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Journal ArticleDOI

Transforming growth factor (TGF)-β signaling in cardiac remodeling.

01 Oct 2011-Journal of Molecular and Cellular Cardiology (NIH Public Access)-Vol. 51, Iss: 4, pp 600-606
TL;DR: Endogenous TGF-β plays an important role in the pathogenesis of cardiac fibrotic and hypertrophic remodeling, and modulates matrix metabolism in the pressure-overloaded heart, and may serve as the "master switch" for the transition of the infarct from the inflammatory phase to formation of the scar.
About: This article is published in Journal of Molecular and Cellular Cardiology.The article was published on 2011-10-01 and is currently open access. It has received 778 citations till now. The article focuses on the topics: Ventricular remodeling & Transforming growth factor beta.
Citations
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Journal ArticleDOI
TL;DR: The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts, and therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.
Abstract: In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin–angiotensin–aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.

1,266 citations


Cites background from "Transforming growth factor (TGF)-β ..."

  • ...cells and the time course of its upregulation after MI, TGFβ1 may serve as the master switch regulating the transition from inflammation to fibrosis.(199) Neutralization experiments...

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Journal ArticleDOI
TL;DR: Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible, and understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.
Abstract: Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins, and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression, and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

1,092 citations


Cites background from "Transforming growth factor (TGF)-β ..."

  • ...Perhaps the best-characterized fibrogenic growth factor [221], TGF-β is markedly and consistently activated in experimental models of cardiac fibrosis [222] and in fibrotic human hearts [223, 224]....

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Journal ArticleDOI
TL;DR: Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies in patients with myocardial infarction.
Abstract: Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

1,033 citations

Journal ArticleDOI
TL;DR: The role of TGF-β signaling pathways in the fibrotic response is summarized in this minireview, which summarizes the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis.
Abstract: Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β bloc...

857 citations


Cites background from "Transforming growth factor (TGF)-β ..."

  • ...Because the Smad3 pathway appears to play an essential role in TGF-bmediated fibrosis, Smad3 inhibition through the administration of endogenous inhibitors (such as Smad7), or through the use of small molecule inhibitors (such as halofuginone) may hold promise....

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  • ...TGF-b induces the expression of CTGF via a functional Smad3 binding site in the CTGF promoter, which in turn stimulates myofibroblast differentiation and collagen synthesis (Duncan et al. 1999)....

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  • ...Activation of the Smad3 signaling pathway appears to be important in mediating TGF-b-induced ECM protein synthesis and TIMP upregulation (Verrecchia et al. 2001)....

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  • ...TGF-b potently stimulates type I collagen gene transcription in a Smad3dependent manner....

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  • ...Moreover, Smad3 null mice exhibit attenuated fibrosis in a wide range of experimental models....

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Journal ArticleDOI
TL;DR: Current knowledge of the mechanisms of both reparative and reactive cardiac fibrosis in response to myocardial infarction are summarized, the potential of inducing cardiac regeneration through direct reprogramming of fibroblast and myofibroblasts into cardiomyocytes are discussed, and the currently available and potential future therapeutic strategies to inhibit cardiac Fibrosis are reviewed.
Abstract: Ischemic cell death during a myocardial infarction leads to a multiphase reparative response in which the damaged tissue is replaced with a fibrotic scar produced by fibroblasts and myofibroblasts. This also induces geometrical, biomechanical, and biochemical changes in the uninjured ventricular wall eliciting a reactive remodeling process that includes interstitial and perivascular fibrosis. Although the initial reparative fibrosis is crucial for preventing rupture of the ventricular wall, an exaggerated fibrotic response and reactive fibrosis outside the injured area are detrimental as they lead to progressive impairment of cardiac function and eventually to heart failure. In this review, we summarize current knowledge of the mechanisms of both reparative and reactive cardiac fibrosis in response to myocardial infarction, discuss the potential of inducing cardiac regeneration through direct reprogramming of fibroblasts and myofibroblasts into cardiomyocytes, and review the currently available and potential future therapeutic strategies to inhibit cardiac fibrosis. Graphical abstract Reparative response following a myocardial infarction. Hypoxia-induced cardiomyocyte death leads to the activation of myofibroblasts and a reparative fibrotic response in the injured area. Right top In adult mammals, the fibrotic scar formed at the infarcted area is permanent and promotes reactive fibrosis in the uninjured myocardium. Right bottom In teleost fish and newts and in embryonic and neonatal mammals, the initial formation of a fibrotic scar is followed by regeneration of the cardiac muscle tissue. Induction of post-infarction cardiac regeneration in adult mammals is currently the target of intensive research and drug discovery attempts.

574 citations


Cites background from "Transforming growth factor (TGF)-β ..."

  • ...TGF-β is probably the best-characterized pro-fibrotic growth factor (Dobaczewski et al. 2011; Kong et al. 2014)....

