Rhynchophylline Protects Against Ischemic Injury Following Myocardial Infarction via Activation of the...

Myocardial infarction (MI) remains the leading cause of death globally. Current treatment strategies involve restoring blood flow to the coronary artery, but have shortcomings in that these procedures cannot reverse damage to the myocardium that has already occurred. Therefore, therapies that can decrease the severity of ischemic damage are needed. Oxidative stress is an early and major driver of cardiomyocyte death following MI. Rhynchophylline (RHY) is a natural alkaloid known for its antioxidant activity; however, whether it can protect against MI-induced ischemic injury, as well as its underlying mechanism of action, remains unexplored. We performed murine models of surgical MI and examined the effects and mechanisms of RHY in protecting against myocardial ischemic injury. A sirtuin 1 (SIRT1)-specific inhibitor, EX-527, was subsequently used to verify that the cardioprotective effects of RHY were dependent upon targeted SIRT1-activation. Mice administered with RHY significantly protected against ischemic injury following MI, with improved cardiac function, reduced infarct size, and decreased levels of oxidative and DNA damage. The cardioprotective effect of RHY is associated with activation of the SIRT1 and its downstream redox-sensitive transcription factors: nuclear factor erythroid 2-related factor 2 (NRF2) and forkhead-box protein O3 (FOXO3a). The cardioprotective and antioxidant effects of RHY were abolished by EX-527, a selective SIRT1 inhibitor. Our findings provide evidence for the robust antioxidant properties of RHY in protecting against MI injury via activating the SIRT1/NRF2/FOXO3a signaling axis. These findings provide new mechanistic insight into the preconditioning-like cardioprotective potential of RHY during myocardial infarction.