Abstract
Managing myocardial infarction (MI) to reduce cardiac cell death relies primarily on timely reperfusion of the affected coronary site, but reperfusion itself induces cell death through a toxic, ROS-mediated process. In this study, we determined whether the PrC-210 aminothiol ROS-scavenger could prevent ROS-induced damage in post-MI hearts. In a series of both in vitro and in vivo experiments, we show that: (a) in vitro, PrC-210 was the most potent and effective ROS-scavenger when functionally compared to eight of the most commonly studied antioxidants in the MI literature, (b) in vitro PrC-210 ROS-scavenging efficacy was both immediate (seconds) and long-lasting (hours), which would make it effective in both (1) real-time (seconds), as post-MI or cardiac surgery hearts are reperfused with PrC-210-containing blood, and (2) long-term (hours), as hearts are bathed with systemic PrC-210 after MI or surgery, (c) systemic PrC-210 caused a significant 36% reduction of mouse cardiac muscle death following a 45-minute cardiac IR insult; in a striking coincidence, the PrC-210 36% reduction in cardiac muscle death equals the 36% of the MI-induced cardiac cell death estimated 6 years ago by Ovize and colleagues to result from "reperfusion injury," (d) hearts in PrC-210-treated mice performed better than controls after heart attacks when functionally analyzed using echocardiography, and (e) the PrC-210 ROS-scavenging mechanism of action was corroborated by its ability to prevent >85% of the direct, H2O2-induced killing of neonate cardiomyocytes in cell culture. PrC-210 does not cause the nausea, emesis, nor hypotension that preclude clinical use of the WR-1065/amifostine aminothiol. PrC-210 is a highly effective ROS-scavenger that significantly reduces IR injury-associated cardiac cell death.