Cardiovascular Research

Cardiovascular Research 2004 63(3):423-432; doi:10.1016/j.cardiores.2004.04.030
© 2004 by European Society of Cardiology

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Copyright © 2004, European Society of Cardiology

TGF-β₁ and angiotensin networking in cardiac remodeling

Stephan Rosenkranz^*

Klinik III für Innere Medizin, Universität zu Köln, Joseph-Stelzmann-Str. 9, D-50924 Cologne, Germany
Center for Molecular Medicine Cologne (CMMC), Universität zu Köln, Germany

^* Klinik III für Innere Medizin, Universität zu Köln, Joseph-Stelzmann-Str. 9, D-50924 Cologne, Germany. Tel.: +49-221-478-5159; fax: +49-221-478-6490. Email address: stephan.rosenkranz{at}medizin.uni-koeln.de

Received 2 January 2004; revised 14 April 2004; accepted 26 April 2004

	Abstract

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
The renin–angiotensin system (RAS) and transforming growth factor-β₁ (TGF-β₁) play a pivotal role in the development of cardiac hypertrophy and heart failure. Recent studies indicate that angiotensin II (Ang II) and TGF-β₁ do not act independently from one another but rather act as part of a signalling network in order to promote cardiac remodeling, which is a key determinant of clinical outcome in heart disease. This review focuses on recent advances in the understanding, how Ang II and TGF-β₁ are connected in the pathogenesis of cardiac hypertrophy and dysfunction. Increasing evidence suggests that at least some of the Ang II-induced effects on cardiac structure are mediated via indirect actions. Ang II upregulates TGF-β₁ expression via activation of the angiotensin type 1 (AT₁) receptor in cardiac myocytes and fibroblasts, and induction of this cytokine is absolutely required for Ang II-induced cardiac hypertrophy in vivo. TGF-β induces the proliferation of cardiac fibroblasts and their phenotypic conversion to myofibroblasts, the deposition of extracellular matrix (ECM) proteins such as collagen, fibronectin, and proteoglycans, and hypertrophic growth of cardiomyocytes, and thereby mediates Ang II-induced structural remodeling of the ventricular wall in an auto-/paracrine manner. Downstream mediators of cardiac Ang II/TGF-β₁ networking include Smad proteins, TGFβ-activated kinase-1 (TAK1), and induction of hypertrophic responsiveness to β-adrenergic stimulation in cardiac myocytes.

KEYWORDS Cardiac hypertrophy; Heart failure; Angiotensin; TGF-β; Smads; β-Adrenoceptors; Cross-talk

	1. Introduction

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
Both the renin–angiotensin system (RAS) and transforming growth factor-β₁ (TGF-β₁) are key mediators of cardiac adaptations to hemodynamic overload, and are thus critically involved in the pathogenesis of cardiac hypertrophy and failure [1–4]. In situations such as hypertension or chronic myocardial infarction, the heart responds to increased afterload by initiating adaptive remodeling processes. These include cardiomyocyte hypertrophy, fibrosis, extracellular matrix (ECM) deposition, and alterations of cardiac gene expression [5–8]. Although these structural alterations represent the heart's efforts to maintain systolic function, they are deleterious over time and ultimately result in progressive heart failure [1]. On the molecular level, cardiac remodeling is mediated by activation of several neurohumoral systems including the RAS, TGF-β₁ and the β-adrenergic system. Recent studies indicate that angiotensin II (Ang II) and TGF-β₁ do not act independently from one another but rather act as part of a network that promotes cardiac remodeling. This review focuses on recent advances in the understanding, how Ang II and TGF-β₁ are connected in the pathogenesis of cardiac hypertrophy and failure. Furthermore, possible downstream mediators of the TGF-β₁/Ang II-connection are discussed.

	2. The RAS and TGF-β1 are critically involved in the pathogenesis of cardiac hypertrophy and failure

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
In humans, myocardial hypertrophy due to hemodynamic overload is characterized by increased deposition of ECM constituents, proliferation of cardiac fibroblasts, and hypertrophic growth of cardiac myocytes [5–8]. As a consequence of this remodeling process, decreased ventricular compliance contributes to diastolic dysfunction which over time is followed by the development of progressive contractile dysfunction and reentry arrhythmias [1,6]. Both the RAS and TGF-β₁ are critically involved in the development of cardiac hypertrophy due to pressure overload and the progression from compensated hypertrophy to heart failure.

2.1. Renin–angiotensin system
The importance of the RAS in cardiac remodeling and the beneficial effects of its inhibition on cardiac structure, function, and survival are well established. Numerous studies have shown that the RAS is activated in response to hemodynamic overload, and that activation of the (local) RAS contributes to myocardial hypertrophy, fibrosis, and dysfunction [1–3,9–11]. In addition, a large number of animal studies [12–15] and clinical trials in humans [16–24] have shown that inhibition of Ang II by angiotensin converting enzyme (ACE) inhibitors or angiotensin type 1 (AT₁) receptor antagonists prevents or reverses ventricular remodeling and improves survival in patients with heart failure.

The effector molecule of the RAS, Ang II, directly induces cellular responses in myocardial cells. However, it may activate distinct signaling pathways in cardiac fibroblasts versus cardiomyocytes, which may result in a differential regulation of genes in these two cell types [25]. In cultured cardiac fibroblasts, Ang II stimulates fibroblast proliferation, collagen synthesis, and the expression of ECM proteins such as collagen, fibronectin, and laminin via activation of the AT₁ receptor [26,27]. In cardiac myocytes, Ang II exerts a direct growth-promoting effect only on neonatal cells, whereas it does not strongly promote growth responses in adult cardiomyocytes [28,29]. In addition, Ang II-induced growth of neonatal cells involves the extracellular signal-regulated kinase (Erk) pathway, whereas growth responses induced by other stimuli, i.e. -adrenoceptors, do not require Erk activation in adult cardiomyocytes [3,30]. It has therefore been postulated that Ang II may not directly stimulate cardiomyocyte growth and fibrosis in adult myocardium in vivo, but may do so indirectly by inducing the expression of growth factors such as TGF-β₁, which then act locally via auto-/paracrine mechanisms [31]. Recent studies indicate that this indirect effect may indeed be the major mechanism by which Ang II induces cardiac remodeling [32,33]. For example, Ang II-induced fibronectin mRNA synthesis in cardiac fibroblasts was shown to be mediated by autocrine or paracrine effects of TGF-β₁ [34].

2.2 Transforming growth factor-β₁
TGF-β₁ is a locally generated cytokine that has been implicated as a major contributor to tissue fibrosis in various organ systems [35]. Recent studies in humans and experimental models have shown increased myocardial TGF-β₁ expression during cardiac hypertrophy and fibrosis. The expression of TGF-β₁ mRNA is increased in left ventricular myocardium of patients with idiopathic hypertrophic cardiomyopathy and dilated cardiomyopathy [36–38], and in animal models of myocardial infarction, progressive coronary artery occlusion, and pressure overload [39–45]. TGF-β₁ is particularly expressed in hypertrophic myocardium during the transition from stable hypertrophy to heart failure in experimental models [46] and human heart failure [47], and—in addition to increased collagen content—is thus one of a few markers discriminating between compensated and decompensated cardiac hypertrophy. In the pressure-overloaded human heart, upregulation of ACE and TGF-β₁ correlated with the degree of fibrosis [48]. In vitro, TGF-β₁ induces the production of ECM components including fibrillar collagen, fibronectin and proteoglycans by cardiac fibroblasts [49–51], stimulates fibroblast proliferation and the phenotypic conversion to myofibroblasts [52–54], and promotes fetal gene expression in cultured neonatal cardiac myocytes [4,55], all hallmarks of cardiac hypertrophy. In addition, TGF-β₁ self-amplifies its expression in myofibroblasts [56]. Overexpression of TGF-β₁ in transgenic mice results in cardiac hypertrophy which is characterized by both interstitial fibrosis and hypertrophic growth of cardiac myocytes [57,58], whereas heterozygous TGF-β₁ (+/–)-deficient mice reveal decreased fibrosis of the aging heart [59]. Finally, functional blockade of TGF-β₁ signaling in vivo by neutralizing antibodies prevents myocardial fibrosis and dysfunction in pressure-overloaded rat hearts [60], and ECM deposition in a model of cardiac hypertrophy induced by long-term blockade of NO synthesis [40].

