Targeting Adiponectin for Cardioprotection in the Ischemic Heart

描述(申请人提供)：糖尿病患者不仅血管损伤增加，导致更高的缺血性心脏病(IHD)发病率，而且在同等程度的初始缺血性损害后，还具有更大的梗塞面积、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，在糖尿病患者中发现其减少不仅导致IHD的发病率增加，而且还增加了这些人的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对缺血心脏的保护作用在很大程度上不依赖于AMPK，但关键依赖于脂联素受体-1/小窝蛋白-3的相互作用。本研究的中心假设是脂联素受体-1/小窝蛋白3相互作用所介导的AMPK非依赖性信号通路(S)可能在APN抗心肌缺血/再灌注损伤中起关键作用。将解决三个具体目标。具体目的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，通过不同的AMPK信号系统参与保护心肌细胞免受MI/R损伤。具体目标2将结合传统药理学和现代遗传学方法，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机制。特定目标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。这项应用中提出的研究所产生的新数据不仅具有重要的科学意义，因为它将帮助我们理解ANP组装和分解(存在不同的亚型)的生物学意义以及每种亚型如何发挥其心脏保护作用，而且还具有临床意义，因为它可能确定在不同病理条件下的治疗需要的最佳干预措施。 与公共健康相关：目前的拨款申请试图确定脂联素(APN)--一种由脂肪细胞制造的蛋白质--如何保护心肌细胞。这一应用中提出的研究的新数据不仅具有重要的科学意义，因为它将有助于理解APN的组装和拆解的生物学意义、其不同的亚型，以及每种APN亚型如何发挥其心脏保护作用，而且还具有临床意义，因为它将为不同病理条件下的治疗应用确定新的靶点。

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.