G, Mueller-Roever S, et al. Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo. FASEB J. 2000;14:752–60. [PubMed]
139. Chen H, Sun J, Buckley S, Chen C, Warburton D, Wang XF, Shi W. Abnormal mouse lung alveolarization caused by Smad3 deficiency is a developmental antecedent of centrilobular emphysema. Am J Physiol Lung Cell Mol Physiol. 2005;288:L683–91. [PubMed]
140. Geiser AG, Zeng QQ, Sato M, Helvering LM, Hirano T, Turner CH. Decreased bone mass and bone elasticity in mice lacking the transforming growth factoR-beta1 gene. Bone. 1998;23:87–93. [PubMed]
141. Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309. [PubMed]
142. Kim SJ, Im YH, Markowitz SD, Bang YJ. Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis. Cytokine Growth Factor Rev. 2000;11:159–68. [PubMed]
143. Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR, Letterio JJ, Wakefield LM. Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency. Nat Med. 1998;4:802–7. [PubMed]
144. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest. 1999;103:197–206. [PMC free article] [PubMed]
145. Massagué J. TGF-β signal transduction. Annu Rev Biochem. 1998;67:753–91. [PubMed]
146. Cui W, Fowlis DJ, Bryson S, Duffie E, Ireland H, Balmain A, Akhurst RJ. TGFbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice. Cell. 1996;86:531–42. [PubMed]
147. Wenner CE, Yan S. Biphasic role of TGF-beta1 in signal transduction and crosstalk. J Cell Physiol. 2003;196:42–50. [PubMed]
148. Rosenbaum J, Blazejewski S, Preaux AM, Mallat A, Dhumeaux D, Mavier P. Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts. Gastroenterology. 1995;109:1986–96. [PubMed]
149. Ravitz MJ, Yan S, Herr KD, Wenner CE. Transforming growth factor beta-induced activation of cyclin E-cdk2 kinase and down-regulation of p27Kip1 in C3H 10T1/2 mouse fibroblasts. Cancer Res. 1995;55:1413–6. [PubMed]
150. Battegay EJ, Raines EW, Seifert RA, Bowen-Pope DF, Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell. 1990;63:515–24. [PubMed]
151. Win KM, Charlotte F, Mallat A, et al. Mitogenic effect of transforming growth factor-beta 1 on human Ito cells in culture: evidence for mediation by endogenous platelet-derived growth factor. Hepatol J. 1993;18:137–45. [PubMed]
152. Kay EP, Lee MS, Seong GJ, Lee YG. TGF-beta s stimulate cell proliferation via an autocrine production of FGF-2 in corneal stromal fibroblasts. Curr Eye Res. 1998;17:286–93. [PubMed]
153. Strutz F, Zeisberg M, Renziehausen A, Raschke B, Becker V, van Kooten C, Muller G. TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2) Kidney Int. 2001;59:579–92. [PubMed]
154. Helske S, Lindstedt KA, Laine M, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004;44:1859–66. [PubMed]
155. Wijffels MC, Kirchhof CJ, Dorland R, Power J, Allessie MA. Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation. Circulation. 1997;96:3710–20. [PubMed]
156. Corradi D, Callegari S, Benussi S, et al. Regional left atrial interstitial remodeling in patients with chronic atrial fibrillation undergoing mitral-valve surgery. Virchows Arch. 2004;445:498–505. [PubMed]
157. Thijssen VL, Ausma J, Liu GS, Allessie MA, van Eys GJ, Borgers M. Structural changes of atrial myocardium during chronic atrial fibrillation. Cardiovasc Pathol. 2000;9:17–28. [PubMed]
158. Tagawa M, Higuchi K, Chinushi M, Washizuka T, Ushiki T, Ishihara N, Aizawa Y. Myocardium extending from the left atrium onto the pulmonary veins: a comparison between subjects with and without atrial fibrillation. Pacing Clin Electrophysiol. 2001;24:1459–63. [PubMed]

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