Hemal H. Patel, Ph.D.

Previous studies have assessed cardiac protection in the whole animal. A shortfall of these studies is the inability to determine if cardiac protection is due to a direct action on the cardiac myocyte or to secondary effects. Cardiac protection has been validated in isolated heart, which negates certain confounding factors (e.g. nerve stimulation, peripheral vascular and endocrine effects). However, isolated hearts contain numerous cell types (e.g. endothelial cells, vascular smooth muscle cells, and fibroblasts). Few studies have evaluated cardiac protection in isolated cardiac myocytes. Preliminary data in isolated myocyctes suggest that caveolae are important for cardiac protective signaling. As a large portion of cellular protein is located outside of caveolae, the possibility exists that upon stimulation, signaling molecules traffic to caveolae to facilitate signal transduction. Data suggest that exposure to volatile anesthetics increases caveolae number and the movement of caveolin protein from non-caveolar regions to caveolar microdomains. G Protein coupled receptors (GPCRs) trafficking into and out of caveolae play a major role in receptor/effector-coupling with agonist stimulation. Trafficking of the opioid receptor, a GPCR involved in opioid- and volatile anesthetic-induced cardiac protection, upon agonist stimulation has not been characterized in cardiac myocytes. Additionally, little is known regarding the impact of anesthetic stimulation on the caveolar proteome. As part of this project, we will specifically address: i) effects of anesthetics on caveolae and caveolins in isolated ACM; ii) trafficking of opioid receptors upon agonist stimulation in isolated ACM; iii) if anesthetic exposure affects interaction of signaling proteins (relevant to cardiac protection) with caveolin.   Myocytes exposed to opioid receptor agonists or isoflurane at concentrations able to produce the most robust cardiac protection will be fixed at various time points after stimulation. Myocytes will be stained with antibodies specific to opioid receptors and various cellular organelles  and imaged to determine the temporal-spatial distribution of the three opioid receptors upon agonist stimulation. Specificity of trafficking will be determined by treatment of myocytes with antagonists described above prior to opioid agonist stimulation. 

Selected References
Patel HH, Murray F, Insel PA. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol 48:359-391, 2008

Head BP, Patel HH, Tsutsumi YM, Hu Y, Mejia T, Mora RC, Insel PA, Roth DM, Drummond JC, Patel PM. Caveolin-1 expression is essential for N-methyl-D-aspartate receptor-mediated Src and extracellular signal-regulated kinase 1/2 activation and protection of primary neurons from ischemic cell death Faseb J. 22:828-840, 2008.

Patel HH, Zhang S, Murray F, Suda RY, Head BP, Yokayama U, Swaney JS, Niesman IR, Schermuly RT, Pullamsetti SS, Thistiethwaite PA, Miyanohara A, Farquhar MG, Yuan JX, Insel PA. Increased smooth muscle cell expression of caveolin-1 and caveolae contribute to the pathophysiology of idiopathic pulmonary arterial hypertension. Faseb J. 21:2970-2979, 2007.

Patel HH, Tutsumi YM, Head BP, Niesman IR, Jennings M, Horikawa Y, Huang D, Moreno AL, Patel PM, Insel PA, Roth DM. Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1. Faseb J. 21:1565-1574, 2007.

Patel HH, Head BP, Petersen HN, Niesman IR, Huang D, Gross GJ, Insel PA, Roth DM. Protection of     adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors Am J Physiol Heart Circ Physiol. 291:H344-350, 2006.