Abstract Aims Myocardial ischemia‒reperfusion (I/R) injury triggers a robust inflammatory storm cascade that critically compromises reperfusion efficacy following acute myocardial infarction (AMI). Enhanced efferocytosis by cardiac resident macrophages (RMs) has therapeutic potential for inflammation resolution. The unsaturated long‒chain fatty acid Maresin1 (MaR1) exhibits potent anti‒inflammatory properties that is devoid of immunosuppressive effects. However, its therapeutic potential in myocardial I/R injury and regulatory mechanisms in cardiac RMs remains unexplored. Methods and Results A clinical case‒control study was conducted and revealed a negative association between circulating MaR1 levels and inflammatory markers and the severity of I/R injury in patients with ST‒elevation myocardial infarction (STEMI). Mice treated with MaR1 after myocardial I/R injury showed improvements in cardiac function and efferocytosis by cardiac RMs. Genetic ablation of cardiac RMs abolished MaR1‒mediated cardioprotection. To explore the mechanism underlying this protection, we performed transcriptomic, metabolomic and lipidomic analyses and identified fatty acid β‒oxidation potentiation as a key metabolic signature in MaR1‒treated RMs. Morever, MaR1 directly bound peroxisome proliferator‒activated receptor γ (PPARγ), inducing the transcriptional activation of its downstream efferocytosis‒related target CD204. Specific knockout of PPARγ in RMs significantly attenuated MaR1‒enhanced efferocytosis. Notably, oral supplementation with the MaR1 precursor docosahexaenoic acid (DHA) recapitulated these cardioprotective effects. Conclusions Our findings prove that MaR1 plays a protective role in myocardial I/R injury by facilitating efferocytosis by RMs and the resolution of inflammation. These results offer novel therapeutic perspectives for the management of myocardial I/R injury.
Sun et al. (Thu,) studied this question.