LIPUS通过外泌体MAT2a介导内皮-Treg细胞间通讯改善心肌缺血再灌注损伤的机制研究

心肌缺血再灌注损伤（MIRI）可导致严重心脏不良事件，探索有效治疗措施已成为临床迫切需求。诱导心脏免疫微环境稳态是改善MIRI的重要手段。低强度脉冲超声（LIPUS）作为无创物理治疗方式，能够调控免疫反应、改善心功能，然而在MIRI中的作用未知。基于LIPUS可缩小MIRI小鼠梗死面积等预实验结果，申请人提出LIPUS辐照可能是改善MIRI的无创治疗策略。前期研究发现LIPUS独特的机械作用可诱导内皮外泌体MAT2a的产生、促进细胞间通讯；并识别出调节性T细胞（Treg）为LIPUS免疫调控作用的关键亚群。由此提出：LIPUS通过内皮外泌体MAT2a介导“内皮-Treg”细胞间通讯，重塑心脏免疫微环境，改善MIRI。本项目将明确和优化LIPUS对MIRI的治疗价值，并从免疫-代谢-表观层面系统揭示潜在的分子机制，为建立非药物、无创性心肌保护策略提供理论依据，助力解决MIRI临床治疗困境。

Myocardial ischemia/reperfusion injury (MIRI) can lead to serious adverse cardiovascular events. Exploring effective therapeutic measures has become an urgent clinical demand. Inducing cardiac immune microenvironmental homeostasis is an important method to improve MIRI. As a non-invasive physical therapy, low intensity pulsed ultrasound (LIPUS) is confirmed to regulate immune responses and improve cardiac function. But it is unknown whether it is effective for the treatment of MIRI. Based on the result that LIPUS could reduce infarct size in MIRI mice, the applicant innovatively suggested that LIPUS irradiation might be a non-invasive therapy strategy to improve MIRI. Our previous studies have found that the unique mechanical effect of LIPUS could induce the production of endothelial exosomal MAT2A and promote intercellular communications. Moreover, we identified regulatory T-cells (Treg) as a key subset of LIPUS immune regulation. Therefore, we proposed that LIPUS could regulate Treg immune functions to restore cardiac immune homeostasis and alleviate MIRI via the transfer of endothelial exosomal MAT2a. This project will clearly optimize the therapeutic effect of LIPUS on MIRI, and reveal its molecular mechanism from the “epigenetics-metabolism-immunity” level. The aim of this project is to provide a theoretical basis for the establishment of non-drug, non-invasive myocardial protection strategies and help to solve the clinical treatment difficulties of MIRI.