Maresin 1 ameliorates myocardial ischaemia‒reperfusion injury by promoting tissue resident macrophage efferocytosis.

Abstract

AIMS: Myocardial ischaemia‒reperfusion (I/R) injury triggers a robust inflammatory storm cascade that critically compromises reperfusion efficacy following acute myocardial infarction. 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. 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, metabolomics, and lipidomic analyses and identified fatty acid β-oxidation potentiation as a key metabolic signature in MaR1-treated RMs. Moreover, 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. CONCLUSION: 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.