Abstract 15113: Inhibition of Mtor With Rapamycin Reverses Cardiomyocyte-Specific Knockout of Pten-Induced Hypertrophic Cardiomyopathy
Background: The role of PTEN (phosphatase and tensin homolog deleted from chromosome 10) in the maintenance of cardiac homeostasis remains controversial. While some studies suggest that muscle-specific loss of PTEN triggers cardiac hypertrophy and cardiomyocyte contractile dysfunction, others indicate that the muscle-specific PTEN deficiency protects against pressure overload-induced heart failure. Autophagy is an evolutionarily conserved pathway for protein degradation. Rapamycin, a specific inhibitor of mTOR (mammalian target of rapamycin, the primary inhibitory regulator of autophagy), is widely used for the induction of autophagy pathway.
Methods and Results: We generated mice with cardiomyocyte-specific knockout of PTEN, α-MHC Cre-PTEN(flox/flox) (CM PTENKO). These adult PTEN-/- mice recapitulated features of hypertrophic cardiomyopathy HCM), including geometric, functional, histological and molecular changes. In particular, cardiomyocyte-specific PTEN knockout promoted cardiac mTOR activity and suppressed autophagy activity. Moreover, treatment with rapamycin (2 mg/kg/d, i.p.), an inhibitor of mTOR, for one month was sufficient to reverse the established hypertrophic cardiomyopathy in cardiomyocyte-specific PTENKO mice. Following rapamycin treatment, autophagy activity was significantly restored in cardiomyocyte-specific PTENKO mice. The cardioprotective effect of rapamycin was associated with ameliorating cardiomyocyte apoptosis in the heart of CM PTENKO mice.
Conclusion: Our results demonstrated an essential role of cardiomyocyte PTEN in maintaining the cardiac homeostasis under physiological condition. Cardiomyocyte-specific deletion of PTEN leads to the development of hypertrophic cardiomyopathy, which may be underscored by mTOR hyperactivation and autophagy suppression. In addition, our data favored a therapeutic potential of mTOR inhibitors in HCM patients with PTEN deficiency.
- © 2013 by American Heart Association, Inc.