Omaveloxolone promotes macrophage M2 polarization by activating the NRF2-Keap1 pathway and improves myocardial remodeling induced by pressure overload.

Abstract

Nuclear factor erythrocyte 2-associated factor 2 (Nrf2) is an important transcriptional regulator that plays a protective role in myocardial remodeling. Omaveloxolone (Omav) acts as an activator of Nrf2 and plays a protective role by decreasing oxidative stress and inflammation. The purpose of this study was to explore the role of Omav in myocardial remodeling and investigate the potential mechanism involved. Transverse aortic constriction was performed to construct a mouse cardiac remodeling model, and sham surgery was used as a control. The results showed that Omav treatment significantly improved TAC-induced myocardial remodeling and cardiac dysfunction. In addition, Omav treatment mitigated M1 macrophage polarization, promoted M2 macrophage polarization, and reduced the cardiac inflammatory response and oxidative stress. Cell experiments revealed that Omav can reduce the expression of p-STAT3 induced by PE, thereby inhibiting the polarization of M1 macrophages and promoting the polarization of M2 macrophages. However, the Nrf2 inhibitor ML385 significantly inhibited OMAV-mediated reduction of p-STAT3, macrophage polarization and activation of the NRf2-KEAP1 pathway. Omav activates the Nrf2-Keap1 pathway, affects STAT3 phosphorylation, ultimately alleviates M1 macrophage polarization, promotes M2 macrophage polarization, and improves myocardial remodeling. Omav may be a potential therapeutic agent for pathological myocardial remodeling.