Targeting Adiponectin for Cardioprotection in the Ischemic Heart

心血管疾病是肥胖/2型糖尿病患者发病和死亡的主要原因。 在最近的大规模临床试验中，严格的血糖控制未能证明心血管死亡率的益处， 2型糖尿病患者。能够保护心脏免受糖尿病后加重的新策略 心肌梗死（MI）重构是迫切需要的。过去十年的研究增加了 了解脂肪细胞（ADp）在健康和疾病中的作用。功能性ADp对于维持 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。心肌细胞是维持心脏功能的最重要的细胞类型 功能它的失效是糖尿病心源性死亡的直接原因。完全理解分子 糖尿病ADp（肥胖引起的肥胖的罪魁祸首） 糖尿病）和糖尿病CM（其中损伤最显著地导致糖尿病心血管疾病的受害者） 死亡）将肯定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（exosomes，Exo），是远程器官通讯中的关键物质。我们最近 已发表的研究首次表明，糖尿病会导致显著的ADp Exo功能障碍， ADp-Exo从运载心脏保护分子的货物到递送来自ADp的心脏毒性分子的载体 严重导致糖尿病性心脏损伤。我们的初步数据进一步表明，糖尿病CM 对非糖尿病ADp-Exo失去保护性反应，而糖尿病ADp-Exo摄取显著增加。 一些体内和体外实验强烈表明，糖尿病诱导的CM脂联素受体-1 （AdipoR 1）磷酸化是一种将Exo介导的ADp-CM通讯从 受体/细胞内补救激酶激活系统与将毒性ADp-Exo递送到糖尿病CM中的媒介物， 增强心肌梗死后重塑并加速心力衰竭。这一新的假设将被严格地 通过使用多个组织特异性遗传操作动物和药理学研究 干预措施。特异性目的1将阐明糖尿病诱导的CM AdipoR 1磷酸化在糖尿病中的关键作用。 阻断ADp-Exo介导的心脏保护作用。具体目标2将检验糖尿病诱导的CM AdipoR 1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 AdipoR 1磷酸化在糖尿病ADp-Exo介导的心脏损伤中起致病作用。 这些研究的成功完成将揭示一种新的糖尿病发病机制 心脏损伤加重，并可能确定新的治疗糖尿病患者心肌梗死后重塑 患者此外，成功完成拟议的研究可能会在以下方面产生更广泛的影响： 我们的工作将有助于填补有关细胞/组织的知识空白， 选择性识别循环的Exo。

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.