The mechanism of MsrB1 mediating the macrophage-endothelial reparative communication in myocardial ischemia reperfusion injury

Abstract Background Myocardial microvascular dysfunction and endothelial cell injury are important risk factor for poor prognosis in patients with coronary heart disease. There is a communication relationship between macrophages and endothelial cells, which regulates inflammatory injury and programmed cell death of endothelial cells, which is a key mechanism to regulate microvascular dysfunction. However, the mechanism of the role of myocardial microvascular injury is still not clear. Previous studies found that ischemia-reperfusion injury induced macrophage phenotype transformation, and promoted macrophage-endothelial cell communication, regulating the endothelial cell ferroptosis. Purpose This study aims to elucidate the mechanism of MsrB1 in circulating macrophages and the protection of reparative cell communication in myocardial microvascular ferroptosis. Method Cardiac I/R injury in C57bl/6 mice and Macrophage-specific MsrB1 knockout mice were established by ligating the left anterior descending artery. The immunofluorescence, flow cytometry assays, single-cell RNA-seq, and proteomics analysis were performed to explore the underlying mechanisms of macrophage recruitment and polarization after IR. Result By analyzing single-cell RNA-seq and proteomics data of cardiac I/R injury, we found that MsrB1 expression was significantly upregulated in circulating reparative macrophages, which enhanced the macrophage endothelial communication. MsrB1 knockout further promotes immune cell inflammation and microvascular ischemia injury, aggravated cardiac remodeling, cardiac dysfunction, and fibrosis after IR and vice versa. Consistently, PCR assays demonstrated that MsrB1 overexpression attenuated macrophage pro-inflammatory factors secretion and promoted anti-inflammatory factors. Furthermore, we discovered that MsrB1 over-expressed macrophages significantly promoted the transcription of anti-ferroptosis proteins, which alleviated ferroptosis and improved endothelial cell function. MsrB1 activated anti-ferroptosis secretion by reducing the transcription factor methionine oxidation (MetO) and promoting the transcription of CP in macrophages. Macrophage-specific knockout of MsrB1 in mice can induce the pro-inflammatory polarization of macrophages, aggravate the ferroptosis of endothelial cells, and aggravate myocardial microvascular ischemia-perfusion injury. Conclusion In conclusion, MsrB1 reduces the oxidized methionine residues in macrophage transcription factors, induces the reprogramming of macrophage secreted proteins, attenuates endothelial ferroptosis by secreting anti-ferroptosis proteins, and finally protects myocardial microvascular I/R injury. The results of this study will provide a new theoretical basis for the strategies targeting MsrB1-centered intervention of myocardial microvascular reperfusion injury.MsrB1 regulates reparative Macs MsrB1 reduces transcription factor