Critical Role of Small Extracellular Vesicles in Diabetic Coronary VascularDysfunction and Diabetic Ischemic Heart Failure efforts

随着再灌注策略的不断改进， 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不断增加， 2型糖尿病患者的血糖升高。确定风险因素、病理机制和有效的 迫切需要阻断糖尿病性IHF恶化的干预措施。内皮损伤和导致的冠状动脉 微血管功能障碍（CMD）是糖尿病心血管并发症的标志，阻碍了充分的 尽管成功再通，但仍存在再灌注。阐明糖尿病CMD的机制， 确定改善冠状动脉循环的有效干预措施对于减少糖尿病IHF至关重要 加重过去十年的研究增加了对脂肪细胞（ADp）在 健康和疾病。功能性ADp在维持全身代谢止血方面至关重要，而ADp 功能障碍是导致2型糖尿病的最公认的致病因素之一。一个完整 了解介导脂肪组织和心脏之间通讯的分子机制 毫无疑问，这将有助于开发有效治疗糖尿病心血管死亡的方法。细胞外 囊泡，特别是外泌体（Exo），越来越多地被认为是介导细胞间相互作用的系统性信使。 细胞/器官间通讯。来自我们最近发表的工作和额外的初步数据的证据 强烈提示GRK 5诱导的冠状动脉微循环内皮细胞（CMEC）脂联素受体1 （AdipoR 1）磷酸化负责减弱ADP衍生的Exo（ADp-Exo）保护性信号传导， 糖尿病CMEC中细胞毒性ADp-Exo摄取增加，导致CMD和IHF的糖尿病恶化。 最终，靶向GRK 5-AdipoR 1系统可能是一种新的治疗糖尿病CMD的干预措施。 保护心脏免受IHF的侵害。这一新的假设将在3个具体目标中进行严格的研究。利用 通过遗传获得和功能丧失的方法，具体目标1将检验糖尿病诱导的CMEC AdipoR 1磷酸化阻断ADp-Exo介导的血管保护作用，导致糖尿病CMD和IHF 加重具体目标2将测试一个新的假设，糖尿病AdipoR 1磷酸化， 内吞作用通过脂联素（在ADp-Exo表面上）与脂联素的相互作用促进CMEC摄取细胞毒性ADp-Exo。 AdipoR 1（在CMEC中表达）。具体目标3将确定1）EC AdipoR 1磷酸化是否介导 糖尿病ADp-Exo诱导的CMD和IHF，和2）阻断EC AdipoR 1磷酸化有效保护 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 负责糖尿病心血管损伤恶化的机制，并可能确定新的 治疗糖尿病患者的CMD和MI后重塑。此外，成功完成了 拟议的研究可能对涉及Exo的其他疾病的发展有更广泛的影响， 这项工作将有助于填补关于循环Exo的细胞/组织选择性识别的知识空白。

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.