Cyclic azapeptide CD36 ligand attenuates cardiac injury and reduces long-chain fatty acid accumulation after myocardial ischemia-reperfusion in mice.

Ischemic heart disease remains a leading global cause of death. We investigated the cardioprotective effects of the selective cluster of differentiation-36 receptor (CD36) modulator azapeptide MPE-298 in a mouse model of myocardial ischemia-reperfusion. Given before reperfusion, a single intravenous dose of azapeptide MPE-298 reduced infarct size by 44% of the area-at-risk and transiently decreased left ventricular long-chain fatty acids (LCFA) accumulation, independently of saturation status. Metabolomic profiling identified changes in amino acids that may fuel the tricarboxylic acid cycle and provide substrates for glutathione-dependent antioxidant defense. Gene expression analysis showed transient modulation of oxidative stress and inflammation-associated genes in both heart and adipose tissue. Thus, we conclude that modulation of CD36 by azapeptide MPE-298 exhibits therapeutic potential for treating acute myocardial ischemia and reperfusion by supporting metabolic recovery and limiting excess LCFA uptake.