Regulator of G Protein Signaling 6 Facilities Cardiac Hypertrophy by Activating Apoptosis Signal-Regulating Kinase 1-P38/c-JUN N-Terminal Kinase 1/2 Signaling.

Abstract

BackgroundRegulator of G protein signaling 6 (RGS6) is an important member of the RGS family and produces pleiotropic regulatory effects on cardiac pathophysiology. However, the role of RGS6 protein in cardiomyocytes during angiotensin II– and pressure overload–induced cardiac hypertrophy remain unknown.Methods and ResultsHere, we used a genetic approach to study the regulatory role of RGS6 in cardiomyocytes during pathological cardiac hypertrophy. RGS6 expression was significantly increased in failing human hearts and in hypertrophic murine hearts. The extent of aortic banding–induced cardiac hypertrophy, dysfunction, and fibrosis in cardiac‐specific RGS6 knockout mice was alleviated, whereas the hearts of transgenic mice with cardiac‐specific RGS6 overexpression exhibited exacerbated responses to pressure overload. Consistent with these findings, RGS6 also facilitated an angiotensin II–induced hypertrophic response in isolated cardiomyocytes. According to the mechanistic studies, RGS6 mediated cardiac hypertrophy by directly interacting with apoptosis signal–regulating kinase 1, which further activates the P38‐c‐JUN N‐terminal kinase 1/2 signaling pathway.ConclusionsBased on our findings, RGS6 aggravates cardiac hypertrophy, and the RGS6‐apoptosis signal–regulating kinase 1 pathway represents a potential therapeutic target to attenuate pressure overload–driven cardiac remodeling.