Journal of the American Heart Association · 2026
Cardiomyocyte-Specific Smad7 Protects the Pressure-Overloaded Heart, Inhibiting the Transforming Growth Factor-β Receptor 1/Smad2/3 Cascade.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Humeres Claudio, Tuleta Izabela, Qin Dongze, Shinde Arti V, Deepak Aadya, Hanna Anis, Frangogiannis Nikolaos G
Аннотация
BACKGROUND: The effects of TGF-βs (transforming growth factor-βs) in failing hearts involve cell-specific actions mediated through receptor-regulated Smads or Smad-independent pathways. The inhibitory Smad, Smad7, is a negative feedback regulator that restrains excessive TGF-β/receptor-regulated Smad signaling, while also exerting TGF-β-independent effects. We hypothesized that cardiomyocyte Smad7 upregulation contributes to the pathogenesis of pressure overload-induced heart failure and investigated the mechanisms underlying its actions.
METHODS: Cardiomyocyte-specific Smad7 knockout mice and corresponding Cre+ and Smad7fl/fl controls underwent transverse aortic constriction. Echocardiographic, histological, transcriptomic, and proteomic analyses were performed. RNA sequencing identified candidate pathways modulated by Smad7. Effects of Smad7 loss on TGF-β and ERBB2 (erb-b2 receptor tyrosine kinase 2) cascades were examined in vivo and in cardiomyocyte-like H9c2 cells using western blotting.
RESULTS: Smad7 was upregulated in cardiomyocytes and fibroblasts following transverse aortic constriction and in patients with nonischemic cardiomyopathy. Cardiomyocyte-specific Smad7 knockout mice had no baseline abnormalities but developed worse systolic and diastolic dysfunction and increased cardiomyocyte hypertrophy after pressure overload. Cardiomyocyte Smad7 loss did not alter fibrosis after transverse aortic constriction but increased macrophage infiltration. Cardiomyocyte-specific Smad7 knockout hearts showed reduced expression of genes associated with cardiac contraction. Bioinformatic analysis identified TGF-β1, angiotensin, and ERBB2 as candidate upstream regulators mediating the effects of Smad7 loss. In vivo, cardiomyocyte Smad7 inhibited activation of TGF-β receptor 1 (TGFBR1)/Smad2/3 and ERBB2 without affecting TGF-β receptor 2 (TGFBR2) activity. In the absence of Smad7, pressure-overloaded cardiomyocytes exhibited increased TGFBR1/Smad3 activation. In H9c2 cells, endogenous Smad7 restrained TGFBR1/Smad3 activation without affecting TGFBR2 or ERBB2 activity.
CONCLUSIONS: Cardiomyocyte Smad7 protects the pressure-overloaded heart from dysfunction, regulating genes involved in muscle contraction, likely through direct suppression of TGFBR1/Smad3.
METHODS: Cardiomyocyte-specific Smad7 knockout mice and corresponding Cre+ and Smad7fl/fl controls underwent transverse aortic constriction. Echocardiographic, histological, transcriptomic, and proteomic analyses were performed. RNA sequencing identified candidate pathways modulated by Smad7. Effects of Smad7 loss on TGF-β and ERBB2 (erb-b2 receptor tyrosine kinase 2) cascades were examined in vivo and in cardiomyocyte-like H9c2 cells using western blotting.
RESULTS: Smad7 was upregulated in cardiomyocytes and fibroblasts following transverse aortic constriction and in patients with nonischemic cardiomyopathy. Cardiomyocyte-specific Smad7 knockout mice had no baseline abnormalities but developed worse systolic and diastolic dysfunction and increased cardiomyocyte hypertrophy after pressure overload. Cardiomyocyte Smad7 loss did not alter fibrosis after transverse aortic constriction but increased macrophage infiltration. Cardiomyocyte-specific Smad7 knockout hearts showed reduced expression of genes associated with cardiac contraction. Bioinformatic analysis identified TGF-β1, angiotensin, and ERBB2 as candidate upstream regulators mediating the effects of Smad7 loss. In vivo, cardiomyocyte Smad7 inhibited activation of TGF-β receptor 1 (TGFBR1)/Smad2/3 and ERBB2 without affecting TGF-β receptor 2 (TGFBR2) activity. In the absence of Smad7, pressure-overloaded cardiomyocytes exhibited increased TGFBR1/Smad3 activation. In H9c2 cells, endogenous Smad7 restrained TGFBR1/Smad3 activation without affecting TGFBR2 or ERBB2 activity.
CONCLUSIONS: Cardiomyocyte Smad7 protects the pressure-overloaded heart from dysfunction, regulating genes involved in muscle contraction, likely through direct suppression of TGFBR1/Smad3.