Critical Role of Small Extracellular Vesicles in Diabetic Coronary Vascular Dysfunction and Diabetic Ischemic Heart Failure efforts.

小细胞外囊泡在糖尿病冠状血管功能障碍和糖尿病缺血性心力衰竭中的关键作用。

• 批准号: 10274392
• 负责人: Yajing Wang
• 金额: $ 40.46万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274392
• 关键词: Acute; Acute myocardial infarction; Adipocytes; Adipose tissue; Affect; Attenuated; Cardiovascular system; Cell Communication; Cells; Cessation of life; Communication; Coronary; Coronary Circulation; Data; Development; Diabetes Mellitus; Disease; Endocytosis; Endothelial Cells; Endothelium; Functional disorder; GRK5 gene; Genetic; Health; Heart; Heart failure; Hemostatic function; Human; Injury; Knowledge; Label; Mediating; Metabolic; Microvascular Dysfunction; Molecular; Morbidity - disease rate; Myocardial Ischemia; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pathologic; Patient Care; Patients; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Prevalence; Production; Publishing; Regulation; Reperfusion Therapy; Reporting; Research; Risk Factors; Role; Severities; Signal Transduction; Surface; System; Testing; Tissues; Type 2 diabetic; Vascular Diseases; Virulence Factors; Work; adipokines; adiponectin; base; cardioprotection; cardiovascular injury; cytotoxic; diabetic; diabetic patient; effective intervention; effective therapy; exosome; experimental study; extracellular vesicles; improved; in vivo; intravenous administration; loss of function; mortality; non-diabetic; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; receptor; uptake

With continually improving reperfusion strategies, the overall mortality of AMI has been significantly reduced in non-diabetic patients. However, both the prevalence and severity of ischemic heart failure (IHF) continually escalate in patients with type 2 diabetes. Identifying risk factors, pathological mechanisms, and effective interventions blocking diabetic exacerbation of IHF are urgently needed. Endothelial injury and resultant coronary microvascular dysfunction (CMD) are the hallmarks of diabetic cardiovascular complications, hindering adequate reperfusion despite successful recanalization. Clarifying mechanisms responsible for diabetic CMD and identifying effective interventions improving coronary circulation are essential in reducing diabetic IHF exacerbation. Research in the past decade has increased understanding of the roles adipocytes (ADp) play in health and disease. Functional ADp are critical in maintaining systemic metabolic hemostasis, whereas ADp dysfunction is one of the most recognized pathogenic factors leading to type 2 diabetes. A complete understanding of the molecular mechanisms mediating the communication between adipose tissue and heart will undoubtedly help the development of effective therapies against diabetic cardiovascular death. Extracellular vesicles, particularly exosomes (Exo), are increasingly recognized as systemic messengers mediating inter- cellular/inter-organ communication. Evidence from our recently published work and additional preliminary data strongly suggest that GRK5-induced coronary microcirculatory endothelial cells (CMEC) adiponectin receptor 1 (AdipoR1) phosphorylation is responsible for attenuated ADp-derived Exo (ADp-Exo) protective signaling and increased cytotoxic ADp-Exo uptake in diabetic CMEC, contributing to diabetic exacerbation of CMD and IHF. Targeting the GRK5-AdipoR1 system may be a novel therapeutic intervention against diabetic CMD, ultimately protecting the heart against IHF. This novel hypothesis will be rigorously investigated in 3 specific aims. Utilizing genetic gain- and loss-of-function approaches, Specific Aim 1 will test a hypothesis that diabetes-induced CMEC AdipoR1 phosphorylation blocks ADp-Exo mediated vasculoprotection, contributing to diabetic CMD and IHF exacerbation. Specific Aim 2 will test a novel hypothesis that diabetic AdipoR1 phosphorylation and resultant endocytosis promotes CMEC uptake of cytotoxic ADp-Exo via adiponectin (on ADp-Exo surface) interaction with AdipoR1 (expressed in CMEC). Specific Aim 3 will determine whether 1) EC AdipoR1 phosphorylation mediates diabetic ADp-Exo induced CMD and IHF, and 2) blocking EC AdipoR1 phosphorylation is effective in protecting diabetes-exacerbated CMD and IHF. Successful completion of these studies will reveal a novel molecular mechanism responsible for the diabetic exacerbation of cardiovascular injury, and potentially identify novel therapy against CMD and post-MI remodeling in diabetic patients. Moreover, successful completion of the proposed studies may have broader implications in the development of other diseases involving Exo, as our work will help to fill a knowledge gap concerning cell/tissue-selective recognition of circulating Exo.

随着再灌注策略的不断改进，AMI 的总体死亡率已显着降低 非糖尿病患者。然而，缺血性心力衰竭（IHF）的患病率和严重程度持续上升 2 型糖尿病患者的病情加重。识别危险因素、病理机制和有效的方法 迫切需要阻止糖尿病 IHF 恶化的干预措施。内皮损伤和由此产生的冠状动脉 微血管功能障碍（CMD）是糖尿病心血管并发症的标志，阻碍了足够的 尽管成功再通，但仍存在再灌注。阐明糖尿病 CMD 的机制 确定改善冠脉循环的有效干预措施对于减少糖尿病 IHF 至关重要 恶化。过去十年的研究加深了人们对脂肪细胞 (ADp) 在 健康和疾病。功能性 ADp 对于维持全身代谢止血至关重要，而 ADp 功能障碍是导致 2 型糖尿病最常见的致病因素之一。一个完整的 了解介导脂肪组织和心脏之间通讯的分子机制 无疑将有助于开发针对糖尿病心血管死亡的有效疗法。细胞外 囊泡，特别是外泌体（Exo），越来越多地被认为是介导相互作用的系统信使。 细胞/器官间通讯。来自我们最近发表的工作和其他初步数据的证据 强烈表明 GRK5 诱导冠状动脉微循环内皮细胞 (CMEC) 脂联素受体 1 (AdipoR1) 磷酸化负责减弱 ADp 衍生的 Exo (ADp-Exo) 保护信号传导和 糖尿病 CMEC 中细胞毒性 ADp-Exo 摄取增加，导致 CMD 和 IHF 糖尿病恶化。 最终，靶向 GRK5-AdipoR1 系统可能是针对糖尿病 CMD 的一种新型治疗干预措施 保护心脏免受 IHF 侵害。这一新颖的假设将在 3 个具体目标上得到严格研究。利用 遗传功能获得和丧失方法，具体目标 1 将检验糖尿病诱发 CMEC 的假设 AdipoR1 磷酸化阻断 ADp-Exo 介导的血管保护，导致糖尿病 CMD 和 IHF 恶化。具体目标 2 将测试糖尿病 AdipoR1 磷酸化及其结果的新假设 内吞作用通过脂联素（在 ADp-Exo 表面）与 AdipoR1（在 CMEC 中表达）。具体目标 3 将确定 1) EC AdipoR1 磷酸化是否介导 糖尿病 ADp-Exo 诱导的 CMD 和 IHF，2) 阻断 EC AdipoR1 磷酸化可有效保护 糖尿病加重的 CMD 和 IHF。这些研究的成功完成将揭示一种新的分子 糖尿病加重心血管损伤的机制，并有可能确定新的机制 针对糖尿病患者 CMD 和 MI 后重塑的治疗。此外，还顺利完成了 拟议的研究可能对涉及 Exo 的其他疾病的发展产生更广泛的影响，因为我们 这项工作将有助于填补有关循环 Exo 的细胞/组织选择性识别的知识空白。