Selective Inhibition of the Immunoproteasome β5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy

• Published in: Frontiers in pharmacology 2020-06, Vol.11, p.885-885
• Main Authors: Xie, Xin, Wang, Hong-Xia, Li, Nan, Deng, Ya-Wen, Bi, Hai-Lian, Zhang, Yun-Long, Xia, Yun-Long, Li, Hui-Hua
• Format: Article
• Language: English
• Subjects: cardiac hypertrophy; immunoproteasome; Pharmacology; phosphatase and tensin homolog on chromosome ten; PR-957; β5i
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2020.00885

Cardiac hypertrophy without appropriate treatment eventually progresses to heart failure. Our recent data demonstrated that the immunoproteasome subunit β5i promotes cardiac hypertrophy. However, whether β5i is a promising therapeutic target for treating hypertrophic remodeling remains unknown. Here, we investigated the effects of PR-957, a β5i-specific inhibitor, on angiotensin II (Ang II)–induced hypertrophic remodeling in the murine heart. The infusion of Ang II increased immunoproteasome chymotrypsin-like activity and β5i catalytic subunit expression in the heart, whereas PR-957 treatment fully blocked the enhanced immunoproteasome activity caused by Ang II. Moreover, the administration of PR-957 significantly suppressed Ang II–induced cardiac hypertrophy, fibrosis, and inflammation. Mechanistically, PR-957 treatment inhibited phosphatase and tensin homolog on chromosome ten (PTEN) degradation, thereby inhibiting multiple signals including AKT/mTOR, ERK1/2, transforming growth factor-β, and IKB/NF-kB. Furthermore, PTEN blocking by its specific inhibitor VO-OHpic markedly attenuated the inhibitory effect of PR-957 on Ang II–induced cardiac hypertrophy in mice. We conclude that PR-957 blocks PTEN degradation and activates its downstream mediators, thereby attenuating Ang II–induced cardiac hypertrophy. These findings highlight that PR-957 may be a potential therapeutic agent for Ang II-induced hypertrophic remodeling.