Shenxiong Yixin Decoction polysaccharides exert therapeutic effects against myocardial ischemia-reperfusion injury via intestinal exosomal microRNA-21 regulation

Background and Objective Myocardial ischemia-reperfusion injury (MIRI) presents a prevalent global clinical challenge without an optimal treatment strategy. Shenxiong Yixin Decoction exhibits promising cardioprotective effects in clinical scenarios. Polysaccharides, particularly pivotal in cardioprotection, act systemically through the intestine. Exosomes, particularly miRNA-rich ones, are crucial in MIRI pathophysiology. However, the specific role of gut-derived exosomal miRNAs in cardiovascular disease remains unclear. This study aimed to evaluate the cardioprotective effects of Shenxiong Yixin Decoction polysaccharides (SXYXP) on MIRI and elucidate its mechanisms. In vitro and in vivo models of MIRI were set up with H9c2 cells, C57BL/6 mice, and Sprague-Dawley rats. Exosomes from IEC-6 cells and plasma were detected. Various techniques like MTT, TTC, H&E staining, echocardiography, flow cytometry, immunofluorescence, RT-qPCR, and Western blot were employed for pharmacodynamic and mechanistic analyses. SXYXP treatment can reduce myocardial infarction area, improve cardiac function, and increase myocardial cell survival rate under MIRI. The SXYXP treatment significantly enhanced the release of enterocyte-derived exosomes and elevated the levels of miR-21 within these exosomes. These SXYXP-modulated exosomes demonstrated a significant protective effect against H/R injury in H9c2 cells. However, the application of miR-21 inhibitors in the SXYXP group negated the protective effects of exosomes, leading to diminished cardiomyocyte proliferation, exacerbated oxidative stress, and elevated apoptosis. SXYXP may protect against MIRI by targeting miR-21 in intestinal cell-derived exosomes, which are transported to the heart through the blood to restore the level of miR-21 in the damaged myocardium, thereby inhibiting oxidative stress and the expression of PDCD4.