Abstract 15598: SDPR/Cavin-2 Modulates Akt Sgnaling Involved in Regulation of Hypertrophy and Apoptosis in Cardiomyocytes
Introduction: SDPR/Cavin-2 is a member of the cavins which belongs to caveolar related proteins. SDPR/Cavin-2 regulates caveolar formation in a variety of cell types.The structural role of SDPR/Cavin-2 in caveolae has been well studied. However, its functional role remains unknown. Here, we present a novel functional role of SDPR/Cavin-2 in cardiomyocytes.
Methods and Results: To examine the functional role of SDPR/Cavin-2 in cardiomyocytes, we generated SDPR/Cavin-2 knock-out (SDPR-/-) mice and knocked down SDPR/Cavin-2 expression in neonatal rat cardiomyocytes using adenovirus expressing SDPR/Cavin-2 shRNA. SDPR-/- mice developed a progressive cardiac hypertrophy. At fourteen weeks of age, SDPR-/- mice had a significantly higher heart weight/body weight ratio than wild-type mice. SDPR-/- mice displayed significant concentric hypertrophy as revealed by echocardiography. In vitro study, increased cardiomyocyte surface area, which was associated with induction of hypertrophy-related fetal gene expression, was observed in SDPR/Cavin-2 knockdown group compared with a control group. TUNEL assay revealed that cardiomyocytes with SDPR/Cavin-2-knockdown were resistant to apoptosis induced by hypoxia and H2O2 stimulation. To assess the signaling associated with cardiomyocyte hypertrophy and apoptosis, we performed immunoblotting for Akt signaling. SDPR/Cavin-2 knockdown increased phosphorylation of Akt in cardiomyocytes. An Akt inhibitor inhibited SDPR/Cavin-2 knockdown-induced hypertrophic and anti-apoptotic responses in a dose-dependent manner. Interestingly, SDPR/Cavin-2 knockdown attenuated PTEN level at the membrane fraction of cardiomyocytes. Immunoprecipitation showed that SDPR/Cavin-2 bound to PTEN.
Conclusions: Our findings suggest that SDPR/Cavin-2 serves as an anchoring protein for PTEN at the plasma membrane in cardiomyocytes and that SDPR/Cavin-2 loss causes hyperactivation of Akt signaling pathway via PTEN attenuation at the plasma membrane.
Author Disclosures: N. Maruyama: None. T. Ogata: None. N. Nakanishi: None. T. Hamaoka: None. K. Miyagawa: None. T. Kasahara: None. T. Ueyama: None.
- © 2014 by American Heart Association, Inc.