Remote Hind Limb Ischemia Mechanism of Cardioprotection

远距离后肢缺血的心脏保护机制

• 批准号: 10215605
• 负责人: Suresh C. Tyagi
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215605
• 关键词: Address; Anti-Inflammatory Agents; Antioxidants; Apoptotic; Area; Attenuated; Biogenesis; Biological Assay; Bone Marrow Stem Cell; Bone Marrow Transplantation; Cardiac; Coronary heart disease; Cystathionine; DNA; Data; Diabetes Mellitus; Endocrine; Enzymes; Epigenetic Process; Event; Female; Fibrosis; Fluorescence; Functional disorder; Gases; Genes; Goals; Heart; Hematopoietic Stem Cell Mobilization; Hindlimb; Histology; Homocysteine; Hormones; Hydrogen Sulfide; Hyperhomocysteinemia; Hypermethylation; Incidence; Injury; Ischemia; Label; Limb structure; Lyase; Measures; Methylation; Mitochondria; Modification; Mouse Protein; Mus; Muscle; Muscle function; Muscular Atrophy; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; PPAR gamma; Plasma; Procedures; Production; Proteins; Recovery; Risk; Sampling; Site; Skeletal Muscle; Supplementation; Testing; cardioprotection; conditioning; diabetic; effective therapy; exosome; gene induction; glucose metabolism; improved; ischemic conditioning; limb ischemia; male; mitochondrial metabolism; myocardial damage; myocardial injury; response

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.

尽管后肢远程缺血调节（RIC）具有心脏保护作用，但其机制是 未知 该项目的长期目标是了解远程保护机制。 该提议的中心假设是短暂性缺血发作。 心肌梗死 (MI) 后，通过分泌有益的有益物质有助于恢复 来自骨骼肌内分泌的外泌体，改善线粒体代谢，硫化氢 （H2S，一种抗氧化、抗炎、抗凋亡、血管活性气体）和骨动员 骨髓干细胞 (BMSC) 到达损伤部位（图 1）。 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) 会减少 H2S。 (CBS) 和胱硫醚 γ 裂解酶 (CSE) 会增加 H2S 并降低 Hcy。 数据表明，RIC 诱导的肌肉激素（一种骨骼肌激素）减弱了心肌肌力 中心假设损害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、诱导肌蛋白并逆转 心肌梗死和糖尿病期间骨骼和心肌功能受损。 具体目标 2： 确定 RIC 是否通过增加 CBS 和 CSE 表达来增强 H2S 产生，以及 MI 和糖尿病期间的表观遗传低甲基化和基因诱导。具体目标 3：确定 RIC 是否会促使 BMSC 动员至心肌损伤部位并减轻肌肉损伤 糖尿病期间心肌梗死后再生造成的损伤。