Abstract 10740: Bendavia, a Mitochondria-targeting Peptide, Reduces Reperfusion Injury and Reactive Oxygen Species Levels Through a Mechanism Independent of Direct Oxygen Radical Scavenging: A Multicenter Study
We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of the present study was to determine the therapeutic timing and mechanism of action that underlie Bendavia’s cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 min prior to reperfusion (0.05mg/kg/hr,iv) reduced myocardial infarct size by ∼50%. Bendavia was no more effective when perfused for 3h of reperfusion (infarct size was 19+/-5% of area-at-risk, AAR) compared to just 1h (19+/-2% AAR), indicating that the mechanism of protection is occurring early in reperfusion (infarcts in vehicle-treated rabbits were 37+/-2% AAR, P<0.05). Interestingly, when Bendavia perfusion began just 10 min after the onset of reperfusion, the protection against infarction and no-reflow was completely lost (P=NS for vehicle vs. Bendavia). In isolated guinea pig hearts exposed to 20 min global ischemia and 2h reperfusion, 1nM Bendavia started just prior to reperfusion reduced infarct size by ∼28% (P<0.05 vs. control). In isolated cardiac cells, Bendavia protected against hypoxia/reoxygenation injury when administered prior to reoxygenation (cell death was 15% compared to 57% in control cells), but when given after the onset of reoxygenation cell death was 64% (n=30,000 cells per group). Since Bendavia lowered levels of reactive oxygen species (ROS) in cells exposed to hypoxia/reoxygenation, we compared the ROS-scavenging capacity of Bendavia to well-known ROS scavengers using an in vitro (cell-free) system that generates ROS using a glucose/glucose oxidase reaction. Across doses ranging from 1nM to 1mM, Bendavia showed no discernible ROS-scavenging properties, clearly differentiating itself from catalase, superoxide dismutase, and TEMPO. We conclude that Bendavia is a promising candidate to reduce cardiac injury when present at onset of reperfusion, but not after reperfusion has already commenced. Given that both infarction and no-reflow are related to increased cellular ROS, Bendavia’s protective mechanism of action likely involves reduced ROS generation (as opposed to augmented scavenging) by endothelial and ventricular mitochondria.
- © 2012 by American Heart Association, Inc.