Quercetin improves myocardial ischemia–reperfusion injury by regulating macrophage M2 polarization through Bcl-2/Beclin-1 complex

BACKGROUND: Myocardial ischemia-reperfusion injury (MIRI) is a common pathological phenomenon during the treatment of acute myocardial infarction. Recent studies suggest that macrophage polarization plays a crucial role in MIRI progression. However, whether quercetin mitigates MIRI by modulating macrophage polarization and the underlying molecular mechanisms remain unclear. METHODS: The protective effects of quercetin against MIRI were assessed using TTC-Evans blue staining, echocardiography, and myocardial enzyme assays. Histological changes, including myocardial fibrosis, were evaluated via HE and Masson staining. Western blot, qPCR, and immunofluorescence were performed to analyze macrophage M1/M2 polarization. Additionally, co-immunoprecipitation (Co-IP) assays were conducted to determine whether quercetin regulates M2 polarization through autophagy modulation. RESULTS: Quercetin significantly reduced infarct size, improved cardiac function, and alleviated inflammation and myocardial fibrosis in a dose-dependent manner. Western blot and immunofluorescence analyses showed that quercetin downregulated M1 markers while upregulating M2 markers and enhancing IL-10 secretion. In vitro experiments further confirmed that quercetin promoted M2 macrophage polarization under H/R conditions, thereby attenuating cardiomyocyte injury through a paracrine mechanism. Mechanistically, quercetin facilitated autophagic flux by reducing the binding affinity between Bcl-2 and Beclin-1, leading to enhanced M2 macrophage polarization, an effect partially reversed by 3-MA. CONCLUSION: This study provides the first evidence that quercetin exerts cardioprotective effects in MIRI by promoting M2 macrophage polarization. Furthermore, it elucidates a novel molecular mechanism in which quercetin regulates autophagy to drive M2 polarization, offering experimental support for quercetin as a potential therapeutic strategy for MIRI.