Etomidate Attenuates the Ferroptosis in Myocardial Ischemia/Reperfusion Rat Model Via Nrf2 Pathway.

Abstract

BACKGROUND\nFerroptosis has been found to play an important role in myocardial ischemia reperfusion (MIR) injury (MIRI). This study aimed to explore whether the improvement effect of Etomidate (Eto) on MIRI was related to ferroptosis.\n\n\nMETHODS\nThe MIRI rats were constructed using left anterior descending artery occlusion for 30\u200amin followed by reperfusion for 3\u200ah. The Eto post-conditioning was performed by Eto administration at the beginning of the reperfusion. For rescue experiments, MIRI rats were pretreated with ferroptosis inducer erastin or Nrf2 inhibitor ML385 intraperitoneally 1\u200ah prior to MIR surgery.\n\n\nRESULTS\nEto mitigated cardiac dysfunction and myocardium damage, as well as the release of CK and LDH caused by IR. Additionally, Eto reduced the expression of myocardial fibrosis-related proteins (collagen II and α-SMA) and the secretion of inflammatory factors (IL-6, IL-1β and TNF-α) in MIRI rats. Also, Eto inhibited IR-induced ferroptosis in myocardium, including reducing SOD content, GSH activity and GPX4 expression, while increasing the levels of MDA and iron and ACSL4. Moreover, the inhibition of Eto on IR-induced myocardial fibrosis and inflammation could be eliminated by erastin. The up-regulation of Nrf2 and HO-1 protein expression, and the nuclear translocation of Nrf2 induced by Eto in the myocardial tissues of MIRI rats could be prevented by erastin. Besides, ML385 eliminated the inhibition of Eto on ferroptosis induced by MIR.\n\n\nCONCLUSIONS\nEto attenuated the myocardial injury by inhibiting IR-induced ferroptosis via Nrf2 pathway, which may provide a new idea for clinical reperfusion therapy.