The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REG gamma is emerging as 11S proteasome activator of 20S proteasome to promote the degradation of cellular proteins in a ubiquitin- and ATP-independent manner. Here, we found that REG gamma was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REG gamma deficiency ameliorated pressure overload-induced cardiac hypertrophy were associated with inhibition of cardiac reactive oxygen species (ROS) accumulation and suppression of protein phosphatase 2A catalytic subunit alpha (PP2Ac alpha) decay. Mechanistically, REG gamma interacted with and targeted PP2Ac alpha for degradation directly, thereby leading to increase of phosphorylation levels and nuclear export of Forkhead box protein O (FoxO) 3a and subsequent of SOD2 decline, ROS accumulation, and cardiac hypertrophy. Introducing exogenous PP2Ac alpha or SOD2 to human cardiomyocytes significantly rescued the REG gamma-mediated ROS accumulation of Ang II stimulation in vitro. Furthermore, treatment with superoxide dismutase mimetic, MnTBAP prevented cardiac ROS production and hypertrophy features that REG gamma caused in vivo, thereby establishing a REG gamma-PP2Ac alpha-FoxO3a-SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REG gamma-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.