Nur77 Translocation from Nucleus to Mitochondria Contributes to the Enhanced Susceptibility to Ischemia-Reperfusion Injury in Diabetic Hearts

Diabetes is associated with increased prevalence of ischemic heart disease which accounts for the high incidence of death in the diabetic population. In response to various pro-apoptotic treatments, Nur77, a nuclear orphan receptor, translocates from the nucleus to mitochondria where it induces cytochrome c release and apoptosis in cancer cells. However, the role of Nur77 in diabetic myocardial ischemia/reperfusion (MI/R) injury remains elusive. Ten-week-old male C57BL/6J mice (WT) and ob/ob mice (OB) were subjected to 30 min of ischemia and 3 or 24 hrs of reperfusion. Compared with WT, the OB hearts exhibited more severe MI/R injury as evidenced by more ROS production, increased infarct size, caspase-3 activity, TUNEL staining and decreased cardiac function (n=8, all P <0.05). There was no significantly difference in total Nur77 expression levels between sham and MI/R group in WT mice. However, MI/R caused significant Nur77 mitochondria translocation as evidenced by decreased nuclear and increased cytosolic/mitochondrial Nur77 levels (all P <0.01). Comparing to WT, total Nur77 expression levels were significantly reduced in OB heart before MI/R ( P <0.01 vs. WT). However, MI/R caused more significant Nur77 mitochondrial translocation in OB mice, reaching a level that was not different from that seen in WT after MI/R ( P >0.01 vs. WT). Intramyocardial small-interfering RNA (Nur77-siRNA) injection specifically knocked-down the myocardial Nur77, increased ejection fraction and reduced infarct size/apoptosis after MI/R in both WT and OB mice (all P <0.05). However, more significant cardioprotection of Nur77 knockdown was observed in OB mice than that seen in WT. Collectively, we demonstrated firstly that the increased translocation of Nur77 from nucleus to mitochondria partly contributes to the enhanced susceptibility to MI/R in diabetic hearts. Interventions blocking this subcellular redistribution of Nur77 may be a potential therapy for the treatment of diabetic heart injury. Key Words: Nur77 • Mitochondria Translocation • Myocardial ischemia/reperfusion • Diabetes