Taken together, these studies collectively indicate that the RAS and TGF-β₁ contribute to the pathological cellular events that are responsible for myocardial fibrosis, hypertrophy and dysfunction.

	3. Evidence for a connection between Ang II and TGF-β1 in cardiac tissue

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
Numerous studies provide indirect evidence for a functional link between Ang II and TGF-β₁ in the heart. Some studies also indicate that these secreted factors act in an auto-/paracrine manner, and furthermore suggest cross-talk between the various myocardial cell types and compartments such as cardiac myocytes, fibroblasts, ECM, and the vasculature.

In vitro studies have shown that TGF-β₁ mRNA and protein are readily upregulated by Ang II in cardiac fibroblasts, myofibroblasts, and myocytes [31,34,61–67]. Stimulation of human atrial tissue with Ang II also caused a significant increase in TGF-β₁ mRNA [68], and chronic administration of Ang II was shown to induce myocardial TGF-β₁ expression in vivo irrespective of its effects on blood pressure [31,69,70]. Tissue culture experiments revealed that paracrine release of TGF-β₁ from fibroblasts mediates Ang II-induced cardiac myocyte hypertrophy as blocking antibodies to TGF-β₁ inhibit myocyte hypertrophy caused by conditioned medium of Ang II-treated fibroblasts [62]. The Ang II-induced upregulation of TGF-β₁ correlates with cardiac hypertrophy, fibrosis, and re-expression of a fetal cardiac genotype [29,31,62,65,68]. Furthermore, TGF-β₁ induction preceded the development of myocardial fibrosis and ECM production in various models [40,42,60]. Although Ang II-induced gene expression of ECM may be mediated by the AT₂ receptor [71], cardiac hypertrophy and the induction of TGF-β₁ as well as hypertrophy-associated genes such as atrial natriuretic factor (ANF), which may represent a marker differentiating between physiological and pathophysiological hypertrophy [72–74], have been shown to result from activation of the AT₁ receptor [66]. Ang II blockade by an AT₁ receptor antagonist reverses both cardiac TGF-β₁ expression and myocardial hypertrophy/fibrosis in rat models in vivo [31,40,75]. When viewed together, these studies demonstrate a strong correlation between Ang II, TGF-β₁ induction, and auto-/paracrine cellular responses in cardiac fibroblasts, the myocardial interstitium, and cardiomyocytes, which promote the development of cardiac hypertrophy (Fig. 1).

View larger version (24K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Schematic diagram illustrating the networking between Ang II and TGF-β1 in mediating cardiac hypertrophy via autocrine and paracrine mechanisms. (AT1R=Angiotensin type 1 receptor; TβR=TGF-β receptor, β-AR=β-adrenergic receptor, ECM=Extracellular matrix, βARK=β-Adrenoreceptor kinase.)

 

	4. Is there a causal relationship between Ang II, TGF-β1 and cardiac hypertrophy?

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
Although the above studies suggest a functional link between Ang II and TGF-β₁ in cardiac hypertrophy, a causal relationship has not been proven until recently. In a hallmark paper, Schultz et al. [32] tested whether Ang II would be able to induce cardiac hypertrophy and fibrosis in vivo in the absence of TGF-β₁. In TGF-β₁^–/–/Rag1^–/– mice (which were created to overcome the lethal phenotype of TGF-β₁^–/– mice which is due to an early-onset autoimmune multiorgan inflammatory disease [76]), the lack of the TGF-β₁ gene fully prevented the development of cardiac hypertrophy and dysfunction induced by subpressor doses of Ang II that was observed in wild type mice (Fig. 2). Disruption of TGF-β₁ signaling in knockout animals completely abolished the increase in left ventricular mass, the increase in myocyte size, the deterioration in systolic function (fractional shortening), and the induction of ANF [32]. This study provides the first direct evidence that Ang II-induced cardiac hypertrophy is mediated by TGF-β₁ and confirms the results from other studies which have suggested a functional link between Ang II and TGF-β₁ in myocardial remodeling in vivo (Table 1). These studies collectively indicate that TGF-β₁ acts downstream of Ang II and promotes myocyte growth and fibrosis in the heart. This paradigm is further supported by the fact that in mice overexpressing activated TGF-β₁ (cys^223,225ser), AT₁ receptor blockade with telmisartan is insufficient to prevent cardiac hypertrophy and dysfunction, whereas disruption of TGF-β₁ signaling by administration of a TGF-β antagonist (sTGFβR-Fc) fully prevented the cardiac phenotype in transgenic mice [77]. Furthermore, reduction of TGF-β₁ mRNA in ventricular tissue was shown to attenuate left ventricular fibrosis and to improve survival of renin-transgenic rats [78].

View larger version (20K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Causal relationship between Ang II and TGF-β1 in cardiac hypertrophy as demonstrated by Schultz et al. [32]. Hypertrophy in response to subpressor doses of Ang II was observed in wild type (TGF-β+/+) but not in TGF-β-deficient mice (TGF-β–/–), indicating that TGF-β is absolutely required for Ang II-induced cardiac hypertrophy in vivo.

 

View this table: [in this window] [in a new window]   Table 1 In vivo studies demonstrating cardiac hypertrophy/fibrosis related to Ang II/TGF-β1

 
In summary, Ang II upregulates TGF-β₁ expression via activation of the AT₁ receptor in cardiac myocytes and fibroblasts, and induction of this cytokine is absolutely required for Ang II-induced cardiac hypertrophy in vivo.

	5. Molecular mechanisms of TGF-β1 induction by angiotensin II

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
Cardiac hypertrophy and induction of TGF-β₁ expression are mediated by the Ang II type 1 (AT₁) receptor in vivo and in vitro [31,40,66,79–81]. Downstream of the AT₁ receptor, Ang II induces the activation of signaling cascades that regulate gene expression. It is well established that gene expression is regulated by the specific interaction of nuclear transacting proteins with corresponding cis-elements in the regulatory region of genes. A recent study investigating the intracellular signaling events that are required for Ang II-dependent upregulation of TGF-β₁ revealed that the induction of TGF-β₁ mRNA by Ang II in adult ventricular cardiomyocytes is mediated by NAD(P)H oxidase, and subsequent activation of protein kinase C (PKC), p38-MAP kinase, and nuclear Activating-Protein-1 (AP-1) binding activity [31] (Fig. 3). This is consistent with previous reports demonstrating that the increase of PKC activity observed in cardiac remodeling following myocardial infarction correlates with increased expression of the PKC-alpha, -beta, -epsilon, and -zeta isozymes [82]. Ang II-induced responses such as regulation of the sarcolemmal Na(+)–K(+) pump are mediated via PKC-epsilon, whereas TGF-β₁-induced collagen I expression is mediated via Smad3 and PKC-delta [83,84]. Ang II also induces c-fos, which is part of the AP-1 binding complex in cardiac myocytes [29,85]. Furthermore, it was previously shown that the AP-1 complex is involved in Ang II-mediated TGF-β₁ induction in smooth muscle cells [86], and Ang II activates AP-1 via transactivation of the epidermal growth factor receptor in cardiac fibroblasts [87]. The fact that Ang II does not induce TGF-β₁ expression in the presence of actinomycin D indicates that Ang II regulates TGF-β₁ expression at the transcriptional level in cardiac myocytes [31]. Ang II-stimulated upregulation of TGF-β₁ mRNA was also shown in cardiac fibroblasts, in which it depends on transactivation of the epidermal growth factor (EGF) receptor and subsequent Erk activation by Ang II [34]. The role of NAD(P)H oxidase in Ang II-mediated TGF-β₁ induction and cardiac hypertrophy was recently confirmed in gp91^phox-deficient mice, in which the lack of this membranous NAD(P)H oxidase subunit completely prevented Ang II-induced cardiac hypertrophy which was observed in wild type mice [88].

