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Cardiomyocyte-Specific Smad7 protects the pressure-overloaded heart, inhibiting the TbR1/Smad2/3 cascade

ABSTRACT: Cardiomyocytes are the major effectors of cardiac remodeling under pressure overload, undergoing hypertrophy and contractile dysfunction in response to sustained mechanical stress. These maladaptive changes are orchestrated by transforming growth factor beta (TGF-β), a key mediator of hypertrophic and profibrotic signaling. Smad7, an inhibitory Smad, negatively regulates TGF-β signaling, but its cardiomyocyte-specific role in pathological remodeling is unclear. We hypothesized that Smad7 acts as an endogenous inhibitor of cardiomyocyte dysfunction during pressure overload. To investigate this, we generated cardiomyocyte-specific Smad7 knockout (CMS7KO) mice and subjected them to transverse aortic constriction (TAC). Echocardiography, RNA-sequencing, histological, and molecular analyses were performed. Smad7 expression was upregulated in cardiomyocytes of TAC mouse hearts and in patients with non-ischemic cardiomyopathy. While baseline cardiac function was preserved in CMS7KO mice, TAC induced an increase in systolic and diastolic dysfunction, ventricular dilation, and hypertrophy compared to controls. Histological analysis revealed increased cardiomyocyte size and macrophage infiltration, without significant fibrosis. Transcriptomic profiling showed downregulation of contractile and sarcomeric genes. Cardiomyocyte-specific Smad7 loss enhanced TGF-β/Smad3 and ERBB2 signaling in vivo. In H9c2 cardiomyocyte-like cells, Smad7 knockdown increased TbR1 and Smad3 phosphorylation, confirming a direct inhibitory effect. These findings identify cardiomyocyte Smad7 as a critical regulator of pathological remodeling and a potential therapeutic target in heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE299359 | GEO | 2026/06/06

REPOSITORIES: GEO

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Project description:Rationale: Expansion and activation of cardiac fibroblasts contributes to adverse remodeling, fibrosis and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β/Smad3 activation protects the pressure overloaded heart by preserving the matrix, sustained TGF-β activation may be deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF- response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. Objective: To study the role of fibroblast-specific induction of Smad7, an inhibitory Smad that restrains TGF-β signaling, in regulation of fibrosis, remodeling and dysfunction of the pressure-overloaded heart. Methods and Results: In a mouse model of pressure overload induced through transverse aortic constriction (TAC), Smad7 was upregulated in cardiac myofibroblasts. Mice with myofibroblast-specific loss of Smad7 (MFS7KO) had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to TAC. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased collagen denaturation, in the absence of effects on cardiomyocyte death. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins, and markedly increases secretion of matrix metalloproteinase-2 (MMP2). In a 3D model of fibroblasts populating collagen lattices the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Secretomic analysis and in vitro experiments suggested that macrophage activation involves the combined effects of the fibroblast-derived matricellular proteins CD5L, SPARC, CTGF, ECM1 and TGFBI. Conclusions: The anti-fibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition, but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

Project description:Rationale: Expansion and activation of cardiac fibroblasts contributes to adverse remodeling, fibrosis and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β/Smad3 activation protects the pressure overloaded heart by preserving the matrix, sustained TGF-β activation may be deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF- response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. Objective: To study the role of fibroblast-specific induction of Smad7, an inhibitory Smad that restrains TGF-β signaling, in regulation of fibrosis, remodeling and dysfunction of the pressure-overloaded heart. Methods and Results: In a mouse model of pressure overload induced through transverse aortic constriction (TAC), Smad7 was upregulated in cardiac fibroblasts and myofibroblasts. Mice with myofibroblast-specific loss of Smad7 (MFS7KO) had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to TAC. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased collagen denaturation, in the absence of effects on cardiomyocyte death. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins, and markedly increases secretion of matrix metalloproteinase-2 (MMP2). In a 3D model of fibroblasts populating collagen lattices the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Secretomic analysis and in vitro experiments suggested that macrophage activation involves the combined effects of the fibroblast-derived matricellular proteins CD5L, SPARC, CTGF, ECM1 and TGFBI. Conclusions: The anti-fibrotic effects of Smad7 in the pressure-overloaded heart protect from dysfunction and involve not only reduction in collagen deposition, but also suppression of MMP2-mediated matrix denaturation and paracrine effects that suppress macrophage activation through inhibition of matricellular proteins.

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Cardiomyocyte-Specific Smad7 protects the pressure-overloaded heart, inhibiting the TbR1/Smad2/3 cascade

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