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.

虽然后肢远端缺血调节（RIC）具有心脏保护作用，但其机制尚不清楚