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Signal relay of Ang II-dependent induction of TGF-β1 expression in cardiac myocytes (adapted from Ref. [31]) (AT1R=Angiotensin type 1 receptor; PKC=protein kinase C; p38 MAPK=p38 mitogen-activated protein kinase; AP-1=nuclear activating protein-1).

 

	6. Downstream mediators of Ang II/TGFβ1 in cardiac hypertrophy

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
Whereas the functional connection between Ang II and TGF-β₁ has been well characterized in recent years, only limited information is currently available on how they elicit their cardiac growth responses downstream of TGF-β receptors. Recent studies indicate that the downstream mediators of cardiac Ang II/TGF-β networking may include Smad proteins, TGFβ-activated kinase-1 (TAK1), and induction of hypertrophic responsiveness to β-adrenergic stimulation in cardiac myocytes.

6.1 TGF-β₁ signaling/Smad proteins
TGF-β₁ elicits its biological responses through a heteromeric receptor complex comprising two serine–threonine kinase receptors, termed TGF-β receptor types 1 and 2 (TβR1 and TβR2) [89,90]. Both TGF-β₁ ligand and the TβR1 and TβR2 receptors are present in the heart, and all are expressed in cardiac myocytes as well as in non-myocytes [4]. The classical signaling cascade of TGF-β receptors involves Smad proteins (R-Smads such as Smad 2 and 3), which are phosphorylated upon receptor activation, associate with Co-Smad (Smad 4) and subsequently translocate to the nucleus where they act as transcription factors [89–91]. Transcriptional control by Smads depends on interactions with other transcription factors, and their association with coactivators or corepressers determines the type of response. Depending on their binding partners, Smads may either activate or inhibit gene transcription [92].

Cardiac remodeling involves changes in Smad expression, and recent studies provide evidence for cross-talk between Ang II and Smads. In a rat model of myocardial infarction, Smads 2, 3, and 4 are upregulated in scar and remnant heart tissue [39,93], whereas Smad 7, an I-Smad which inhibits phosphorylation of R-Smads, is downregulated [94]. AT₁ receptor blockade was shown to attenuate the expression of Smads in this model, since administration of losartan normalized the increased expression of Smad 2 and Smad 4 in infarct scar and remnant tissue [93]. Normalization of Smad expression was associated with a significant reduction in cardiac fibrosis and improvement of myocardial function. Consistently, AT₁ receptor blockade significantly reduced the elevated Smad 2 and Smad 4 expression in cardiomyopathic hamsters, and this effect correlated with decreased fibrosis and expression of fibrillar collagen [95]. In cultured cardiac fibroblasts, Ang II directly promotes TGF-β₁/Smad signaling by elevating Smad 2 levels and inducing the translocation of phosphorylated Smad 2 into the nuclei, and these responses also depend on the AT₁ receptor [93]. These studies indicate that cross-talk between Ang II and TGF-β₁ at the postreceptor level (Smad signaling) is associated with fibrosis in cardiac remodeling.

6.2. TGF-β-activated kinase-1
TGF-β-activated kinase-1 (TAK1) belongs to the superfamily of mitogen-activated protein kinase kinase kinases (MAPKKK) that couple extracellular stimuli to gene transcription, and has been shown to transduce TGF-β₁ signaling [96]. Together with Smads, TAK1 is involved in cardiomyocyte differentiation and cardiac development via induction of cardiac-restricted transcription factors Csx/Nkx-2.5, GATA-4, and ATF-2 [97,98]. A recent study demonstrated that cardiac hypertrophy and induction of TGF-β₁ after mechanical load by aortic banding were associated with a significant upregulation of TAK1 kinase activity in the mouse heart [99]. TGF-β₁ activates TAK1 in cultured ventricular myocytes, and constitutively activated TAK1 mimicks hypertrophy-associated TGF-β₁ responses such as induction of the skeletal actin (SkA) promoter, signaling to serum response factor (SRF) through p38, and the SRF-associated transcription factor ATF-6 in these cells [99]. Furthermore, overexpression of constitutively active TAK1 at pathophysiological levels in transgenic mice led to cardiac hypertrophy, fibrosis, fetal gene expression, severe myocardial dysfunction and early lethality [99]. Thus, TAK1 is induced in response to mechanical load and may serve as an essential mediator of Ang II/TGF-β₁-associated cardiac remodeling. Since ATFs bind directly to heterooligomers of Smads and are phosphorylated by TGF-β₁ signaling via TAK1 and p38 [100,101], they are common nuclear targets of the Smad and TAK1 pathways in TGF-β₁ signaling, and thus are good candidates for downstream mediators of Ang II/TGF-β₁-induced growth responses in the heart.

6.3. The β-adrenergic system
Recent studies indicate that β-adrenergic signaling may be involved in the growth responses of the heart by serving as a downstream mediator of Ang II/TGF-β₁ [57,77,102,103]. The detrimental effects of chronic and excessive adrenergic drive have been shown in a number of experimental studies and in man [104–110]. These studies have also shown that the consequences of enhanced β-AR function in the heart are largely dependent on the extent and duration of β-adrenergic overdrive. Stimulation of the sympathetic nervous system is critically involved in the development of myocardial hypertrophy and heart failure particularly by inducing cardiomyocyte hypertrophy [110]. Although the hypertrophic effect of catecholamines on cardiac myocytes in vitro is solely mediated via stimulation of -adrenoceptors (ARs), myocardial hypertrophy in vivo may also be induced by selective stimulation of β-ARs [111,112]. Hence, autocrine and/or paracrine mechanisms may alter the responsiveness to β-AR stimulation in vivo. In vitro studies have shown that TGF-β₁ affects β-adrenergic signaling by modulating the number and function of β-ARs in various cell types [113–115]. In transgenic mice overexpressing TGF-β₁, the hypertrophic cardiac phenotype correlates with alterations of β-adrenergic signaling, which include an increase in myocardial β-AR density and downregulation of negative regulators such as G_i and βARK-1 [57]. This observation is consistent with an in vitro study demonstrating that TGF-β₁ induces hypertrophic responsiveness to β-adrenergic stimulation in cardiac myocytes [102]. In isolated perfused hearts, TGF-β₁ overexpression promotes the isoprenaline-induced expression of hypertrophy-associated proteins including ANF and c-fos, and this effect depends specifically on induction of ornithine decarboxylase (ODC), the rate limiting enzyme of the polyamine metabolism [103]. It is interesting to note that chronic β-AR blockade in TGF-β₁ transgenic mice—which display alterations of β-adrenergic signaling—prevents cardiac hypertrophy and the induction of hypertrophic resposiveness to β-adrenergic stimulation, and furthermore improves the diminished functional responsiveness to catecholamines, whereas chronic administration of an AT₁ receptor antagonist did not affect the cardiac phenotype [77]. The latter observation could be expected from previous studies as TGF-β₁, which was induced by Ang II in other models of hypertrophy, is already present in transgenic mice, and AT₁ receptor blockade is expected to be insufficient in this scenario. These data indicate that β-AR-mediated growth responses may act downstream of Ang II/TGF-β₁ in cardiac remodeling, and enhancement of β-adrenergic signaling by TGF-β₁ may contribute to excessive catecholamine stimulation during the transition from stable hypertrophy to heart failure. Hence, networking between Ang II and TGF-β₁ in cardiac hypertrophy may also involve the β-adrenergic system (Fig. 4).