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  • ...Additionally, TGF-β is synthesized and secreted by platelets, leukocytes, and fibroblasts in the infarcted myocardium (Dobaczewski et al. 2011)....

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References
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Journal ArticleDOI
13 Jun 2003-Cell
TL;DR: Current understanding on the mechanisms of TGF-β signaling from cell membrane to the nucleus is presented and the transcriptional regulation of target gene expression is reviewed.

5,340 citations


"Transforming growth factor (TGF)-β ..." refers background in this paper

  • ...proteins [13]; Smad2 and Smad3 are activated through phosphorylation by ALK5, whereas Smad1, Smad5 and Smad8 are activated by...

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Journal ArticleDOI
09 Oct 2003-Nature
TL;DR: Transforming growth factor-β (TGF-β) proteins regulate cell function, and have key roles in development and carcinogenesis, and combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smadracing proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF- β family responses.
Abstract: Transforming growth factor-beta (TGF-beta) proteins regulate cell function, and have key roles in development and carcinogenesis The intracellular effectors of TGF-beta signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-beta family responses Other signalling pathways further regulate Smad activation and function In addition, TGF-beta receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-beta responses

4,690 citations

Journal ArticleDOI
TL;DR: The results demonstrate a functional involvement of fibronectin in mediating cellular responses to TGFbeta, and suggest a model for TGF beta action based on the control of the extracellular matrix in target cells.

2,469 citations


"Transforming growth factor (TGF)-β ..." refers background in this paper

  • ...activation of a molecule that has a primary role in maintaining matrix integrity and stability [2,6,7]....

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Journal ArticleDOI
TL;DR: It is shown that the subcutaneous administration of transforming growth factor- beta 1 to rats results in the formation of a granulation tissue in which alpha-SM actin expressing myofibroblasts are particularly abundant, suggesting that TGF beta 1 plays an important role in my ofibroblast differentiation during wound healing and fibrocontractive diseases by regulating the expression of alpha- SM actin in these cells.
Abstract: Granulation tissue fibroblasts (myofibroblasts) develop several ultrastructural and biochemical features of smooth muscle (SM) cells, including the presence of microfilament bundles and the expression of alpha-SM actin, the actin isoform typical of vascular SM cells. Myofibroblasts have been proposed to play a role in wound contraction and in retractile phenomena observed during fibrotic diseases. We show here that the subcutaneous administration of transforming growth factor-beta 1 (TGF beta 1) to rats results in the formation of a granulation tissue in which alpha-SM actin expressing myofibroblasts are particularly abundant. Other cytokines and growth factors, such as platelet-derived growth factor and tumor necrosis factor-alpha, despite their profibrotic activity, do not induce alpha-SM actin in myofibroblasts. In situ hybridization with an alpha-SM actin probe shows a high level of alpha-SM actin mRNA expression in myofibroblasts of TGF beta 1-induced granulation tissue. Moreover, TGF beta 1 induces alpha-SM actin protein and mRNA expression in growing and quiescent cultured fibroblasts and preincubation of culture medium containing whole blood serum with neutralizing antibodies to TGF beta 1 results in a decrease of alpha-SM actin expression by fibroblasts in replicative and non-replicative conditions. These results suggest that TGF beta 1 plays an important role in myofibroblast differentiation during wound healing and fibrocontractive diseases by regulating the expression of alpha-SM actin in these cells.

2,154 citations


"Transforming growth factor (TGF)-β ..." refers background in this paper

  • ...TGF-β stimulation induces myofibroblast differentiation [31] and enhances extracellular matrix protein synthesis....

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Journal ArticleDOI
TL;DR: The current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor‐β (TGF‐β), connective tissue growth factor (CTGF, CCN2), and ED‐A fibronectin (ED‐A FN) and the antifib rotic proteins tumor necrosis factor‐α (TNF‐α) and γ‐interferon (IFN‐γ) is discussed.
Abstract: The cause of fibrotic diseases, pathologies characterized by excessive production, deposition, and contraction of extracellular matrix, is unknown. To understand the molecular basis of fibrotic disease, it is essential to appreciate how matrix deposition is normally controlled and how this process is dysregulated in fibrogenesis. This review discusses the current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF, CCN2), and ED-A fibronectin (ED-A FN) and the antifibrotic proteins tumor necrosis factor-α (TNF-α) and γ-interferon (IFN-γ).—Leask, A., Abraham, D. J. TGF-β signaling and the fibrotic response.

2,147 citations


"Transforming growth factor (TGF)-β ..." refers background in this paper

  • ...In addition, TGF-β is a potent inducer of connective tissue growth factor (CTGF), a fibrogenic mediator that acts in concert with TGF-β to promote persistent fibrosis [32]....

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