Inhibition of mammalian target of rapamycin with rapamycin reverses hypertrophic cardiomyopathy in mice with cardiomyocyte-specific knockout of PTEN.

ABSTRACT

The role of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) in the maintenance of cardiac homeostasis still remains controversial. This study was designed to evaluate the role of cardiomyocyte-specific PTEN in the maintenance of cardiac homeostasis and the underlying mechanisms involved with a focus on autophagy, an evolutionarily conserved pathway for protein degradation. Cardiomyocyte-specific PTEN((flox/flox))/α-myosin heavy chain Cre mice, henceforth referred to as CM-PTENKO, were generated by crossing the floxed PTEN mice with α-myosin heavy chain Cre mice driven by a Cre recombinase promoter. The adult PTEN(-/-) mice displayed the phenotype of established hypertrophic cardiomyopathy, including unfavorable geometric, functional, and histological changes. Furthermore, cardiomyocyte-specific PTEN knockout mice exhibited increased cardiac mammalian target of rapamycin although suppressed autophagy. Treatment with rapamycin (2 mg/kg per day, IP), an inhibitor of mammalian target of rapamycin, for 1 month effectively reversed the established hypertrophic cardiomyopathy in CM-PTENKO mice. With rapamycin treatment, autophagy activity was significantly restored in the heart of CM-PTENKO mice. Taken together, our results demonstrate an essential role for cardiomyocyte PTEN in maintaining cardiac homeostasis under physiological condition. Cardiomyocyte-specific deletion of PTEN results in the development of hypertrophic cardiomyopathy possibly through a mechanism associated with mammalian target of rapamycin hyperactivation and autophagy suppression.