Role of sarcolemmal versus mitochondrial ATP-regulated potassium channels (KATP channels) in myocardial ischemia-reperfusion injury. Currently, the heart contains two potassium channels that are regulated by the metabolic state of the cell, a sarcolemmal and a mitochondrial channel which have been termed the sarc and mito KATP channel, respectively. Both channels are regulated by the intracellular concentration of ATP and other nucleotides and have been shown to play an important endogenous protective role against irreversible tissue damage. By using specific pharmacological tools and isolated mitochondria we will attempt to discover mechanisms by which these channels exert their cardioprotective effects during prolonged periods of ischemia and reperfusion. We will also determine the critical time at which these channels need to be open for cardioprotection to occur. The importance of these channels in acute and chronic preconditioning will also be assessed.
Cardioprotective Effects of Opioids and the Intracellular Signaling Pathways Involved. Recently, we have discovered that endogenous opioids play a key role in the phenomenon termed ischemic preconditioning (IPC). IPC occurs following either single or multiple brief periods of ischemia and results in a marked reduction in infarct size following a more prolonged period of ischemia. We have found that the mito KATP channel appears to be the end effector in IPC and that adenosine and opioids are two endogenous substances involved in triggering the preconditioning response. There are two phases following IPC, an early protective phase termed acute preconditioning that lasts for 60-90 minutes and a delayed phase that lasts for 24-72 hours. We have found that exogenous opioids trigger both phases and we are currently investigating the specific receptors involved in triggering these responses and the intracellular mediators of this response. Specifically, we are looking at the role of G proteins and several kinases such as tyrosine kinases, various isoforms of protein kinase C (PKC) and members of the mitogen-activated protein kinase (MAPK) superfamily such as the extracellular regulated kinases (ERK 1/2) and p38 MAPK. Finally, we will study the potential role of oxygen-derived free radicals (ODFRs) and heat shock proteins in mediating the cardioprotective effects of opioids and acute and delayed IPC. These studies have important clinical manifestations since opioids are already approved for the treatment of pain and could be easily tested for their cardioprotective potential in patients.
Gross, G.J., Peart, J.N.: Opioids and myocardial reperfusion injury. Arch. Mal. Coeur. Vaiss 100: 163-174, 2007.
Gross, E.R., Gross, G. J.: Pharmacological therapeutics for cardiac re-perfusion injury. Expert Opinion Review 12: 1-22, 2007.
Gauthier, K.M., Yang, W., Gross, G.J., Campbell, W.B.: Roles of epoxyeicosatrienoic acids in vascular regulation and cardiac pre-conditioning. J. Cardiovasc. Pharmacol. 50: 601-608, 2007.
Baker, J.E., Su J., Fu, X., Hsu, A.K., Gross, G.J., Tweddel, J.S., Hogg, N.: Nitrite confers protection against myocardial infarction: Role of xanthine oxidoreductase, NADPH oxidase and KATP channels. J. Mol. Cell. Cardiol. 43: 437-444, 2007.
Gross, E.R., Gross, G.J.: Preconditioning and myocardial infarction: An up-date and perspective. Drug Discovery Today: Disease Mechanisms 238: 1-10, 2007.
Wan,T., Ge Z.D., Tampo, A., Mio, Y., Kwok, W.M., Bienengraeber, M.W., Tracey, W.R., Seino, S., Gross, G.J., Auchampach, J. A.: The A3 adenosine receptor agonist CP-532,903 protects against myocardial ischemia/reperfusion injury via activation of the sarcolemmal ATP-sensitive potassium channel. J. Pharmacol. Exp. Ther. 324: 234-243, 2008.
Baker, J.E., Su, J. Hsu, A.K., Shi, Y., Zhao, M., Strande, J.L., Fu, X., Xu, H., Eis, A., Komorowski, R., Jensen, E.S., Tweddell, J.S., Rafiee, P., Gross, G.J.: Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischemia/reperfusion in rats. Cardiovasc Res. 77:44-53, 2008.
Anuradha, D., Gruenloh,S., Buonaccorsi,J., Zhang,R., Gross, G.J., Falck,J., Patel, P., Jacobs, E., Medhora, M.: Multiple antiapoptotic targets of the PI3K-Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia. Am J Physiol 294: H724-H735, 2008.
Strande, J.L., Hsu, A., Su, J., Fu, X., Gross, G.J., Baker, J.E.: Inhibiting protease-activated receptor 4 limits myocardial ischemia/reperfusion injury in rat hearts by unmasking adenosine signaling. J Pharmacol Exp Ther 324: 1045-1054,2008.
Gross, E.R., Hsu, A.K., Gross, G.J.: Delayed cardioprotection afforded by the glycogen synthase-3 inhibitor SB 216763 occurs via a KATP and MPTP dependent mechanism at reperfusion. Am J Physiol 294: H1497-H1500, 2008.