Abstract 1359: The Heme Oxygenase Inducer Hemin Protects Against Cardiac Dysfunction And Ventricular Fibrillation In Ischemic/reperfused Rat Hearts: Role Of Connexin 43
Cardiac expression of the cytoprotective gene heme oxygenase-1 (HO-1) is modulated by ischemia and reperfusion (I/R). Therefore, we hypothesized that pretreatment with hemin, an inductor of HO-1, would precondition the heart against postischemic dysfunction and ventricular fibrillation (VF). Male Wistar rats were injected i.p. either with hemin (50 μmol/kg; −24 h) or HO enzyme inhibitor zinc protoporphyrin IX (ZnPP IX, 50 μmol/kg; −1 h). Isolated hearts were subjected to 30 min global ischemia followed by 120 min of reperfusion or were aerobically perfused in a time-matched non-ischemic protocol. Control animals received no pretreatment. Compared to non-perfused controls, pretreatment with hemin increased HO-1 mRNA 13-fold (p<0.001) and HO-1 protein 3.5-fold (p≤0.001) in both I/R hearts and time-matched non-ischemic controls. Hemin pretreatment improved postischemic aortic flow, coronary flow, LVDP and −Dp/dt (p<0.01) and decreased LVEDP (p<0.001) and the incidence of VF from 100% to 12.5% (p=0.001). The improved postischemic cardiac function and reduction of VF were accompanied by accumulation of non-phosphorylated gap junction protein connexin 43 (Cx43) in intercalated discs and lateral plasma membrane of cardiomyocytes. Cardioprotection by HO-1 appeared to be independent of cGMP. The administration of ZnPP IX increased HO-1 mRNA in both I/R hearts and time-matched non-ischemic controls (15–20-fold, p<0.001), but it had no effect on HO-1 protein level or cardiac function and it did not influence VF. Our results show that pharmacological modulation of HO-1 pathway may provide a new therapeutic approach to protect the heart against postischemic dysfunction and I/R-induced VF possibly by a Cx43 dependent mechanism.