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

随着不断改进的再灌注策略，急性心肌梗死的总死亡率显著降低。 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不断增加 在2型糖尿病患者中升级。确定风险因素、病理机制和有效性 迫切需要干预措施来阻止糖尿病加重的IHF。血管内皮损伤和由此导致的冠状动脉 微血管功能障碍(CMD)是糖尿病心血管并发症的特征，阻碍了足够的 尽管血管再通成功，但仍可进行再通。阐明糖尿病CMD的致病机制 寻找有效的干预措施改善冠脉循环是降低糖尿病IHF的关键 病情恶化。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是维持全身代谢止血的关键，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。一个完整的 脂肪组织与心脏沟通的分子机制研究进展 无疑将有助于开发有效的治疗糖尿病心血管死亡的方法。胞外 囊泡，特别是外体(Exo)，越来越被认为是系统内的信使，调节细胞间的相互作用。 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 强烈提示GRK5诱导的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)保护信号和 糖尿病CMEC细胞毒性ADP-Exo摄取增加，导致糖尿病CMD和IHF加重。 靶向GRK5-AdipoR1系统最终可能成为治疗糖尿病CMD的一种新的治疗手段 保护心脏免受IHF的侵袭。这一新的假设将在三个具体目标上进行严格的研究。利用 基因获得和功能丧失的方法，特定目标1将检验一种假设，即糖尿病诱导的CMEC AdipoR1磷酸化阻断ADP-Exo介导的血管保护，促进糖尿病CMD和IHF 病情恶化。特定目标2将测试一种新的假说，即糖尿病患者的AdipoR1磷酸化和由此产生的 脂联素(在ADP-Exo表面)与脂联素相互作用促进CMEC摄取细胞毒性ADP-Exo AdipoR1(以CMEC表示)。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的磷酸化有效地保护 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，并有可能发现新的 糖尿病患者心肌梗死和心肌梗死后重构的治疗。此外，成功完成 拟议的研究可能对其他涉及Exo的疾病的发展具有更广泛的影响，因为我们的 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.