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

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.