Abstract P062: Loss of Plasma Membrane Integrity Occurs in 2 Stages During Early Myocardial Ischemia/Reperfusion Injury

Myocardial ischemia is an acute health emergency. Reperfusion, critical for salvaging ischemic tissues, contributes to the acute tissue damage known as ischemia-reperfusion (I/R) injury. While therapeutic approaches aimed at reducing I/R injury have been promising in preclinical studies, clinical studies have been inconclusive, suggesting an inadequate knowledge of the mechanisms underlying I/R injury and their time-frame. In the current work, myocardial necrosis was evaluated in a murine I/R model using a propidium iodide-based fluorescent method that evaluated loss of plasma membrane integrity (LPMI) during the first 24 hours of reperfusion and permitted histological analysis of other pathological events on adjacent sections. LPMI was found to develop in two stages in WT animals: a significant increase occurred between 0 and 1 hour of reperfusion and was maintained through 6 hours; an additional increase was apparent at 24 hours. Complement C3 deposition lagged LPMI by 2 hours and C3 −/− mice were protected from second-stage LPMI but not first-stage. Transgenic mice overexpressing the anti-oxidant enzymes superoxide dismutase or catalase were protected from first stage LPMI but not second stage. The results provide support for the development of therapeutic approaches that are directed at the early stages of reperfusion and take into account the two phases of ischemia-related myocardial damage, designing strategies targeting the reactive oxygen species of first stage and the complement-mediated events of second stage.