Dysregulated Adiponectin Transmembrane Signaling in Diabetic CoronaryVascular Injury and Heart Failure

糖尿病冠状血管损伤和心力衰竭中脂联素跨膜信号传导失调

• 批准号: 10765297
• 负责人: Yajing Wang
• 金额: $ 55.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765297
• 关键词: Acute; Acute myocardial infarction; Address; Adipocytes; Affect; Animal Model; Animals; Antioxidants; Attenuated; Blood; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Clinical Research; Coronary; Coronary Circulation; Data; Diabetes Mellitus; Diabetic mouse; Disease; Down-Regulation; Endocrine system; Endothelial Cells; Exhibits; Extravasation; Family member; Functional disorder; G protein coupled receptor kinase; GRK5 gene; Genetic; Goals; Health; Heart; Heart Injuries; Heart failure; Homeostasis; Human; Hyperglycemia; Impairment; Incidence; Injury; Intervention; Knock-in; Knock-out; Knockout Mice; Knowledge; Leptin; Mediating; Membrane; Microcirculation; Molecular; Morbidity - disease rate; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Organ; Oxidative Stress; Pathologic; Patient Care; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Play; Post-Translational Protein Processing; Prevention; Production; Prognosis; Proteins; Proteomics; Publishing; Regulation; Reporting; Research; Resistance; Role; Signal Transduction; Site; Supplementation; System; Testing; Time; Type 2 diabetic; Ubiquitination; Up-Regulation; Vascular Diseases; Vascular blood supply; Work; adipokines; adiponectin; angiogenesis; cardiovascular risk factor; desensitization; diabetic; diabetic patient; effective therapy; experimental study; gain of function; glycemic control; improved; in vitro Model; in vivo; ischemic cardiomyopathy; loss of function; mRNA Expression; mortality; new therapeutic target; non-diabetic; novel; preservation; protein expression; prototype; receptor; response; success; therapeutically effective; therapy development; treatment strategy

With extensive application of treatment strategies, the acute mortality of patients having myocardial infarct (MI) has significantly reduced but these patients turn to ischemic cardiomyopathy (IC). Importantly, the incidence of IC is much higher in diabetic patients, a major risk factor for cardiovascular disease. Despite the major advances in cardiac interventions, diabetic IC (DIC) morbidity and mortality continue to rise. It is increasingly recognized that integrative approaches, rather than purely focusing on cardiomyocytes, must be undertaken for DIC prevention/treatment. Supplementation of adiponectin (APN), a protein identified as an adipokine, protects the acute ischemic heart in animal model. However, several clinical studies demonstrate that elevated APN levels are strongly associated with poor prognosis of chronic HF. We and others previously report that APN function is markedly attenuated in diabetic animals and patients. Our most recent study demonstrates that diabetes injures heart not only on cardiomyocytes, the impaired coronary endothelial cells (EC) in diabetes leading to microcirculation dysfunction dramatically enhancing cardiac dysfunction. Our recently published work and preliminary experiments further demonstrate that 1) in human diabetic coronary EC, APN receptor 1 knockout (AdipoR1, prototypic APN receptor in EC) mRNA expression is unchanged, but AdipoR1 protein expression is significantly reduced; 2) coronary vascular dysfunction (CVDy) is markedly exaggerated in diabetic animals as well as in AdipoR1KO mice; in type 2 diabetic mice, AdipoR1 expression is significantly reduced in the coronary EC. 3) proteomics reveal that AdipoR1 phosphorylation is the most significant post-translational modification in diabetic coronary EC; 4) GRK5 (not GRK2), the prototypical GRK family member in EC, is markedly upregulated in diabetic coronary EC; 5) GRK5OE in coronary EC has no effect upon AdipoR1 mRNA expression. However, GRK5OE largely reproduces the pathologic phenotypes in human coronary EC concerning APN/AdipoR1 signaling; 6) conversely, GRK5KO restores APN angiogenic effect in diabetic coronary EC. Based upon these exciting preliminary results, we will test a novel hypothesis that diabetic GRK5 upregulation and resultant AdipoR1 phosphorylation plays causative roles in diabetic CVDy and contributes to the deleterious consequences of DIC. GRK5-AdipoR1 system may be a novel therapeutic target against diabetic CVDy, ultimately ameliorating the DIC. This hypothesis will be rigorously tested by addressing the following 3 scientific questions: 1) what is the molecular mechanism that causes AdipoR1 desensitization and blocks AdipoR1 function in diabetes? (Aim 1); 2) How is APN’s coronary vascular protective action impaired when AdipoR1 is phosphorylated? (Aim 2), and 3) which intervention is most effective in restoring coronary vascular function in the diabetic heart against DIC? (Aim 3). Successful completion of proposed studies will greatly advance our knowledge in understanding the basis of diabetic cardiac injury through integrating regulation of coronary microcirculatory function, and identify novel therapeutic targets against DIC.

随着治疗策略的广泛应用，心肌梗死（MI）患者的急性死亡率逐渐降低。