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）发病率较高，而且梗死面积更大，心力衰竭严重，初始缺血损伤程度相当后死亡率更高。脂联素（APN）是一种新型的代谢调节、血管保护和心脏保护分子，其在糖尿病患者中的表达降低不仅导致IHD发病率增加，而且增加了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在缺血心脏中的心脏保护作用在很大程度上是AMPK独立的，但关键取决于脂联素受体1/小窝蛋白3的相互作用。在本授权申请中待检验的中心假设是，新型脂联素受体-1/小窝蛋白-3相互作用介导的、由具有特异性受体活化的特定APN同种型引发的AMPK非依赖性信号通路可能在APN对MI/R损伤的心脏保护作用中起关键作用。将讨论三个具体目标。Specific Aim 1将利用基因敲除小鼠和siRNA沉默技术来确定不同形式的APN是否可以优先与不同类型的受体结合，并通过AMPK信号系统的不同参与来保护心肌细胞免受MI/R损伤。具体目标2将结合联合收割机传统的药理学和现代遗传学的方法，并试图确定细胞内信号转导机制，APN发挥其抗氧化，抗硝化，心肌保护作用的MI/R心脏。具体目标3将为APN-小窝蛋白信号转导受损的糖尿病个体确定新的心脏保护靶点。从本申请中提出的研究中得到的新数据不仅具有科学意义，因为它将帮助我们理解ANP组装和拆卸（不同亚型的存在）的生物学意义以及每种亚型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。 公共卫生相关性：目前的拨款申请试图确定脂联素（APN），一种由脂肪细胞产生的蛋白质，如何保护心肌细胞。本申请中提出的研究所产生的新数据不仅具有科学意义，因为它将有助于理解APN组装和拆卸的生物学意义、其不同的亚型以及每种APN亚型如何发挥其心脏保护作用，而且具有临床意义，因为它将鉴定用于不同病理状况下的治疗应用的新靶标。

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.