Myocardial ischemia/reperfusion injury remains a major cause of morbidity and mortality worldwide. The discovery of ischemic preconditioning in the 1980's revealed the presence of a potent endogenous protective mechanism to increase ischemic tolerance in the heart that could be produced by brief periods of ischemia and reperfusion preceding a prolonged ischemia/reperfusion event. Ischemic postconditioning, evoked prior to reperfusion of ischemic tissue, has provided a clinically relevant target for cardiac protection. Numerous endogenous ligands and pharmaceuticals, includeing volatile anesthetics, produce pre and post conditioning in the heart, providing cardiac protection from myocardial ischemia/reperfusion injury. Despite significant insights gained over the last 30 years into mechanisms of cardiac protection, the full potential of harnessing pre and post conditioning in the clinical setting remains unfulfilled. Cardiac protection strategies in the clinical setting are limited by several factors including age and diseases related to aging. We have shown previously that the signaling molecules involved in cardioprotection need to function within caveolae and interact with caveolins to produce effective cardioprotection. We propose to test the novel hypothesis that loss of caveolin and disruption of precise cardioprotective signaling within caveolar microdomains results in the impaired volatile anesthetic-induced cardiac protection evident in aged animals and that re- expression of caveolin can restore volatile anesthetic-induced cardiac protective signaling that has been impaired by aging.
The aims of the grant will 1: Determine mechanisms involved the interaction of volatile anesthetics and caveolins at the sarcolemmal membrane in young and aged cardiac myocytes, 2: Determine the mechanisms involved in the interaction of volatile anesthetic-induced cardioprotective signaling molecules, caveolins and mitochondria in young and aged cardiac myocytes, and 3: Determine if overexpression of Cav-3 restores volatile anesthetic-induced cardiac protection in aged mice and human hearts. We will use state of the art molecular biology techniques, electron paramagnetic resonance technology, imaging technology, and physiological techniques in cardiac myocytes, human myocardium and clinically relevant models of I/R injury to focus on mechanism and produce important preclinical data to support the use of caveolins as novel therapeutics for aged veteran patients at risk of myocardial ischemia/reperfusion injury.
Ischemic heart disease is an increasing health concern in the veteran population with new links being drawn between heart disease and service related factors such as Agent Orange exposure and post-traumatic stress disorder. Currently, nearly 70% of male veterans are older than 55 years of age and the majority of female veterans are over 45 years of age (National Center for Veterans Analysis and Statistics report 2011). The current proposal aims to address the molecular mechanism involved in the interaction of volatile anesthetics with caveolins and caveolar microdomains and explore how this interaction may be impaired in the aged heart. We will utilize re-expression strategies to restore cardioprotective signaling in the aged heart. The work described in this proposal focuses on elucidating mechanisms to support the use of caveolins as novel therapeutic targets for veterans at risk of myocardial ischemia/reperfusion injury in the clinical setting.
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