Loss of Cavin-2 destabilizes phosphatase and tensin homologue and enhances Akt signalling pathway in cardiomyocytes

Abstract

Abstract Aims Specific cavins and caveolins, known as caveola-related proteins, have been implicated in cardiac hypertrophy and myocardial injury. Cavin-2 forms complexes with other caveola-related proteins, but the role of Cavin-2 in cardiomyocytes (CMs) is poorly understood. Here, we investigated an unknown function of Cavin-2 in CMs. Methods and results Under cardiac stress-free conditions, systemic Cavin-2 knockout (KO) induced mild and significant CM hypertrophy. Cavin-2 KO suppressed phosphatase and tensin homologue (PTEN) associated with Akt signalling, whereas there was no difference in Akt activity between the hearts of the wild-type and the Cavin-2 KO mice under cardiac stress-free conditions. However, after swim training, CM hypertrophy was more facilitated with enhanced phosphoinositide 3-kinase (PI3K)-Akt activity in the hearts of Cavin-2 KO mice. Cavin-2 knockdown neonatal rat CMs (NRCMs) using adenovirus expressing Cavin-2 short hairpin RNA were hypertrophied and resistant to hypoxia and H2O2-induced apoptosis. Cavin-2 knockdown increased Akt phosphorylation in NRCMs, and an Akt inhibitor inhibited Cavin-2 knockdown-induced anti-apoptotic responses in a dose-dependent manner. Cavin-2 knockdown increased phosphatidylinositol-3,4,5-triphosphate production and attenuated PTEN at the membrane fraction of NRCMs. Immunostaining and immunoprecipitation showed that Cavin-2 was associated with PTEN at the plasma membrane of NRCMs. A protein stability assay showed that Cavin-2 knockdown promoted PTEN destabilization in NRCMs. In an Angiotensin II (2-week continuous infusion)-induced pathological cardiac hypertrophy model, CM hypertrophy and CM apoptosis were suppressed in CM-specific Cavin-2 conditional KO (Cavin-2 cKO) mice. Because Cavin-2 cKO mouse hearts showed increased Akt activity but not decreased extracellular signal-regulated kinase activity, suppression of pathological hypertrophy by Cavin-2 loss may be due to increased survival of healthy CMs. Conclusion Cavin-2 plays a negative regulator in the PI3K-Akt signalling in CMs through interaction with PTEN. Loss of Cavin-2 enhances Akt activity by promoting PTEN destabilization, which promotes physiological CM hypertrophy and may enhance Akt-mediated cardioprotective effects against pathological CM hypertrophy.