View larger version (15K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 4 Schematic diagram illustrating the connection between the RAS, TGF-β1, and the β-adrenergic system in cardiac remodeling, and targeting of interventional strategies (AT1R=Angiotensin type 1 receptor; β-AR=β-adrenergic receptor, ACE Inhibitors=Angiotensin converting enzyme inhibitors). Note that in addition to the RAS and TGF-β1, other systems and mechanisms are also involved in the pathogenesis of myocardial hypertrophy and failure.

 

	7. Conclusions

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 
The RAS and TGF-β₁ play an essential role in the progression of cardiac remodeling. There is a large body of evidence that the development of cardiac hypertrophy, fibrosis, and dysfunction is controlled by a regulatory network involving the RAS and TGF-β₁ rather than by independent actions of individual players, although other systems and mechanisms are clearly involved [6,11,116]. Ang II induces the expression of TGF-β₁ in cardiac myocytes and fibroblasts. TGF-β₁ stimulates fibroblast proliferation, ECM deposition, and myocyte hypertrophy via autocrine/paracrine mechanisms, thereby mediating Ang II-induced cardiac remodeling (Fig. 1). In addition to TGF-β₁ signaling via Smad proteins and TAK1, β-adrenergic signaling may represent a pathophysiologically important component of this network as TGF-β₁ induces hypertrophic responsiveness to β-adrenergic stimulation in cardiac myocytes.

	Acknowledgements

 
This work was supported in part by the Deutsche Forschungsgemeinschaft (Ro 1306-2), and by the Center for Molecular Medicine (CMMC; Project 84) of the University of Cologne.

	Notes

 
Time for primary review 22 days

	References

Top Abstract 1. Introduction 2. The RAS and... 3. Evidence for a... 4. Is there a... 5. Molecular mechanisms of... 6. Downstream mediators of... 7. Conclusions References

 

