Targeting Adiponectin for Cardioprotection in the Ischemic Heart

描述（由申请人提供）：糖尿病患者不仅血管损伤增加，导致缺血性心脏病（IHD）的发病率更高，而且在相当程度的初始缺血性损伤后，还会有更大的梗死面积、严重的心力衰竭和更高的死亡率。最近的临床和实验结果表明，脂联素（APN）是一种新的代谢调节、血管保护和心脏保护分子，其在糖尿病患者中的减少不仅会增加IHD的发病率，而且会增加这些个体的MI/R损伤。大量证据表明AMP激活的蛋白激酶（AMPK）在APN的代谢和血管保护作用中起重要作用。然而，我们的初步实验表明，APN在缺血性心脏中的心脏保护作用在很大程度上与ampk无关，但关键取决于脂联素受体-1/caveolin-3的相互作用。本研究的中心假设是，新的脂联素受体-1/Caveolin-3相互作用介导，由特定APN异构体启动的ampk独立信号通路，具有特定受体激活，可能在APN对心肌梗死/心肌梗死损伤的心脏保护作用中发挥关键作用。将讨论三个具体目标。Specific Aim 1将利用敲除小鼠和siRNA沉默技术来确定不同形式的APN是否可以优先结合不同类型的受体，并保护心肌细胞免受AMPK信号系统不同参与的MI/R损伤。特异性目的2将结合传统药理学和现代遗传学方法，并试图确定APN在MI/R心脏中发挥其抗氧化、抗硝化和心脏保护作用的细胞内信号传导机制。特异性Aim 3将为APN-Caveolin信号受损的糖尿病患者确定新的心脏保护靶点。本应用程序中提出的研究产生的新数据不仅具有科学意义，因为它将帮助我们了解ANP组装和拆卸（不同同种异构体的存在）的生物学意义以及每种同种异构体如何发挥其心脏保护作用，而且具有临床意义，因为它可以确定不同病理条件下治疗需求的最佳干预措施。

DESCRIPTION (provided by applicant): Diabetic patients not only have increased vascular injury that causes higher morbidity of ischemic heart disease (IHD), but also have larger infarct size, severe heart failure, and higher mortality following a comparable degree of initial ischemic insult. Recent clinical and experimental results have demonstrated that adiponectin (APN) is a novel metabolic regulatory, vasculoprotective and cardioprotective molecule whose reduction found in diabetic patients contribute not only to increased morbidity of IHD, but also to increased MI/R injury in these individuals. Substantial evidence exists that AMP activated protein kinase (AMPK) plays an essential role in APN's metabolic and vasculoprotective effects. However, our preliminary experiments demonstrated that APN's cardioprotective effect in the ischemic heart is largely AMPK-independent but critically depends on adiponectin receptor-1/caveolin-3 interaction. The central hypothesis to be tested in this grant application is that novel adiponectin receptor-1/Caveolin-3 interaction mediated, AMPK-independent signaling pathway(s) initiated by specific APN isoform(s) with specific receptor activation may play a critical role in APN's cardioprotective effects against MI/R injury. Three specific aims will be addressed. Specific Aim 1 will utilize knockout mice and siRNA silencing technique to determine whether different forms of APN may preferentially bind to different type of receptors and protect cardiomyocytes against MI/R injury with different involvement of AMPK signaling system. Specific Aim 2 will combine traditional pharmacologic and modern genetic approaches and attempt to identify the intracellular signaling mechanisms by which APN exerts its anti-oxidative, anti-nitrative, and cardioprotective actions in MI/R hearts. Specific Aim 3 will identify novel cardioprotective targets for diabetic individuals with impaired APN-Caveolin signaling. The novel data resulting from the studies proposed in this application are not only scientifically significant because it will help us to understand the biological significance of ANP assembling and disassembling (presence of different isoforms) and how each isoform exerts its cardioprotective effect, but also clinically significant because it may identify optimal interventions for therapeutical needs under different pathologic conditions. PUBLIC HEALTH RELEVANCE: The current grant application attempt to determine how adiponectin (APN), a protein made by fat cell, protect cardiomyocytes. The novel data resulting from the studies proposed in this application is not only scientifically significant because it will contribute to understanding the biological significance of APN assembling and disassembling, its different isoforms, and how each APN isoform exerts its cardioprotective effect, but is also clinically significant because it will identify novel targets for therapeutic application in different pathologic conditions.