TY - JOUR
T1 - The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα–SOD2 pathway
AU - Xie, Yifan
AU - Gao, Yang
AU - Gao, Rifeng
AU - Yang, Wenlong
AU - Dong, Zheng
AU - Moses, Robb E.
AU - Sun, Aijun
AU - Li, Xiaotao
AU - Ge, Junbo
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REGγ 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 REGγ was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REGγ 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 α (PP2Acα) decay. Mechanistically, REGγ interacted with and targeted PP2Acα 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 PP2Acα or SOD2 to human cardiomyocytes significantly rescued the REGγ-mediated ROS accumulation of Ang II stimulation in vitro. Furthermore, treatment with superoxide dismutase mimetic, MnTBAP prevented cardiac ROS production and hypertrophy features that REGγ caused in vivo, thereby establishing a REGγ–PP2Acα–FoxO3a–SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REGγ-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.
AB - Pathological cardiac hypertrophy eventually leads to heart failure without adequate treatment. REGγ 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 REGγ was significantly upregulated in the transverse aortic constriction (TAC)-induced hypertrophic hearts and angiotensin II (Ang II)-treated cardiomyocytes. REGγ 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 α (PP2Acα) decay. Mechanistically, REGγ interacted with and targeted PP2Acα 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 PP2Acα or SOD2 to human cardiomyocytes significantly rescued the REGγ-mediated ROS accumulation of Ang II stimulation in vitro. Furthermore, treatment with superoxide dismutase mimetic, MnTBAP prevented cardiac ROS production and hypertrophy features that REGγ caused in vivo, thereby establishing a REGγ–PP2Acα–FoxO3a–SOD2 pathway in cardiac oxidative stress and hypertrophy, indicates modulating the REGγ-proteasome activity may be a potential therapeutic approach in cardiac hypertrophy-associated disorders.
UR - http://www.scopus.com/inward/record.url?scp=85085169952&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085169952&partnerID=8YFLogxK
U2 - 10.1038/s41418-020-0554-8
DO - 10.1038/s41418-020-0554-8
M3 - Article
C2 - 32424140
AN - SCOPUS:85085169952
SN - 1350-9047
VL - 27
SP - 2952
EP - 2972
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 10
ER -