Insulin-like growth factor-1 protects ischemic murine myocardium from ischemia/reperfusion associated injury

Abstract

INTRODUCTION: Ischemia/reperfusion occurs in myocardial infarction, cardiac dysfunction during sepsis, cardiac transplantation and coronary artery bypass grafting, and results in injury to the myocardium. Although reperfusion injury is related to the nature and duration of ischemia, it is also a separate entity that may jeopardize viable cells and ultimately may impair cardiac performance once ischemia is resolved and the organ heals. METHOD: The present study was conducted in an ex vivo murine model of myocardial ischemia/reperfusion injury. After 20 min of ischemia, isolated hearts were perfused for up to 2 hours with solution (modified Kreb's) only, solution plus insulin-like growth factor (IGF)-1, or solution plus tumor necrosis factor (TNF)-alpha. Cardiac contractility was monitored continuously during this period of reperfusion. RESULTS: On the basis of histologic evidence, IGF-1 prevented reperfusion injury as compared with TNF-alpha; TNF-alpha increased perivascular interstitial edema and disrupted tissue lattice integrity, whereas IGF-1 maintained myocardial cellular integrity and did not increase edema. Also, there was a significant reduction in detectable creatine phosphokinase in the perfusate from IGF-1 treated hearts. By recording transduced pressures generated during the cardiac cycle, reperfusion with IGF-1 was accompanied by markedly improved cardiac performance as compared with reperfusion with TNF-alpha or modified Kreb's solution only. The histologic and functional improvement generated by IGF-1 was characterized by maintenance of the ratio of mitochondrial to nuclear DNA within heart tissue. CONCLUSION: We conclude that IGF-1 protects ischemic myocardium from further reperfusion injury, and that this may involve mitochondria-dependent mechanisms.