1. Cohn J.N, Ferrari R, Sharpe N. Cardiac remodeling-concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf on an international forum on cardiac remodelling. J. Am. Coll. Cardiol. (2000) 35:569–582.[Abstract/Free Full Text]
2. Schnee J.M, Hsueh W.A. Angiotensin II, adhesion, and cardiac fibrosis. Cardiovasc. Res. (2000) 46:264–268.[Abstract/Free Full Text]
3. Yamazaki T, Komuro I, Yazaki Y. Role of the renin–angiotensin system in cardiac hypertrophy. Am. J. Cardiol. (1999) 83:H53–H57.[CrossRef][Web of Science][Medline]
4. Brand T, Schneider M.D. The TGFβ superfamily in myocardium: ligands, receptors, transduction, and function. J. Mol. Cell. Cardiol. (1995) 27:5–18.[Web of Science][Medline]
5. Manabe I, Shindo T, Nagai R. Gene expression in fibroblasts and fibrosis: involvement in cardiac hypertrophy. Circ. Res. (2002) 91:1103–1113.[Abstract/Free Full Text]
6. Swynghedauw B. Molecular mechanisms of myocardial remodelling. Physiol. Rev. (1999) 79:215–262.[Abstract/Free Full Text]
7. Sudgen P.H, Clerk A. Cellular mechanisms of cardiac hypertrophy. J. Mol. Med. (1998) 76:725–746.[CrossRef][Web of Science][Medline]
8. Parker T.G, Schneider M.D. Growth factors, protooncogenes, and plasticity of the cardiac phenotype. Annu. Rev. Physiol. (1991) 53:179–200.[Web of Science][Medline]
9. Ohta K, Kim S, Wanibuchi H, et al. Contribution of the local renin–angiotensin system to cardiac hypertrophy, phenotypic modulation, and remodeling in TGR(mRen2)27 transgenic rats. Circulation (1996) 94:785–791.[Abstract/Free Full Text]
10. Pfeffer J.M, Fischer T.A, Pfeffer M.A. Angiotensin converting enzyme inhibition and ventricular remodeling after myocardial infarction. Annu. Rev. Physiol. (1995) 57:805–826.[CrossRef][Web of Science][Medline]
11. Weber K.T, Brilla C.G. Pathological hypertrophy and cardiac interstitium: fibrosis and renin–angiotensin-aldosterone system. Circulation (1991) 83:1849–1865.[Abstract/Free Full Text]
12. Nakamura Y, Yoshiyama M, Omura T, et al. Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction. Cardiovasc. Res. (2003) 57:48–54.[Abstract/Free Full Text]
13. Kim S, Yoshiyama M, Izumi Y, et al. Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circulation (2001) 103:148–154.[Abstract/Free Full Text]
14. Liu Y.H, Yang X.P, Sharov V.G, et al. Effects of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure: role of kinins and angiotensin II type 2 receptors. J. Clin. Invest. (1997) 99:1926–1935.[Web of Science][Medline]
15. Schieffer B, Wirger A, Meybrunn M, et al. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation (1994) 2273–2282.
16. Pfeffer M.A, McMurray J.J.V, Velazquez E.J. on behalf of the VALIANT Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N. Engl. J. Med. (2003) 349:1893–1906.[Abstract/Free Full Text]
17. Pfeffer M.A, Swedberg K, Granger C.B, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall programme. Lancet (2003) 362:759–766.[CrossRef][Web of Science][Medline]
18. McMurray J.J.V, Östergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin-converting enzyme inhibitors: the CHARM-added trial. Lancet (2003) 362:767–771.[CrossRef][Web of Science][Medline]
19. Cohn J.N, Tognoni G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N. Engl. J. Med. (2001) 345:1667–1675.[Abstract/Free Full Text]
20. Flather M.D, Yusuf S, Kober L, et al. Long-term ACE inhibitor therapy in patients with heart failure or left ventricular dysfunction: a systematic overview of data from individual patients. Lancet (2000) 355:1575–1581.[CrossRef][Web of Science][Medline]
21. Kober L, Torp-Pedersen C, Carlsen J.E, et al. A clinical trial of the angiotensin converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. (1995) 333:1670–1676.[Abstract/Free Full Text]
22. Pitt B, Poole-Wilson P.A, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II. Lancet (2000) 355:1582–1587.[CrossRef][Web of Science][Medline]
23. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet (1993) 342:821–824.[Web of Science][Medline]
24. Pfeffer M.A, Braunwald E, Moyé L.A, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival And Ventricular Enlargement (SAVE) trial. N. Engl. J. Med. (1992) 327:669–677.[Abstract]
25. Zou Y, Komuro I, Yamazaki T, et al. Cell type-specific angiotensin II-evoked signal transduction pathways: critical roles of G_β subunit, Src family, and Ras in cardiac fibroblasts. Circ. Res. (1998) 82:337–345.[Abstract/Free Full Text]
26. Bouzegrhane F, Thibault G. Is angiotensin II a proliferative factor of cardiac fibroblasts? Cardiovasc. Res. (2002) 53:304–312.[Abstract/Free Full Text]
27. Schorb W, Booz G.W, Dostal D.E, Conrad K.M, Chang K.C, Baker K.M. Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ. Res. (1993) 72:1245–1254.[Abstract/Free Full Text]
28. Wada H, Zile M.R, Ivester C.T, Cooper G IV, McDermott P.J. Comparative effects of contraction and angiotensin II on growth of adult feline cardiocytes in primary culture. Am. J. Physiol. (1996) 271:H29–H37.[Web of Science][Medline]
29. Sadoshima J, Izumo S. Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT₁ receptor. Circ. Res. (1993) 73:413–423.[Abstract/Free Full Text]
30. Schlüter K.D, Simm A, Schäfer M, Taimor G, Piper H.M. Early response kinase and PI 3-kinase activation in adult cardiomyocytes and their role in hypertrophy. Am. J. Physiol. (1999) 276:H1655–H1663.[Web of Science][Medline]
31. Wenzel S, Taimor G, Piper H.M, Schlüter K.D. Redox-sensitive intermediates mediate angiotensin II-induced p38 MAP kinase activation, AP-1 binding activity, and TGF-β expression in adult ventricular cardiomyocytes. FASEB J. (2001) 15:2291–2293.[Free Full Text]
32. Schultz J.E.J, Witt S.A, Glascock B.J, et al. TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J. Clin. Invest. (2002) 109:787–796.[CrossRef][Web of Science][Medline]
33. Dostal D.E. Regulation of cardiac collagen: angiotensin and cross-talk with local growth factors. Hypertension (2001) 37:841–844.[Free Full Text]
34. Moriguchi Y, Matsubara H, Mori Y, et al. Angiotensin II-induced transactivation of epidermal growth factor receptor regulates fibronectin and transforming growth factor-beta synthesis via transcriptional and posttranscriptional mechanisms. Circ. Res. (1999) 84:1073–1084.[Abstract/Free Full Text]
35. Border W.A, Nobel N.A. Transforming growth factor-β in tissue fibrosis. N. Engl. J. Med. (1994) 331:1286–1292.[Free Full Text]
36. Pauschinger M, Knopf D, Petschauer S, et al. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation (1999) 99:2750–2756.[Abstract/Free Full Text]
37. Li G, Li R.K, Mickle D.A, et al. Elevated insulin-like growth factor-I and transforming growth factor-beta 1 and their receptors in patients with idiopathic hypertrophic cardiomyopathy: a possible mechanism. Circulation (1998) 98(Suppl. 19):II-144–II-149.[Web of Science][Medline]
38. Li R.K, Mickle D.A, Weisel R.D, et al. Overexpression of transforming growth factor-beta 1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation (1997) 96:874–881.[Abstract/Free Full Text]
39. Hao J, Ju H, Zhao S, Junaid A, Scammell-La Fleur T, Dixon M.C. Elevation of expression of Smads 2, 3, and 4, decorin and TGF-β in the chronic phase of myocardial infarct scar healing. J. Mol. Cell. Cardiol. (1999) 31:667–678.[CrossRef][Web of Science][Medline]
40. 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) 32:273–279.[Abstract/Free Full Text]
41. Takahashi N, Calderone A, Izzo J.N, et al. Hypertrophic stimuli induce transforming growth factor-β1 expression in rat ventricular myocytes. J. Clin. Invest. (1994) 94:1470–1476.[Web of Science][Medline]
42. Villarreal F.K, Dillmann W.H. Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin and collagen. Am. J. Physiol. (1992) 262:H1861–H1866.[Web of Science][Medline]
43. Wünsch M, Sharma H.S, Markert T, et al. In situ localization of transforming growth factor beta 1 in porcine heart: enhanced expression after chronic coronary artery occlusion. J. Mol. Cell. Cardiol. (1991) 23:1051–1062.[CrossRef][Web of Science][Medline]
44. Casscells W, Bazoberry F, Speir E, et al. Transforming growth factor-β1 in normal heart and in myocardial infarction. Ann. N. Y. Acad. Sci. (1990) 593:148–160.[Web of Science][Medline]
45. Thompson N.L, Bazoberry F, Speir E.H, et al. Transforming growth factor beta-1 in acute myocardial infarction in rats. Growth Factors (1988) 1:91–99.[Medline]
46. Bolyut M.O, O'Neill L, Meredith A.L, et al. Alterations in cardiac gene expression during the transition from stable hypertrophy to heart failure: marked upregulation of genes encoding extracellular matrix components. Circ. Res. (1994) 75:23–32.[Abstract/Free Full Text]
47. Song H, Foster A.H, Conte J.V, Chi-Ming W. Presentation and localization of transforming growth factor beta isoforms and its receptor subtypes in human myocardium in the absence and presence of heart failure. Circulation (1997) 96(Suppl. I):I-362.
48. 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) 107:984–991.[Abstract/Free Full Text]
49. Villarreal F.J, Lee A.A, Dillmann W.H, Giordano F.J. Adenovirus-mediated overexpression of human transforming growth factor-beta 1 in rat cardiac fibroblasts, myocytes and smooth muscle cells. J. Mol. Cell. Cardiol. (1996) 28:735–742.[CrossRef][Web of Science][Medline]
50. Heimer R, Bashey R.I, Kyle J, Jiminez S.A. TGF-beta modulates the synthesis of proteoglycans by myocardial fibroblasts in culture. J. Mol. Cell. Cardiol. (1995) 27:2191–2198.[CrossRef][Web of Science][Medline]
51. Eghbali M, Tomek R, Sukhatme V.P, Woods C, Bhambi B. Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts: regulation of fibrillar collagen mRNAs and expression of early transcription factors. Circ. Res. (1991) 69:483–490.[Abstract/Free Full Text]
52. Tomasek J.J, Gabbiani G, Hinz B, Chaponnier C, Brown R.A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. (2002) 3:349–363.[CrossRef][Web of Science][Medline]
53. Hautmann M.B, Adam P.J, Owens G.K. Similarities and differences in smooth muscle -actin induction by TGF-β in smooth muscle versus non-smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. (1999) 19:2049–2058.[Abstract/Free Full Text]
54. Sappino A.P, Schürch W, Gabbiani G. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as markers of phenotypic modulations. Lab. Invest. (1990) 63:144–161.[Web of Science][Medline]
55. Parker T.G, Packer S.E, Schneider M.D. Peptide growth factors can provoke "fetal" contractile protein gene expression in rat cardiac myocytes. J. Clin. Invest. (1990) 85:507–514.[Web of Science][Medline]
56. Desmoulière A, Geinoz A, Gabbiani F, et al. Transforming growth factor-β1 induces -smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J. Biol. Chem. (1993) 122:103–111.
57. Rosenkranz S, Flesch M, Amann K, et al. Alterations of β-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-β1. Am. J. Physiol. Heart Circ. Physiol. (2002) H1253–H1262.
58. Nakajima H, Nakajima H.O, Salcher O, et al. Atrial but not ventricular fibrosis in mice expressing a mutant transforming growth factor-β₁ transgene in the heart. Circ. Res. (2000) 86:571–579.[Abstract/Free Full Text]
59. Brooks W.W, Conrad C.H. Myocardial fibrosis in transforming growth factor heterozygous mice. J. Mol. Cell. Cardiol. (2000) 32:187–195.[CrossRef][Web of Science][Medline]
60. Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-β function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation (2002) 106:130–135.[Abstract/Free Full Text]
61. van Wamel A.J, Ruwhof C, van der Valk-Kokshoorn L.J.M, Schrier P.I, van der Laarse A. Stretch-induced paracrine hypertrophic stimuli increase TGF-β₁ expression in cardiomyocytes. Mol. Cell. Biochem. (2002) 236:147–153.[CrossRef][Web of Science][Medline]
62. Gray M.O, Long C.S, Kalinyak J.E, Li H.T, Karliner J.S. Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-beta 1 and endothelin-1 from fibroblasts. Cardiovasc. Res. (1998) 40:352–363.[Abstract/Free Full Text]
63. Campbell S.E, Katwa L.C. Angiotensin II stimulated expression of transforming growth factor-beta 1 in cardiac fibroblasts and myofibroblasts. J. Mol. Cell. Cardiol. (1997) 29:1947–1958.[CrossRef][Web of Science][Medline]
64. Fisher S.A, Absher M. Norepinephrine and angiotensin II stimulate secretion of TGF-beta by neonatal rat cardiac fibroblasts in vitro. Am. J. Physiol. (1995) 268:C910–C917.[Web of Science][Medline]
65. Lee A.A, Dillmann W.H, McCulloch A.D, Villarreal F.J. Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J. Mol. Cell. Cardiol. (1995) 27:2347–2357.[CrossRef][Web of Science][Medline]
66. Everett A.D, Tufro-McReddie A, Fisher A, Gomez R.A. Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-beta 1 expression. Hypertension (1994) 23:587–592.[Abstract/Free Full Text]
67. Sadoshima J, Xu Y.H, Slayter H.S, Izumo S. Autocrine release of angiotensin-II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell (1993) 75:977–984.[CrossRef][Web of Science][Medline]
68. 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) 46:463–475.[Abstract/Free Full Text]
69. Kim S, Ohta K, Hamaguchi A, et al. Angiotensin II type I receptor antagonist inhibits the gene expression of TGF-β1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J. Pharmacol. Exp. Ther. (1995) 273:509–515.[Abstract/Free Full Text]
70. Crawford D, Chobanian A, Brecher P. Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ. Res. (1994) 74:727–739.[Abstract/Free Full Text]
71. Ichihara S, Senbonmatsu T, Price E Jr., et al. Angiotensin type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation (2001) 104:346–351.[Abstract/Free Full Text]
72. Calderone A, Murphy R.J, Lavoie J, Colombo F, Beliveau L. TGF-beta(1) and prepro-ANP mRNAs are differentially regulated in exercise-induced cardiac hypertrophy. J. Appl. Physiol. (2001) 91:771–776.[Abstract/Free Full Text]
73. Silberbach M, Roberts C.T Jr. Natriuretic peptide signaling: molecular and cellular pathways to growth regulation. Cell. Signal. (2001) 13:221–231.[CrossRef][Web of Science][Medline]
74. Buttrick P.M, Kaplan M, Leinwand L.A, Scheuer J. Alterations in gene expression in the rat heart after chronic pathological and physiological loads. J. Mol. Cell. Cardiol. (1994) 26:61–67.[CrossRef][Web of Science][Medline]
75. Tokuda K, Kai H, Kuwahara F, et al. Pressure-independent effects of angiotensin II on hypertensive myocardial fibrosis. Hypertension (2004) 43:499–503.[Abstract/Free Full Text]
76. Diebold R.J, Eis M.J, Yin M, et al. Early-onset multifocal inflammation in the transforming growth factor-β 1-null mouse is lymphocyte mediated. Proc. Natl. Acad. Sci. U.S.A. (1995) 92:12215–12229.[Abstract/Free Full Text]
77. Rosenkranz S, Amann K, Caglayan E, et al. β-adrenoceptor blockade prevents cardiac hypertrophy and failure in TGF-β transgenic mice. Eur. J. Heart (2003) 24:665. [Suppl. (Abstract)].
78. Pinto Y.M, Pinto-Sietsma S.J, Philipp T, et al. Reduction in left ventricular messenger RNA for transforming growth factor beta(1) attenuates left ventricular fibrosis and improves survival without lowering blood pressure in the hypertensive TGR(mRen2)27 rat. Hypertension (2000) 36:747–754.[Abstract/Free Full Text]
79. Nishikawa K. Angiotensin AT₁ receptor antagonism and protection against cardiovascular end organ damage. J. Hum. Hypertens. (1998) 12:301–309.[CrossRef][Web of Science][Medline]
80. Sun Y, Zhang J.Q, Zhang J, Ramires F.J. Angiotensin II, transforming growth factor-β₁ and repair in the infarcted heart. J. Mol. Cell. Cardiol. (1998) 30:1559–1569.[CrossRef][Web of Science][Medline]
81. Kim S, Ohta K, Hamaguchi A, Yukimura T, Miura K, Iwao H. Effects of an AT₁ receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expression in hypertensive rats. Br. J. Pharmacol. (1996) 118:549–556.[Web of Science][Medline]
82. Wang J, Liu X, Sentex E, Takeda N, Dhalla N.S. Increased expression of protein kinase C isoforms in heart failure due to myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. (2003) 284:H2277–H2287.[Abstract/Free Full Text]
83. Buhagiar K.A, Hansen P.S, Bewick N.L, Rasmussen H.H. Protein kinase C-epsilon contributes to regulation of the sarcolemmal Na(+)–K(+) pump. Am. J. Physiol. Cell Physiol. (2001) 281:C1059–C1063.[Abstract/Free Full Text]
84. Runyan C.E, Schnaper H.W, Poncelet A.C. Smad 3 and PKCdelta mediate TGF-beta1-induced collagen I expression in human mesangial cells. Am. J. Physiol. Renal Physiol. (2003) 285:F413–F422.[Abstract/Free Full Text]
85. Kojima M, Shiojima I, Yamazaki T, et al. Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signalling pathway of strech-mediated cardiomyocyte hypertrophy in vitro. Circulation (1994) 89:2204–2211.[Abstract/Free Full Text]
86. Morishita R, Gibbons G.H, Horiuchi M, Kaneda Y, Ogihara T, Dzau V.J. Role of the AP-1 complex in angiotensin II-mediated TGF-β expression and growth of smooth muscle cells: using decoy approach against AP-1 binding. Biochem. Biophys. Res. Commun. (1998) 243:361–367.[CrossRef][Web of Science][Medline]
87. Puri P.L, Avantaggiati M.L, Bugio V.L, et al. Reactive oxygen intermediates mediate angiotensin II-induced c-fos/c-jun heterodimer DNA binding activity and proliferative hypertrophic response in myogenic cells. J. Biol. Chem. (1995) 270:22129–22134.[Abstract/Free Full Text]
88. Byrne J.A, Grieve D.J, Bendall J.K, et al. Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ. Res. (2003) 93:802–804.[Abstract/Free Full Text]
89. Massague J. How cells read TGF-β signals. Nat. Rev. Mol. Cell Biol. (2000) 1:169–178.[CrossRef][Web of Science][Medline]
90. Massague J. TGF-β signaling: receptors, transducers, and mad proteins. Cell (1996) 85:947–950.[CrossRef][Web of Science][Medline]
91. Moustakas A, Souchelnytskyi S, Heldin C.-H. Smad regulation in TGF-β signal transduction. J. Cell Sci. (2001) 114:4359–4369.[Web of Science][Medline]
92. Ng H.H, Bird A. Histone deacetylases: silencers for hire. Trends Biochem. Sci. (2000) 25:121–126.[CrossRef][Web of Science][Medline]
93. Hao J, Wang B, Jones S.C, Jassal D.S, Dixon I.M.C. Interaction between angiotensin II and Smad proteins in fibroblasts in failing heart and in vitro. Am. J. Physiol. Heart Circ. Physiol. (2000) 279:H3020–H3030.[Abstract/Free Full Text]
94. Wang B, Hao J, Jones S.C, Yee M.S, Roth J.C, Dixon I.M. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am. J. Physiol. Heart Circ. Physiol. (2002) 282:H1685–H1696.[Abstract/Free Full Text]
95. Dixon I.M, Hao J, Reid N.L, Roth J.C. Effect of chronic AT(1) receptor blockade on cardiac Smad overexpression in hereditary cardiomyopathic hamsters. Cardiovasc. Res. (2000) 46:286–297.[Abstract/Free Full Text]
96. Yamaguchi K, Shirakabe H, Shibuya H, et al. Identification of a member of the MAPKKK family as a potential mediator of TGF-β signal transduction. Science (1995) 270:2008–2011.[Abstract/Free Full Text]
97. Monzen K, Hiroi Y, Kudoh S, et al. Smads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiation. J. Cell Biol. (2001) 153:687–698.[Abstract/Free Full Text]
98. Monzen K, Shiojima I, Hiroi Y, et al. Bone morphogenic proteins induce cardiomyocyte differentiation through the mitogen-activated protein kinase kinase kinase TAK1 and cardiac transcription factors Csx/Nkx-2.5 and GATA4. Mol. Cell. Biol. (1999) 19:7096–7105.[Abstract/Free Full Text]
99. Zhang D, Gaussin V, Taffet G.E, et al. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat. Med. (2000) 6:556–563.[CrossRef][Web of Science][Medline]
100. Hanafusa H, Ninomiya-Tsuji J, Masuyama N, et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-β-induced gene expression. J. Biol. Chem. (1999) 274:27161–27167.[Abstract/Free Full Text]
101. 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-β signaling. J. Biol. Chem. (1999) 274:8949–8957.[Abstract/Free Full Text]
102. Schlüter K.-D, Zhou X.J, Piper H.M. Induction of hypertrophic responsiveness to isoproterenol by TGF-β in adult rat cardiomyocytes. Am. J. Physiol. (1995) 269:C1311–C1316.[Web of Science][Medline]
103. Schlüter K.-D, Frischkopf K, Flesch M, Rosenkranz S, Taimor G, Piper H.M. Central role for ornithine decarboxylase in β-adrenoceptor mediated hypertrophy. Cardiovasc. Res. (2000) 45:410–417.[Abstract/Free Full Text]
104. Liggett S.B, Tepe N.M, Lorenz J.N, et al. Early and delayed consequences of β₂-adrenergic receptor overexpression in mouse hearts. Critical role for expression level. Circulation (2000) 101:1707–1714.[Abstract/Free Full Text]
105. Engelhardt S, Hein L, Wiesmann F, Lohse M.J. Progressive hypertrophy and heart failure in beta 1-adrenergic receptor transgenic mice. Proc. Natl. Acad. Sci. U.S.A. (1999) 96:7059–7064.[Abstract/Free Full Text]
106. Gao M.H, Lai N.C, Roth D.M, et al. Adenylyl cyclase increases responsiveness to catecholamine stimulation in transgenic mice. Circulation (1999) 99:1618–1622.[Abstract/Free Full Text]
107. Iwase M, Uechi M, Vatner D.E, et al. Cardiomyopathy induced by cardiac Gs alpha overexpression. Am. J. Physiol. (1997) 272:H585–H589.[Web of Science][Medline]
108. Milano C.A, Allen L.F, Rockman H.A, et al. Enhanced myocardial function in transgenic mice overexpressing the β₂-adrenergic receptor. Science (1994) 264:582–586.[Abstract/Free Full Text]
109. Koch W.J, Rockman H.A, Samama P, et al. Cardiac function in mice overexpressing the β-adrenergic receptor kinase or a βARK inhibitor. Science (1995) 268:1350–1353.[Abstract/Free Full Text]
110. Böhm M, Kouchi I, Schnabel P, Zolk O. Transition from hypertrophy to failure-β-adrenergic desensitization of the heart. Heart Failure Rev. (1999) 4:329–351.[CrossRef]
111. Simpson P, McGrath A. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an ₁-adrenergic response. J. Clin. Invest. (1983) 72:732–738.[Web of Science][Medline]
112. Bartolome J, Guguenard J, Slotkin T.A. Role of ornithine decarboxylase in cardiac growth and hypertrophy. Science (1990) 210:793–794.[CrossRef]
113. Kimura M, Ogihara M. Transforming growth factor-beta 1 inhibits the growth of primary hepatocyte cultures by increasing cAMP levels. Eur. J. Pharmacol. (1999) 386:271–277.[CrossRef][Web of Science][Medline]
114. Iizuka K, Sano H, Kawaguchi H, Kitabatake A. Transforming growth factor β-1 modulates the number of β-adrenergic receptors in cardiac fibroblasts. J. Mol. Cell. Cardiol. (1994) 26:435–440.[CrossRef][Web of Science][Medline]
115. Nogami M, Romberger D.J, Rennard S.I, Toews M.L. TGF-β₁ modulates β-adrenergic receptor number and function in cultured human tracheal smooth muscle cells. Am. J. Physiol. (1994) 266:L187–L191.[Web of Science][Medline]
116. Weber K.T, Brilla C.G, Janicki J.S. Myocardial fibrosis: its functional significance and regulatory factors. Cardiovasc. Res. (1993) 27:341–348.[Free Full Text]

