Remote Hind Limb Ischemia Mechanism of Cardioprotection

尽管后肢远端缺血性处理（RIC）具有心脏保护作用，但其机制是： 未知本项目的长期目标是了解远程保护的机制 后肢缺血该建议的中心假设是短暂性缺血发作， 从心肌梗死（MI），有助于恢复通过分泌有益的 骨骼肌内分泌外泌体，改善线粒体代谢，硫化氢 (H2S抗氧化、抗炎、抗凋亡、血管活性气体）和骨动员 骨髓干细胞（BMSC）的损伤部位（图1）。已知DNA超甲基化通过 表观遗传修饰抑制基因并产生同型半胱氨酸（Hcy），导致 高同型半胱氨酸血症（HHcy），减少H2S。有趣的是，胱抑素β合酶的增加 (CBS)胱硫醚γ裂解酶（CSE）增加H2S并降低Hcy。我们的初步 数据表明，RIC诱导的musclin（一种骨骼肌激素）减弱心肌 损伤和功能障碍。中心假设将通过以下三个具体目标进行检验： 具体目标1：确定RIC是否释放外泌体，诱导肌肉蛋白和逆转 心肌梗死和糖尿病期间骨骼肌和心肌功能受损。具体目标2： 确定所述RIC是否通过增加CBS和CSE表达来增强H2S产生，以及 表观遗传低甲基化和基因诱导在MI和糖尿病。具体目标3：确定 RIC是否促使BMSC动员到心肌损伤部位， 糖尿病期间心肌梗死后再生损伤。

Although hind limb remote ischemic conditioning (RIC) is cardioprotective, the mechanism is unknown. The long-term goal of this project is to understand the mechanism of protection by remote hind-limb ischemia. The central hypothesis of this proposal is that transient ischemic episodes, away from the myocardial infarction (MI), contribute to the recovery through secretion of beneficial exosomes from skeletal muscle endocrine, improving mitochondrial metabolism, hydrogen sulfide (H2S, an anti-oxidant, anti-inflammatory, anti-apoptotic, vasoactive gas) and mobilization of bone marrow stem cells (BMSC) to the site of injury (Figure 1). It is known that DNA hypermethylation by epigenetic modification inhibits the gene and produces homocysteine (Hcy), leading to hyperhomocysteinemia (HHcy) that decreases H2S. Interestingly, increase in cystathione β synthase (CBS) and cystathionine γ lyase (CSE) enzymes increases H2S and decreases Hcy. Our preliminary data suggests that RIC induced musclin (a skeletal muscle hormone) attenuated myocardial muscle damage and dysfunction. The central hypothesis will be tested by the following three specific aims: Specific Aim 1: To determine whether the RIC releases exosomes, induces musclin and reverses compromised skeletal and cardiac muscle function during MI and diabetes. Specific Aim 2: To determine whether the RIC enhances H2S production by increasing CBS and CSE expression, and epigenetic hypomethylation and gene induction during MI and diabetes. Specific Aim 3: To determine whether the RIC instigates BMSC mobilization to the site of myocardial injury and mitigates muscle damage by regeneration after MI during diabetes.