Ginsenoside RG1‐induced mesenchymal stem cells alleviate diabetic cardiomyopathy through secreting exosomal circNOTCH1 to promote macrophage M2 polarization

Abstract Diabetic cardiomyopathy (DCM) is a cardiac complication resulting from long‐term uncontrolled diabetes, characterized by myocardial fibrosis and abnormal cardiac function. This study aimed at investigating the potential of ginsenoside RG1 (RG1)‐induced mesenchymal stem cells (MSCs) in alleviating DCM. A DCM mouse model was constructed, and the effects of RG1‐induced MSCs on myocardial function and fibrosis in diabetic mice were evaluated. RG1‐induced MSCs were cocultured with high glucose‐treated fibroblasts for subsequent functional and mechanism assays. It was discovered that RG1‐induced MSCs secrete exosomes that induce macrophage M2 polarization. Mechanistically, exosomes derived from RG1‐induced MSCs transferred circNOTCH1 into macrophages, activating the NOTCH signaling pathway. A competing endogenous RNA (ceRNA) regulatory axis consisting of circNOTCH1, miR‐495‐3p, and NOTCH1 was found to contribute to DCM alleviation.. This study unveiled that exosomal circNOTCH1 secreted by RG1‐induced MSCs can alleviate DCM by activating the NOTCH signaling pathway to induce macrophage M2 polarization. This finding may contribute to the development of new therapeutic approaches for DCM.