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				A. Zhang, J. J. David, S. V. Subramanian, X. Liu, M. D. Fuerst, X. Zhao, C. V. Leier, C. G. Orosz, R. J. Kelm Jr., and A. R. Strauch Serum response factor neutralizes Pur{alpha}- and Pur{beta}-mediated repression of the fetal vascular smooth muscle {alpha}-actin gene in stressed adult cardiomyocytes Am J Physiol Cell Physiol, March 1, 2008; 294(3): C702 - C714. [Abstract] [Full Text] [PDF]

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				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				C. Prante, H. Milting, A. Kassner, M. Farr, M. Ambrosius, S. Schon, D. G. Seidler, A. E. Banayosy, R. Korfer, J. Kuhn, et al. Transforming Growth Factor beta1-regulated Xylosyltransferase I Activity in Human Cardiac Fibroblasts and Its Impact for Myocardial Remodeling J. Biol. Chem., September 7, 2007; 282(36): 26441 - 26449. [Abstract] [Full Text] [PDF]

				S. Belmadani, J. Bernal, C.-C. Wei, M. A. Pallero, L. Dell'Italia, J. E. Murphy-Ullrich, and K. H. Berecek A Thrombospondin-1 Antagonist of Transforming Growth Factor-{beta} Activation Blocks Cardiomyopathy in Rats with Diabetes and Elevated Angiotensin II Am. J. Pathol., September 1, 2007; 171(3): 777 - 789. [Abstract] [Full Text] [PDF]

				H.-L. Li, Z.-G. She, T.-B. Li, A.-B. Wang, Q. Yang, Y.-S. Wei, Y.-G. Wang, and D.-P. Liu Overexpression of Myofibrillogenesis Regulator-1 Aggravates Cardiac Hypertrophy Induced by Angiotensin II in Mice Hypertension, June 1, 2007; 49(6): 1399 - 1408. [Abstract] [Full Text] [PDF]

				M. Bujak and N. G. Frangogiannis The role of TGF-{beta} signaling in myocardial infarction and cardiac remodeling Cardiovasc Res, May 1, 2007; 74(2): 184 - 195. [Abstract] [Full Text] [PDF]

