sRAGE inhibits myocardial ischemia/reperfusion injuries via regulating Treg cells

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Abstract Background Regulatory T cells (Tregs) have been documented to accumulate in damaged myocardial tissue, where they play a pivotal role in attenuating excessive inflammatory responses during myocardial ischemia/reperfusion (I/R) injury. Concurrently, soluble receptor for advanced glycation end-products (sRAGE) has been demonstrated to alleviate myocardial I/R injury by suppressing inflammation, suggesting a potential involvement of Tregs in the inhibitory effects of sRAGE on myocardial I/R injury. Methods I/R surgery or glucose deprivation/reoxygenation was employed to explore myocardial injury and the related mechanisms by using cardiomyocyte-specific sRAGE knock-in mice or cultured cardiomyocytes. Potential molecular mechanisms were analyzed via western blotting, immunohistochemistry, and flow cytometric analysis. Results The findings revealed that sRAGE overexpression significantly increased the numbers of Tregs. Depletion of Tregs abrogated the protective effects of sRAGE against I/R-induced cardiac dysfunction, myocardial fibrosis, and inflammatory response in cardiac-specific sRAGE transgenic mice. Mechanistically, sRAGE was found to enhance the expression of programmed cell death ligand 1 (PD-L1) and its upstream JAK2/STAT3 signaling axis, thereby facilitating CD4 + T cells differentiation into Tregs within myocardial tissue during I/R. Conclusions The study demonstrated that sRAGE protected against myocardial I/R injury by modulating the differentiation of Tregs through upregulation of the JAK2/STAT3-PD-L1 signaling pathway.

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