Background: Heart diseases, especially ischemic heart disease (IHD), remain the leading cause of death globally and are expected to increase due to aging, diabetes, and obesity. A major complication of IHD is myocardial infarction (MI). Prompt reperfusion is critical to prevent irreversible damage to the heart. Upon reperfusion, oxygen reintroduction triggers immunometabolic changes, including leukocyte recruitment and an increase in fatty acid oxidation, which can be harmful in the early stages by generating reactive oxygen species and promoting inflammation. CD36 is a multifunctional, multiligand receptor implicated in several immunometabolic diseases, including atherosclerosis and IHD. It is expressed in various cell types such as cardiomyocytes where it plays a role in the uptake of long chain fatty acids (LCFA).
METHODS AND RESULTS: In this study, we investigated the role of CD36 in a murine model of transient ischemia using both pharmacological and genetic approaches. C57BL/6J CD36+/+ or CD36-/- male mice underwent left coronary artery ligation for 30 minutes followed by reperfusion for 3 or 24 hours. A selective CD36 ligand, MPE-298, was administered intravenously prior to reperfusion. MI was assessed at 24 hours, and fatty acid profiles of left ventricles were analyzed by GC-MS. Our results demonstrated a 37% reduction of MI at 24 hours that was dependant on the presence of CD36 in the model. Furthermore, MPE-298 treatment led to a transient reduction in left ventricular LCFA levels at 3 hours including myristic, pentadecanoic, palmitic, palmitoleic, eicosatrienoic and arachidonic acids.
Conclusion: We found that targeting the CD36 receptor with an azapeptidic ligand such as MPE-298 is a promising therapeutic avenue for the reduction of infarct size and mitigation of the metabolic use of fatty acids as substrates. This suggests that the CD36 receptor plays a role in regulating LCFA uptake during early reperfusion, which may protect the heart from oxidative damage and inflammation.