				P. L. Hermonat, D. Li, B. Yang, and J. L. Mehta Mechanism of action and delivery possibilities for TGF{beta}1 in the treatment of myocardial ischemia Cardiovasc Res, May 1, 2007; 74(2): 235 - 243. [Abstract] [Full Text] [PDF]

				N. K. Kapur, C. B. Deming, S. Kapur, C. Bian, H. C. Champion, J. K. Donahue, D. A. Kass, and J. J. Rade Hemodynamic Modulation of Endocardial Thromboresistance Circulation, January 2, 2007; 115(1): 67 - 75. [Abstract] [Full Text] [PDF]

				G. Avila, I. M. Medina, E. Jimenez, G. Elizondo, and C. I. Aguilar Transforming growth factor-beta1 decreases cardiac muscle L-type Ca2+ current and charge movement by acting on the Cav1.2 mRNA Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H622 - H631. [Abstract] [Full Text] [PDF]

				M. Sakamoto, T. Minamino, H. Toko, Y. Kayama, Y. Zou, M. Sano, E. Takaki, T. Aoyagi, K. Tojo, N. Tajima, et al. Upregulation of Heat Shock Transcription Factor 1 Plays a Critical Role in Adaptive Cardiac Hypertrophy Circ. Res., December 8, 2006; 99(12): 1411 - 1418. [Abstract] [Full Text] [PDF]

				H. Masuyama, T. Tsuruda, J. Kato, T. Imamura, Y. Asada, J.-P. Stasch, K. Kitamura, and T. Eto Soluble Guanylate Cyclase Stimulation on Cardiovascular Remodeling in Angiotensin II-Induced Hypertensive Rats Hypertension, November 1, 2006; 48(5): 972 - 978. [Abstract] [Full Text] [PDF]

				M. Podgorska, K. Kocbuch, M. Grden, A. Szutowicz, and T. Pawelczyk Reduced ability to release adenosine by diabetic rat cardiac fibroblasts due to altered expression of nucleoside transporters J. Physiol., October 1, 2006; 576(1): 179 - 189. [Abstract] [Full Text] [PDF]

				H.-J. Park, S. M. Ward, J. S. Desgrosellier, S. P. Georgescu, A. G. Papageorge, X. Zhuang, J. V. Barnett, and J. B. Galper Transforming Growth Factor beta Regulates the Expression of the M2 Muscarinic Receptor in Atrial Myocytes via an Effect on RhoA and p190RhoGAP J. Biol. Chem., July 21, 2006; 281(29): 19995 - 20002. [Abstract] [Full Text] [PDF]

				C. K. Sen, S. Khanna, and S. Roy Perceived hyperoxia: Oxygen-induced remodeling of the reoxygenated heart Cardiovasc Res, July 15, 2006; 71(2): 280 - 288. [Abstract] [Full Text] [PDF]

				D. Sorescu Smad3 Mediates Angiotensin II- and TGF-{beta}1-Induced Vascular Fibrosis: Smad3 Thickens the Plot Circ. Res., April 28, 2006; 98(8): 988 - 989. [Full Text] [PDF]

				S. Mitchell, A. Ota, W. Foster, B. Zhang, Z. Fang, S. Patel, S. F. Nelson, S. Horvath, and Y. Wang Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation Physiol Genomics, March 13, 2006; 25(1): 50 - 59. [Abstract] [Full Text] [PDF]

				A. M. Deschamps and F. G. Spinale Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation Cardiovasc Res, February 15, 2006; 69(3): 666 - 676. [Abstract] [Full Text] [PDF]

				M. Matsumoto-Ida, Y. Takimoto, T. Aoyama, M. Akao, T. Takeda, and T. Kita Activation of TGF-{beta}1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H709 - H715. [Abstract] [Full Text] [PDF]

				S. J. Watkins, L. Jonker, and H. M. Arthur A direct interaction between TGF{beta} activated kinase 1 and the TGF{beta} type II receptor: Implications for TGF{beta} signalling and cardiac hypertrophy Cardiovasc Res, February 1, 2006; 69(2): 432 - 439. [Abstract] [Full Text] [PDF]

				C.L. Tower, S.L. Chappell, K. Morgan, N. Kalsheker, P.N. Baker, and L.J. Morgan Transforming growth factor {beta}1 regulates angiotensin II type I receptor gene expression in the extravillous trophoblast cell line SGHPL-4 Mol. Hum. Reprod., December 1, 2005; 11(12): 847 - 852. [Abstract] [Full Text] [PDF]

				P. F.H. Lai, D. W. Courtman, and D. J. Stewart NO to Small Mothers Against Decapentaplegic (Smad) Circ. Res., November 25, 2005; 97(11): 1087 - 1089. [Full Text] [PDF]

				P. Rocic and P. A. Lucchesi NAD(P)H Oxidases and TGF-{beta}-Induced Cardiac Fibroblast Differentiation: Nox-4 Gets Smad Circ. Res., October 28, 2005; 97(9): 850 - 852. [Full Text] [PDF]

				I. Cucoranu, R. Clempus, A. Dikalova, P. J. Phelan, S. Ariyan, S. Dikalov, and D. Sorescu NAD(P)H Oxidase 4 Mediates Transforming Growth Factor-{beta}1-Induced Differentiation of Cardiac Fibroblasts Into Myofibroblasts Circ. Res., October 28, 2005; 97(9): 900 - 907. [Abstract] [Full Text] [PDF]

				J. Wang, N. Xu, X. Feng, N. Hou, J. Zhang, X. Cheng, Y. Chen, Y. Zhang, and X. Yang Targeted Disruption of Smad4 in Cardiomyocytes Results in Cardiac Hypertrophy and Heart Failure Circ. Res., October 14, 2005; 97(8): 821 - 828. [Abstract] [Full Text] [PDF]

				J. B. Patel, M. L. Valencik, A. M. Pritchett, J. C. Burnett Jr., J. A. McDonald, and M. M. Redfield Cardiac-specific attenuation of natriuretic peptide A receptor activity accentuates adverse cardiac remodeling and mortality in response to pressure overload Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H777 - H784. [Abstract] [Full Text] [PDF]

				A. Bubikat, L. J. De Windt, B. Zetsche, L. Fabritz, H. Sickler, D. Eckardt, A. Godecke, H. A. Baba, and M. Kuhn Local Atrial Natriuretic Peptide Signaling Prevents Hypertensive Cardiac Hypertrophy in Endothelial Nitric-oxide Synthase-deficient Mice J. Biol. Chem., June 3, 2005; 280(22): 21594 - 21599. [Abstract] [Full Text] [PDF]

				J. Herrmann, S. Samee, A. Chade, M. R. Porcel, L. O. Lerman, and A. Lerman Differential Effect of Experimental Hypertension and Hypercholesterolemia on Adventitial Remodeling Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 447 - 453. [Abstract] [Full Text] [PDF]

				Y. Sugano, T. Anzai, T. Yoshikawa, Y. Maekawa, T. Kohno, K. Mahara, K. Naito, and S. Ogawa Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction Cardiovasc Res, February 1, 2005; 65(2): 446 - 456. [Abstract] [Full Text] [PDF]

				T. Arimura, A. Helbling-Leclerc, C. Massart, S. Varnous, F. Niel, E. Lacene, Y. Fromes, M. Toussaint, A.-M. Mura, D. I. Keller, et al. Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies Hum. Mol. Genet., January 1, 2005; 14(1): 155 - 169. [Abstract] [Full Text] [PDF]

				K.-D. Schluter and K. C Wollert Synchronization and integration of multiple hypertrophic pathways in the heart Cardiovasc Res, August 15, 2004; 63(3): 367 - 372. [Full Text] [PDF]

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