Caveolae and Anesthetic Induced Cardiac Protection

描述（由申请人提供）：已知阿片类药物和挥发性麻醉剂具有心脏保护作用。有证据表明，阿片类药物和挥发性麻醉药诱导的心脏保护具有共同的信号转导途径。参与心脏保护的分子途径是复杂的。信号转导的一个新兴观点表明，在质膜富含脂质的微域（称为小泡）中存在空间组织的信号分子复合物。小泡蛋白是一种富含小泡蛋白的蛋白质，为信号分子的组织、运输和调节提供了一个支架。我们有证据表明，小泡在阿片类药物诱导的心脏保护中起着至关重要的作用，并且挥发性麻醉剂可以改变小泡的数量和蛋白质含量。我们还表明，小鼠心肌细胞特异性过表达小窝蛋白-3（小窝蛋白的肌肉特异性亚型）会导致：仅在心脏中增加小窝蛋白-3蛋白的表达；心肌细胞小泡增多；正常的心脏功能和增强Akt（一种参与细胞存活的信号分子）的激活。我们的假设是：1)参与心脏保护的信号分子定位于亚细胞腔泡微域以及这些分子与腔泡蛋白的相互作用对阿片类药物和挥发性麻醉剂产生的心脏保护至关重要；2)心脏特异性过表达的小窝蛋白会增加信号分子与小窝蛋白在小窝内的相互作用，增强麻醉诱导的心脏保护作用。我们将通过解决以下具体目标来检验这些假设。目的1：确定阿片类药物和挥发性麻醉药诱导的心脏保护对体外心肌细胞小窝的影响。目的2：确定体外心肌细胞小窝和小窝蛋白表达的改变是否影响麻醉诱导的心脏保护。目的3：确定在体内心脏特异性过表达小窝蛋白是否能增强麻醉诱导的心脏保护作用。这项工作将为心肌缺血患者或接受心脏或非心脏手术的高危患者提供具有特定临床意义的新数据。

DESCRIPTION (provided by applicant): Opioids and volatile anesthetics are known to produce cardiac protection. Evidence suggests a common signal transduction pathway for opioid and volatile anesthetic-induced cardiac protection. The molecular pathways implicated in cardiac protection are complex. An emerging idea in signal transduction suggests the existence of spatially organized complexes of signaling molecules in lipid-rich microdomains of the plasma membrane known as caveolae. Caveolins, proteins abundant in caveolae, provide a scaffold to organize, traffic and regulate signaling molecules. We have evidence that caveolae are vitally important to opioid- induced cardiac protection and that volatile anesthetics can alter the number and protein content of caveolae. We also have shown that cardiac myocyte specific overexpression of caveolin-3 (a muscle specific isoform of caveolin) in mice results in: increased caveolin-3 protein expression exclusively in the heart; increased numbers of caveolae in cardiac myocytes; normal cardiac function and enhanced activation of Akt (a signaling molecule involved in cell survival). Our hypotheses are: 1) The localization of signaling molecules involved in cardiac protection into subcellular caveolar microdomains and the interaction of these molecules with caveolins are essential for cardiac protection produced by opioids and volatile anesthetics; 2) Cardiac specific overexpression of caveolin protein will increase interactions between signaling molecules and caveolin within caveolae to augment anesthetic-induced cardiac protection. We will test the hypotheses by addressing the following specific aims. Aim 1: Will define the effects of opioid- and volatile anesthetic-induced cardiac protection on caveolae in cardiac myocytes in vitro. Aim 2: Will determine if altered caveolae and caveolin expression in cardiac myocytes in vitro affects anesthetic-induced cardiac protection. Aim 3: Will determine if cardiac specific overexpression of caveolin in vivo enhances anesthetic-induced cardiac protection. The proposed work will provide novel data with specific clinical implications for patients with myocardial ischemia or patients at high cardiac risk undergoing cardiac or noncardiac surgery.