Remote Hind Limb Ischemia Mechanism of Cardioprotection

远距离后肢缺血的心脏保护机制

• 批准号: 10247852
• 负责人: Suresh C. Tyagi
• 金额: $ 6.49万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247852
• 关键词: Address; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Attenuated; Bone Marrow Stem Cell; Coronary heart disease; Cystathionine; DNA; Data; Diabetes Mellitus; Endocrine; Enzymes; Epigenetic Process; Functional disorder; Gases; Genes; Goals; Heart; Hematopoietic Stem Cell Mobilization; Hindlimb; Homocysteine; Hormones; Hydrogen Sulfide; Hyperhomocysteinemia; Hypermethylation; Incidence; Injury; Ischemia; Limb structure; Lyase; Modification; Muscle; Muscle function; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Production; Recovery; Risk; Site; Skeletal Muscle; Testing; cardioprotection; diabetic; effective therapy; exosome; gene induction; improved; ischemic conditioning; limb ischemia; mitochondrial metabolism; myocardial injury

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.

尽管后肢远端缺血适应(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。这一提议的中心假设是短暂性脑缺血发作 从心肌梗死(MI)开始，通过分泌有益于恢复的激素 来自骨骼肌内分泌的外切体，改善线粒体代谢，硫化氢 (硫化氢，一种抗氧化、抗炎、抗凋亡、血管活性气体)和骨动员 将骨髓干细胞(BMSC)移植到损伤部位(图1)。众所周知，DNA超甲基化是通过 表观遗传修饰抑制该基因并产生同型半胱氨酸(Hcy)，导致 高同型半胱氨酸血症(HHcy)可降低硫化氢。有趣的是，胱硫酮β合成酶增加 (Cbs)和胱硫醚γ裂解酶(Cse)增加硫化氢，降低同型半胱氨酸。我们的预赛 数据表明，RIC诱导的肌肉抑制蛋白(一种骨骼肌激素)可以减弱心肌。 损伤和功能障碍。核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是否释放外切体，诱导肌肉粘连蛋白并逆转 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RIC是否通过增加CBS和CSE的表达来促进硫化氢的产生，以及 心肌梗塞和糖尿病的表观遗传低甲基化和基因诱导。具体目标3：确定 RIC是否促使骨髓间充质干细胞动员到心肌损伤部位并减轻肌肉 糖尿病患者心肌梗死后再生所致损害。