Remote Hind Limb Ischemia Mechanism of Cardioprotection

远距离后肢缺血的心脏保护机制

• 批准号: 10438112
• 负责人: Suresh C. Tyagi
• 金额: $ 10.45万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438112
• 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.

尽管后肢远程缺血性调节（RIC）是心脏保护性的，但机制是 未知。该项目的长期目标是了解远程保护机制 Hind-Limb缺血。该提议的中心假设是瞬态缺血发作， 从心肌梗塞（MI）中，通过分泌有益的恢复有助于恢复 骨骼肌内分泌的外泌体，改善线粒体代谢，硫化氢 （H2S，一种抗氧化剂，抗炎，抗凋亡，血管活性气）和动员骨骼 骨髓干细胞（BMSC）到损伤部位（图1）。众所周知，通过 表观遗传修饰抑制基因并产生同型半胱氨酸（HCY），导致 降低H2S的高脑结晶质血症（HHCY）。有趣的是，胱硫酸β-合酶的增加 （CBS）和胱淀粉γ裂解酶（CSE）酶增加H2s并降低HCY。我们的初步 数据表明RIC诱导肌肉（骨骼肌激素）减弱了心肌肌肉 伤害和功能障碍。中心假设将通过以下三个特定目的进行检验： 特定目的1：确定RIC是否释放外泌体，诱导肌细胞并逆转 在MI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CB和CSE表达来增强H2S的产生，并且 MI和糖尿病期间的表观遗传性低甲基化和基因诱导。特定目标3：确定 RIC是否促使BMSC动员到心肌损伤部位并减轻肌肉 糖尿病期间MI后再生损害。

项目成果

High Fat Diet Dysbiotic Mechanism of Decreased Gingival Blood Flow.

• DOI: 10.3389/fphys.2021.625780
• 发表时间: 2021
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Stanisic D;Jeremic N;Majumder S;Pushpakumar S;George A;Singh M;Tyagi SC
• 通讯作者: Tyagi SC

Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.

• DOI: 10.3390/ijms222413546
• 发表时间: 2021-12-17
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Homme RP;George AK;Singh M;Smolenkova I;Zheng Y;Pushpakumar S;Tyagi SC
• 通讯作者: Tyagi SC

TFAM overexpression diminishes skeletal muscle atrophy after hindlimb suspension in mice.

TFAM 过表达可减少小鼠后肢悬吊后的骨骼肌萎缩。

• DOI: 10.1016/j.abb.2018.12.015
• 发表时间: 2019
• 期刊: Archives of biochemistry and biophysics
• 影响因子: 3.9
• 作者: Theilen,NicholasT;Jeremic,Nevena;Weber,GregoryJ;Tyagi,SureshC
• 通讯作者: Tyagi,SureshC

Hydrogen sulfide mitigates skeletal muscle mitophagy-led tissue remodeling via epigenetic regulation of the gene writer and eraser function.

• DOI: 10.14814/phy2.15422
• 发表时间: 2022-08
• 期刊: Physiological reports
• 影响因子: 2.5

Remodeling of Retinal Architecture in Diabetic Retinopathy: Disruption of Ocular Physiology and Visual Functions by Inflammatory Gene Products and Pyroptosis.

• DOI: 10.3389/fphys.2018.01268
• 发表时间: 2018
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Homme RP;Singh M;Majumder A;George AK;Nair K;Sandhu HS;Tyagi N;Lominadze D;Tyagi SC
• 通讯作者: Tyagi SC