Smad-dependent pathways in the infarcted and failing heart

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Abstract

In infarcted and failing hearts, TGF-β superfamily members play an important role in regulation of inflammatory, reparative, fibrogenic, and hypertrophic responses through activation of Smad-dependent and Smad-independent cascades. This review manuscript discusses the mechanisms of regulation and role of Smad pathways in myocardial infarction and in heart failure. Cardiomyocyte-specific Smad1 activation exerts protective anti-apoptotic actions following ischemia/reperfusion. In contrast, the role of the Smad1/5/8 cascade in reparative, immune, and vascular cells infiltrating the infarcted heart is unknown. Smad3, but not Smad2 is implicated in repair of the infarcted heart, by activating reparative myofibroblasts and by promoting anti-inflammatory transition in macrophages. However, prolonged activation of Smad3 may promote adverse remodeling and fibrosis. The inhibitory Smad, Smad7 restrains TGF-β-induced fibroblast activation, but also exerts TGF-independent actions through inhibition of receptor tyrosine kinase signaling. Cell-specific approaches targeting Smad pathways may hold therapeutic promise in myocardial infarction and in heart failure.

Introduction

The members of the TGF-β superfamily are highly conserved across species and serve as central regulators of inflammatory, reparative, and fibrotic responses in many different organs and pathologic conditions [1,2]. In humans, the superfamily is comprised of more than 30 structurally related proteins, which can be subclassified into several subfamilies, including the TGF-βs (TGF-β1,-β2 and -β3), the bone morphogenetic proteins (BMP2/10 and BMP12/15) [3], the growth differentiation factors (GDFs), the inhibins, activins, Nodal, Lefty, and anti-Mullerian hormone proteins. TGF-β superfamily members signal by binding to specific combinations of type I and type II TGF-β receptors, thus transducing downstream signaling cascades, involving intracellular effectors, the receptor-activated Smads (R-Smads) [4], or Smad-independent cascades [5]. R-Smad signaling is negatively regulated through induction of the inhibitory Smads (I-Smads), Smad6 and Smad7, which suppress TGF-β superfamily signaling. The relative significance of Smad-mediated and non-Smad signaling is dependent on the specific cell type stimulated by TGF-β superfamily members, and on context-dependent factors

Cardiac injury is associated with induction of a wide range of TGF-β superfamily members, including TGF-βs [6], BMPs [7] and GDFs [8], resulting in downstream activation of Smad-dependent [9] and non-Smad signaling pathways [10]. A growing body of evidence suggests that activation of Smad signaling cascades plays an important role in regulation of myocardial remodeling, inflammation, and fibrosis. The current review manuscript discusses our knowledge on the effects of Smad-dependent signaling in repair, remodeling and fibrosis in infarcted and failing hearts, with an emphasis on recently published studies examining the cell-specific actions of specific R-Smads, and the role of I-Smads in myocardial pathologic conditions.

Section snippets

The biology of smad signaling cascades

TGF-β superfamily members signal by binding to dual specificity cell surface receptors, called TGF-β receptors (TβR). Humans have seven type I TβRs (ALK1-7) and 5 type II TβRs (TβRII, ActRII, ActRIIB, AMHRII and BMPRII). Binding to a member of the TGF-β superfamily results in formation of a heterotetramer, a complex comprised two type I and two type II receptors [11]. Depending on the cell type and context, individual TGF-β superfamily members bind to their respective type II TβRs that then

Cell-specific actions of smad cascades in the infarcted myocardium

Myocardial infarction increases the levels of bioactive TGF-β in the myocardium through activation of latent stores of TGF-β, via release of TGF-β stored in platelet granules, and through de novo synthesis and secretion of TGF-β isoforms by ischemic cardiomyocytes, macrophages, vascular cells, and fibroblasts [6,18,19]. Unfortunately, experimental evidence on the mechanisms of TGF-β activation in the infarcted heart is limited, and the relative significance of de novo synthesis of TGF-β

Smad signaling cascades in conditions associated with chronic heart failure

Chronic heart failure in patients exhibits remarkable pathophysiologic heterogeneity. TGF-β signaling cascades have been suggested to play an important role in the pathogenesis of cardiac remodeling and dysfunction in several heart failure-associated pathophysiologic conditions. Patients with end-stage Heart Failure with reduced Ejection Fraction (HFrEF) exhibit persistent myocardial activation of Smad2 and Smad3 cascades, associated with increased levels of TGF-β1 [41]. Evidence showing

Inhibitory signals that restrain smad-mediated signaling: The role of the I-Smads and c-Ski

Effective cardiac repair is dependent on timely suppression of TGF-β/Smad responses. This is particularly important for fibroblast-mediated actions, as unrestrained TGF-β/Smad2/3 signaling in fibroblasts would be expected to stimulate progression of fibrosis and development of heart failure. During the maturation phase of infarct healing, activated matrix-synthetic myofibroblasts convert into matrifibrocytes [49], a differentiated fibroblast phenotype that does not express significant amounts

