Smad-dependent pathways in the infarcted and failing heart
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.
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