A Potent Inhibitor of Aminopeptidase P2 Reduces Reperfusion Injury in Models of Myocardial Infarction and Stroke

During a myocardial infarction or ischemic stroke, blood flow to the heart or brain is partially blocked. This results in reduced delivery of oxygen and nutrients and, ultimately, tissue damage. Initial treatment involves removing the clot and restoring blood flow (reperfusion). However, this treatment is not as effective as one would hope because the reperfusion process itself can cause a different type of damage (reperfusion injury) that contributes up to 50% of the total damage. Bradykinin is an autocoid that is released from blood vessel endothelial cells during ischemia and reperfusion and has the potential to prevent reperfusion injury. However, bradykinin is rapidly inactivated by enzymes on endothelial cells, limiting its beneficial effects. One of these enzymes is aminopeptidase P2. We designed a potent and specific inhibitor of aminopeptidase P2 called ST-115, [(S)-2-mercapto-4-methylpentanoyl]-4(S)-fluoro-Pro-Pro-3(R)-beta-Pro. When ST-115 is administered intravenously at the start of reperfusion, it reduces bradykinin degradation. This increases bradykinin's concentration in the capillaries and enhances its protective effects. We tested ST-115 in a mouse model of myocardial infarction and found that the damaged area of the heart was reduced by 58% compared with mice given saline. In a rat model of ischemic stroke, ST-115 reduced functional deficits in a skilled walking test by 60% and reduced brain edema by 51%. It reduced brain infarct size by 48% in a major subset of rats with small strokes. The results indicate that ST-115 can ameliorate reperfusion injury and can ultimately serve as a therapeutic for acute myocardial infarction and ischemic stroke. SIGNIFICANCE STATEMENT: We have shown that our aminopeptidase P2 inhibitor, ST-115, can reduce tissue injury caused by episodes of ischemia followed by reperfusion. It was successful in rodent models of myocardial infarction and stroke. The clinical use would involve the intravenous administration of ST-115 at the induction of reperfusion. In the case of stroke, the successful technique of thrombectomy could be combined with ST-115 administration to simultaneously reduce both ischemic and reperfusion injury.