Targeting Adiponectin for Cardioprotection in the Ischemic Heart

心血管疾病是肥胖/2型糖尿病患者发病率和死亡率的主要原因。 在最近的大规模临床试验中，严格控制血糖未能证明心血管死亡有益于 2型糖尿病患者。能够保护心脏免受糖尿病加重的新策略 心肌梗死(MI)的重塑是迫切需要的。在过去的十年里，研究增加了 了解脂肪细胞(ADP)在健康和疾病中的作用。功能ADP在维护中至关重要 全身代谢止血，而ADP功能障碍是最公认的致病因素之一 导致肥胖/2型糖尿病。心肌细胞(CM)是维持心脏最重要的细胞类型 功能。它的失败是糖尿病心脏死亡的直接原因。对分子的完全理解 糖尿病ADP(肥胖的罪魁祸首)之间的不良沟通机制 糖尿病)和糖尿病CM(伤害对糖尿病心血管疾病的影响最大的受害者 死亡)肯定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，特别是外周小体(Exo)，是远程器官通讯的关键物质。我们最近的一次 已发表的研究首次表明，糖尿病导致显著的ADP外周功能障碍，转换 ADP-Exo从载货心脏保护分子到运送ADP心脏毒性分子的车辆 对CM来说，是导致糖尿病心脏损伤的关键因素。我们的初步数据进一步表明，糖尿病CM 失去对非糖尿病ADP-Exo的保护性反应，而对糖尿病ADP-Exo的摄取显著增加。 一些体内和体外实验有力地表明糖尿病诱导的CM脂联素受体-1 (AdipoR1)磷酸化是将外源介导的ADP-CM通讯从 受体/细胞内挽救激酶激活系统向糖尿病CM运送有毒ADP-Exo的载体， 促进心肌梗死后重塑和加速心力衰竭。这一新颖的假设将被严格地 通过利用多种组织特异性的基因操作动物和药理学进行研究 干预措施。特定目标1将阐明糖尿病诱导的CM AdipoR1磷酸化在 阻断ADP-Exo介导的心肌保护。《特定目标2》将检验一种假说，即糖尿病引起的CM AdipoR1磷酸化促进毒性ADP-Exo内吞作用。具体目标3将证明一个概念，糖尿病- 诱导的CM AdipoR1磷酸化在糖尿病ADP-Exo介导的心脏损伤中起重要作用。 这些研究的成功完成将揭示糖尿病的一种新的分子机制 加重心脏损伤，并有可能找到新的治疗方法来对抗糖尿病患者的心肌梗死后重构 病人。此外，成功完成拟议的研究可能会对 涉及外周的其他疾病的发展，因为我们的工作将有助于填补关于细胞/组织的知识空白 循环Exo的选择性识别。

Cardiovascular disease is the leading cause of morbidity and mortality in patients with obesity/type 2 diabetes. Strict glycemic control in recent large-scale clinical trials failed to demonstrate cardiovascular mortality benefit in type 2 diabetic patients. Novel strategies capable of protecting the heart against diabetes-exacerbated post- myocardial infarction (MI) remodeling are urgently needed. 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 obesity/type 2 diabetes. The cardiomyocyte (CM) is the most important cell type maintaining heart function. Its failure is the direct cause of diabetic cardiac death. Complete understanding of the molecular mechanisms mediating the adverse communication between diabetic ADp (the culprit of obesity-induced diabetes) and diabetic CM (the victim in which injury most significantly contributes to diabetic cardiovascular death) will certainly help development of effective therapies against diabetic cardiovascular death. Extracellular vesicles, particularly exosomes (Exo), are critical agents in remote organ communication. Our most recently published study demonstrates for the first time that diabetes causes significant ADp Exo dysfunction, switching ADp-Exo from cargo-carrying cardioprotective molecules to vehicles delivering cardiotoxic molecules from ADp to CM, critically contributing to diabetic cardiac injury. Our preliminary data further demonstrate that diabetic CM lose protective response to non-diabetic ADp-Exo, while uptake of diabetic ADp-Exo significantly increases. Several in vivo and in vitro experiments strongly suggest that diabetes-induced CM adiponectin receptor-1 (AdipoR1) phosphorylation is a central mechanism switching Exo-mediated ADp-CM communication from a receptor/intracellular salvage kinase activation system to a vehicle delivering toxic ADp-Exo into diabetic CM, enhancing post-MI remodeling and accelerating heart failure. This novel hypothesis will be rigorously investigated by utilizing multiple tissue-specific genetically manipulated animals and pharmacological interventions. Specific Aim 1 will clarify the critical role of diabetes-induced CM AdipoR1 phosphorylation in blocking ADp-Exo mediated cardioprotection. Specific Aim 2 will test a hypothesis that diabetes-induced CM AdipoR1 phosphorylation promotes toxic ADp-Exo endocytosis. Specific Aim 3 will prove a concept that diabetes- induced CM AdipoR1 phosphorylation plays a causative role in diabetic ADp-Exo mediated cardiac injury. Successful completion of these studies will reveal a novel molecular mechanism responsible for diabetic exacerbation of cardiac injury, and potentially identify novel therapy against 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.