ENHANCED EXPRESSION OF HEPATOCYTE GROWTH-FACTOR C-MET BY MYOCARDIAL-ISCHEMIA AND REPERFUSION IN A RAT MODEL

Background Hepatocyte growth factor (HGF) is a multifunctional factor implicated in tissue regeneration, wound healing, and angiogenesis. Ci rculating HGF is reportedly elevated during the early stage of myocard ial infarction. However, its precise effect on the heart is unknown. T o evaluate the regulation of HGF in ischemically damaged myocardium, t he production of HGF and its high-affinity receptor, c-Met, was studie d in a rat model of myocardial ischemia and reperfusion. Methods and R esults The plasma concentration of HGF began to increase within 1 hour of reperfusion after 1 hour of ischemia. The peak level was reached a t 3 hours after reperfusion. Northern blotting revealed that HGF mRNA expression in the heart was augmented threefold at 24 and 48 hours and remained elevated by twofold at 120 hours after the myocardium was re perfused. The signal for c-met, high-affinity HGF receptor mRNA, was a lso upregulated parallel to upregulation for HGF. In the kidney, liver , lung, and spleen, HGF mRNA was also maximally increased at 12 hours after reperfusion. However, c-met was not upregulated in these organs. Immunohistochemical studies disclosed that capillary endothelial and interstitial cells, including infiltrating macrophages, were intensely stained for HGF, whereas capillary endothelial cells in the reperfuse d myocardium were positive for c-Met. Conclusions This study is the fi rst to show that myocardial ischemia and reperfusion induced HGF expre ssion in various organs in vivo. These results indicate that HGF/c-Met plays a role in capillary endothelial cell regeneration in the ischem ically injured heart.