Sex-specific effects of smad cascades in cardiac remodeling

In the mouse model of non-reperfused myocardial infarction, female animals have better outcome, exhibiting a much lower incidence of cardiac rupture than males [71]. This observation may reflect sex-specific differences in the cellular responses involved in cardiac repair and remodeling [72]. Comparative analysis of data from studies on the role of Smad cascades in the infarcted myocardium have suggested, at least in some cases, sex-specific effects. Although both male and female

Therapeutic implications and conclusions

A growing body of evidence suggests that activation of Smad pathways regulates cellular responses with a critical role in repair, remodeling, and dysfunction of the infarcted and failing heart [76]. However, the cell-specific and context-dependent actions of Smad signaling cascades pose major challenges in designing therapeutic interventions to improve outcome in patients with myocardial infarction, or heart failure. For example, Smad3 plays an important protective role in the early stages of

Sources of funding

Dr. Frangogiannis’ laboratory is supported by NIH R01 grants HL76246, HL85440, and R01 HL149407 and by Department of Defense grant PR181464. Dr. Humeres is supported by an American Heart Association post-doctoral award 19POST34450144.

Conflict of interest statement

Nothing declared.

References (80)

  • Q. Chen et al.

    Smad7 is required for the development and function of the heart

    J Biol Chem

    (2009)
  • J.A. Faress et al.

    Bleomycin-induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2

    J Appl Physiol

    (1985)
  • S. Akiyoshi et al.

    c-Ski acts as a transcriptional co-repressor in transforming growth factor-beta signaling through interaction with smads

    J Biol Chem

    (1999)
  • C. Montalvo et al.

    Androgens contribute to sex differences in myocardial remodeling under pressure overload by a mechanism involving TGF-beta

    PLoS One

    (2012)
  • A. Hanna et al.

    The role of the TGF-beta superfamily in myocardial infarction

    Front Cardiovasc Med

    (2019)
  • T. Katagiri et al.

    Bone morphogenetic proteins

    Cold Spring Harbor Perspect Biol

    (2016)
  • J. Massague

    How cells read TGF-beta signals

    Nat Rev Mol Cell Biol

    (2000)
  • A. Moustakas et al.

    Non-Smad TGF-beta signals

    J Cell Sci

    (2005)
  • L.N. Sanders et al.

    BMP antagonist gremlin 2 limits inflammation after myocardial infarction

    Circ Res

    (2016)
  • T. Kempf et al.

    GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice

    Nat Med

    (2011)
  • M. Bujak et al.

    Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling

    Circulation

    (2007)
  • J.D. Molkentin et al.

    Fibroblast-specific genetic manipulation of p38 mitogen-activated protein kinase in vivo reveals its central regulatory role in fibrosis

    Circulation

    (2017)
  • C.H. Heldin et al.

    Signaling receptors for TGF-beta family members

    Cold Spring Harbor Perspect Biol

    (2016)
  • A. Hata et al.

    TGF-beta signaling from Receptors to Smads

    Cold Spring Harbor Perspect Biol

    (2016)
  • M. Kretzschmar et al.

    Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1

    Nature

    (1997)
  • P. Li et al.

    Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts

    Circ Res

    (2008)
  • A. Hanyu et al.

    The N domain of Smad7 is essential for specific inhibition of transforming growth factor-beta signaling

    J Cell Biol

    (2001)
  • H. Hayashi et al.

    The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling

    Cell

    (1997)
  • T. Ebisawa et al.

    Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation

    J Biol Chem

    (2001)
  • B. Chen et al.

    Macrophage Smad3 protects the infarcted heart, stimulating phagocytosis and regulating inflammation

    Circ Res

    (2019)
  • O. Dewald et al.

    Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction

    Am J Pathol

    (2004)
  • R.M. Lyons et al.

    Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium

    J Cell Biol

    (1988)
  • M. Guo et al.

    Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-betaL a process initiated by the exocytosis of cathepsin B

    J Biol Chem

    (2002)
  • S. Maeda et al.

    The first stage of transforming growth factor beta1 activation is release of the large latent complex from the extracellular matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3)

    Calcif Tissue Int

    (2002)
  • K. Bourd-Boittin et al.

    Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta

    Hepatology

    (2011)
  • Y. Yao et al.

    ADAMTS16 activates latent TGF-beta, accentuating fibrosis and dysfunction of the pressure-overloaded heart

    Cardiovasc Res

    (2019)
  • M. Masaki et al.

    Smad1 protects cardiomyocytes from ischemia-reperfusion injury

    Circulation

    (2005)
  • P. Kong et al.

    Opposing actions of fibroblast and cardiomyocyte Smad3 signaling in the infarcted myocardium

    Circulation

    (2018)
  • P.P. Rainer et al.

    Cardiomyocyte-specific transforming growth factor beta suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction

    Circ Res

    (2014)
  • M. Dobaczewski et al.

    Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction

    Circ Res

    (2010)
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