The proteasome activator REG? accelerates cardiac hypertrophy by declining PP2Ac?-SOD2 pathway.

Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REG? 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? was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts ...
and angiotensin II (Ang II)-treated cardiomyocytes. REG? 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 ? (PP2Ac?) decay. Mechanistically, REG? interacted with and targeted PP2Ac? 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? or SOD2 to human cardiomyocytes significantly rescued the REG?-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? caused in vivo, thereby establishing a REG?-PP2Ac?-FoxO3a-SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REG?-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.
Mesh Terms:
Animals, Animals, Newborn, Autoantigens, Cardiomegaly, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac, Oxidative Stress, Primary Cell Culture, Proteasome Endopeptidase Complex, Rats, Rats, Sprague-Dawley, Reactive Oxygen Species
Cell Death Differ
Date: Dec. 01, 2019
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