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可产生心脏保护作用。有证据表明阿片类药物和挥发性麻醉药诱导的心脏保护存在共同的信号转导途径。涉及心脏保护的分子途径是复杂的。一个新兴的想法在信号转导表明存在空间组织的信号分子复合物在富含脂质的微区质膜称为小窝。窖蛋白是窖蛋白中丰富的蛋白质，为组织、运输和调节信号分子提供了一个支架。我们有证据表明小窝对阿片诱导的心脏保护至关重要，挥发性麻醉剂可以改变小窝的数量和蛋白质含量。我们还表明，小鼠中心肌细胞特异性过度表达小窝蛋白-3（一种肌肉特异性小窝蛋白亚型）导致：仅在心脏中增加小窝蛋白-3蛋白表达;心肌细胞中小窝数量增加;心脏功能正常和Akt（一种参与细胞存活的信号分子）活化增强。我们的假设是：1）参与心脏保护作用的信号分子定位于亚细胞小窝微区，并与小窝蛋白相互作用，是阿片类药物和挥发性麻醉药产生心脏保护作用的关键; 2）心脏特异性过表达小窝蛋白可增加小窝内信号分子与小窝蛋白的相互作用，增强麻醉药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假设。目的1：明确阿片类和挥发性麻醉药对离体心肌细胞膜小窝的保护作用。目的2：将确定是否改变小窝和小窝蛋白表达在体外心肌细胞麻醉诱导的心脏保护。目的3：将确定是否在体内心脏特异性过度表达小窝蛋白增强麻醉诱导的心脏保护。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心脏风险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.