Cardiomyocyte-Specific Smad7 Protects the Pressure-Overloaded Heart, Inhibiting the Transforming Growth Factor-β...

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Cellular Signaling

Background:

• Transforming growth factor-β (TGF-β) signaling impacts heart failure through receptor-regulated Smads or Smad-independent pathways.
• Smad7, an inhibitory Smad, negatively regulates TGF-β signaling and has independent effects.
• The role of cardiomyocyte Smad7 in pressure overload-induced heart failure pathogenesis was investigated.

Purpose of the Study:

• To investigate the role and mechanisms of cardiomyocyte Smad7 in pressure overload-induced heart failure.
• To determine if Smad7 upregulation in cardiomyocytes contributes to heart failure progression.

Main Methods:

• Generated cardiomyocyte-specific Smad7 knockout mice and subjected them to transverse aortic constriction.
• Performed echocardiographic, histological, transcriptomic, and proteomic analyses.
• Examined TGF-β and ERBB2 signaling cascades in vivo and in H9c2 cells via western blotting.

Main Results:

• Smad7 knockout mice exhibited worsened systolic/diastolic dysfunction and hypertrophy post-pressure overload.
• Loss of Smad7 increased macrophage infiltration but not fibrosis.
• Smad7 knockout hearts showed reduced expression of cardiac contraction genes and increased TGFBR1/Smad3 activation.
• Smad7 inhibited TGFBR1/Smad3 and ERBB2 activation in cardiomyocytes.

Conclusions:

• Cardiomyocyte Smad7 plays a protective role in pressure-overloaded hearts.
• Smad7 regulates genes involved in cardiac muscle contraction.
• Smad7 likely exerts its protective effects by directly suppressing TGFBR1/Smad3 signaling.