Selective Inhibition of the Immunoproteasome ß5i Prevents PTEN Degradation and Attenuates Cardiac Hypertrophy.
Front Pharmacol
; 11: 885, 2020.
Article
en En
| MEDLINE
| ID: mdl-32595507
ABSTRACT
Cardiac hypertrophy without appropriate treatment eventually progresses to heart failure. Our recent data demonstrated that the immunoproteasome subunit ß5i promotes cardiac hypertrophy. However, whether ß5i is a promising therapeutic target for treating hypertrophic remodeling remains unknown. Here, we investigated the effects of PR-957, a ß5i-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 ß5i 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-ß, 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.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Front Pharmacol
Año:
2020
Tipo del documento:
Article
País de afiliación:
China