Abstract 5140: The Transcription Factor Nrf2 is a Novel Target for the Treatment of Myocardial Ischemia-Reperfusion Injury

Abstract

Background: Nuclear-factor-E2-related factor 2 (Nrf2), a member of the NF-E2 family of nuclear basic leucine zipper transcription factors, regulates the gene expression of a number of proteins that attenuate pro-oxidative and pro-apoptotic signaling pathways. The role of Nrf2 in myocardial ischemia-reperfusion (MI/R) injury has not been investigated. Therefore, we evaluated its role using an in vivo murine model of myocardial ischemia-reperfusion (MI/R) injury. Methods: Mice deficient in Nrf2 (Nrf2 KO; ICR background) were subjected to 30 minutes of MI followed by reperfusion for 24 hr, at which time the extent of myocardial infarction per area-at-risk (INF/AAR) or per left ventricle (INF/LV) was evaluated with TTC and serum troponin-I levels were measured. In separate studies, C57BL/6J mice were also subjected to MI followed by 24 hr of reperfusion. The known activator of Nrf2, sulforaphane (5 mg/kg) or vehicle was administered 30 min prior to myocardial ischemia. Results: Myocardial injury following I/R was found to be exacerbated in Nrf2 KO mice compared with Wild-Type mice, as evidenced by a 61% increase in infarct size relative to the area-at-risk (Inf/AAR; 43±7 vs. 27±0.1%, p<0.01), a 59% increase in INF relative to the entire left ventricle (Inf/LV; 25±4 vs. 14.9±1.6%, p<0.05), and an increase in circulating Troponin-I levels from 26±5.2 to 52.4±9 ng/mL (p<0.05). In contrast, the administration of sulforaphane induced myocardial Nrf2 nuclear translocation and reduced infarct size by 40%. Conclusions: These data reveal that Nrf2 is an endogenous cardioprotective-signaling molecule that represents a novel target for the treatment of acute myocardial infarction.