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

基本信息

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
项目类别：
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

项目摘要

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）患者的急性死亡率但这些患者转为缺血性心肌病（IC）的发病率已显着降低。尽管取得了重大进展，但糖尿病患者的 IC 值要高得多，这是心血管疾病的一个主要危险因素。在心脏介入治疗中，糖尿病IC（DIC）的发病率和死亡率不断上升，人们越来越认识到这一点。治疗 DIC 必须采取综合方法，而不是仅仅关注心肌细胞补充脂联素 (APN)（一种被鉴定为脂肪因子的蛋白质）可保护身体。然而，一些临床研究表明，APN 水平升高。与慢性心力衰竭的不良预后密切相关，我们和其他人之前报道 APN 功能与慢性心力衰竭的不良预后密切相关。我们最近的研究表明，糖尿病会损害动物和患者。心脏不仅影响心肌细胞，糖尿病中受损的冠状动脉内皮细胞（EC）也会导致我们最近发表的工作和微循环功能障碍显着加剧了心脏功能障碍。初步实验进一步证明，1）在人类糖尿病冠状动脉EC中，APN受体1敲除（AdipoR1，EC 中的原型 APN 受体）mRNA 表达不变，但 AdipoR1 蛋白表达 2) 冠状血管功能障碍 (CVDy) 的显着降低在糖尿病动物中被明显夸大为在 AdipoR1KO 小鼠中；在 2 型糖尿病小鼠中，冠状动脉中的 AdipoR1 表达显着降低 EC.3) 蛋白质组学揭示 AdipoR1 磷酸化是最重要的翻译后修饰糖尿病冠状动脉 EC；4) GRK5（不是 GRK2），EC 中典型的 GRK 家族成员，显着上调糖尿病冠状动脉 EC 中；5) 冠状动脉 EC 中的 GRK5OE 对 AdipoR1 mRNA 表达没有影响。 GRK5OE 很大程度上再现了人类冠状动脉 EC 中有关 APN/AdipoR1 的病理表型 6) 相反，GRK5KO 恢复糖尿病冠状动脉 EC 中的 APN 血管生成作用。令人兴奋的初步结果，我们将测试一个新的假设，即糖尿病患者 GRK5 上调并由此产生 AdipoR1 磷酸化在糖尿病 CVDy 中起致病作用，并导致有害的 GRK5-AdipoR1 系统可能是糖尿病 CVDy 的新治疗靶点。最终改善 DIC 这一假设将通过解决以下 3 个科学问题进行严格检验。问题：1）引起AdipoR1脱敏并阻断AdipoR1的分子机制是什么（目标 1）；2）当 AdipoR1 存在时，APN 的冠状血管保护作用如何受损？磷酸化？（目标 2）和 3）哪种干预对于恢复冠状血管功能最有效糖尿病心脏对抗 DIC？（目标 3）。通过冠状动脉的整合调节了解糖尿病心脏损伤的基础知识微循环功能，并确定针对 DIC 的新治疗靶点。