Abstract 225: The Mitochondria-localizing Peptide Bendavia Reduces Cardiac Injury By Targeting Cardiolipin

Bendavia is a cardioprotective mitochondria-targeting peptide that is currently being utilized in the EMBRACE-STEMI clinical trial for acute coronary syndromes (ACS). Across a variety of pre-clinical models examining ACS and heart failure, administration of Bendavia reduces infarction and coronary “no-reflow”, improves function, preserves mitochondrial energetics, and lowers ROS-dependent cell death. Despite the clear effects in mitigating reperfusion injury, Bendavia’s molecular targets and underlying mechanisms are not fully understood. The objective of these studies was to determine Bendavia’s molecular mechanism of action and pharmacokinetic profile. In diabetic animals, Bendavia treatment reversed the decline in 18:2 cardiolipin composition observed in diabetic heart. In vivo (i.v.) administration of 3H-Bendavia showed tissue distribution that correlated with tissue mitochondrial volume density. 3H-Bendavia levels in heart mitochondria peaked 1 hour after treatment, and by 24 hours there was no discernible 3H-Bendavia in the myocardium. Biologic processing of Bendavia results in two major metabolites, and neither of these metabolites showed cardioprotective efficacy, suggesting that the cardioprotection is unique to the intact, tetra-peptide. In isolated heart cells, 3H-Bendavia uptake was found to be independent of mitochondrial membrane potential, and respiratory studies revealed no discernible uncoupling activity. We then tested the hypothesis that Bendavia selectively targeted cardiolipin biophysical organization by synthesizing lipid vesicles of differing phospholipid composition. Fluorescence quenching and electrostatically sensitive probes revealed Bendavia preferentially associated with cardiolipin-enriched lipid vesicles. We modeled changes in inner membrane lipids during cardiac ischemia/reperfusion. Bendavia augmented membrane microviscosity in proportion to the cardiolipin content. As a number of disease states (heart failure, diabetes, ischemia/reperfusion) are characterized by low membrane microviscosity, Bendavia’s putative ability to restore the lipid microenvironment represents a novel paradigm for preserving tissue bioenergetics.