Abstract 3328: Inducible Knock-down of Type II but Not Type I Receptor of Transforming Growth Factor Beta in Cardiomyocytes is Sufficient to Prevent Heart Failure in Pressure-overloaded Mouse Heart
[Background] Cellular signaling mechanism of transition from cardiac hypertrophy to heart failure is still largely unknown. Transforming growth factor-beta (TGFβ) is a multifunctional cytokine involved with heart growth, development, and extracellular matrix regulation. Its role in cardiomyocytes remains to be elucidated. TGFβ binds to type2 receptor (TGFBR2) which then activates type1 receptor (ALK5) and subsequently Smad transcriptional regulators (particularly Smad2/3). To test the role of TGFβ signaling in cardiomyocytes, we generated temporally controlled myocyte specific-knockout mice for Tgfbr2 and Alk5.
[Methods and Results] We crossed αMHC-driven tamoxifen-inducible Cre (MCM) with Tgfbr2 floxed mice (MCM/Tgfr2) or Alk5 floxed (MCM/Alk5) mice. Baseline cardiac function was similar among MCM/Tgfbr2, MCM/Alk5, MCM-no flox, and littermate controls. Transverse aortic constriction (TAC) resulted in similar hypertrophy/remodeling (echocardiography) the first 3 wks after TAC, however, after 10-weeks, MCM/TGFBR2 mice had no cardiac dilatation, dysfunction, while MCM/Alk5 mice or MCM/no floxed mice had progressive dilatation and dysfunction. In spite of similar afterload, diastolic and systolic dysfunction in chronic phases of pressure overload were remarkably attenuated in MCM/TGFB2 mice (pressure-volume analysis) but not in MCM/Alk5 mice. Cardiac hypertrophy evaluated by heart weight or by histochemical cardiomyocyte area was less in MCM/TGFBR2 than MCM/no floxed mice. Smad3 activation was blunted in both MCM/Tgfbr2 and MCM/Alk5. However, myocardial regulator of calcineurin (RCAN1) expression, reflecting calcineurin (CN) activity, was blocked in MCM/Tgfbr2 but not MCM/Alk5. TGFβ-activation kinase-1 (TAK1) is a key pathway of Smad-independent TGFβ signaling that couples to CN activation. TAC-mediated TAK1 autophosphorylation, was markedly blunted in MCM/Tgfbr2 but not in MCM/Alk5 mice.
[Conclusion] Temporally controlled Tgfbr2 or Alk5 knockout reveals TGFBR2 plays a central role in pressure- overload mediated cardiac hypertrophy and remodeling, while, ALK5 does not. This supports TGFBR2 and Smad-independent TGFβ signaling as a key target for anti- hypertrophic and anti-remodeling therapy of the heart.