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.