Caveolae and Anesthetic Induced Cardiac Protection

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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.