Protecting myocytes from death is the best way to lower the mortality associated with myocardial infarction. Despite the description of many interventions capable of protecting myocytes from lethal injury, the potential promise of applying these interventions in the clinical arena has remained unfulfilled due in part to a lack of an integrative understanding of the heart's response to stress. One specific area that remains poorly understood is how myocardial stress is transduced across the sarcolemmal membrane into a protective signal at the level of the individual myocyte. The long term goal of our laboratory is to understand better the cellular and molecular mechanism(s) responsible for cardioprotective signaling at the level of the myocyte. The goal of this proposal is to demonstrate that signaling through a cytoskeletal based pathway can be activated to enhance myocyte survival against lethal ischemic injury. Focal adhesion kinase (FAK) has become recognized as a key mediator of cell survival signaling pathways in heart as well as other tissues. Recent data has demonstrated that an integrated signaling pathway exists involving FAK, the cytoskeleton, and other subcelluar signaling proteins that can be amplified or stimulated by stress;specifically ischemia/reperfusion, heat shock, and/or membrane receptor stimulation. This proposal will test the hypothesis that myocardial stress, either directly or through receptor activation, amplifies a cytoskeletal- based signaling cascade that results in prolonged myocyte survival.
Specific aims of the proposal will demonstrate that: 1) activation of FAK plays a central role in the response to extracellular myocardial stress;2) activation of the cytoskeletal-based pathway results in cardioprotection through activation of Akt;and 3) activation of the pathway occurs in intact hearts and may provide a common pathway for many described cardioprotective interventions. The specific cell survival proteins activated by stress will be evaluated in a series of integrated experiments utilizing recombinant adenoviruses, biochemical, and microscopic analysis of cultured cardiomyocytes, and will be confirmed in intact hearts using isolated perfused rat and mouse models of ischemic cell death. Characterization of the underlying mechanism(s) of this survival/adaptive pathway will enhance our understanding of irreversible injury and may lead to new and innovative clinical strategies in the therapy of acute myocardial infarction.
|Perricone, Adam J; Bivona, Benjamin J; Jackson, Fannie R et al. (2013) Conditional knockout of myocyte focal adhesion kinase abrogates ischemic preconditioning in adult murine hearts. J Am Heart Assoc 2:e000457|
|L'Ecuyer, Thomas J; Aggarwal, Sanjeev; Zhang, Jiang Ping et al. (2012) Effect of hypothermia on doxorubicin-induced cardiac myoblast signaling and cell death. Cardiovasc Pathol 21:96-104|
|Undyala, Vishnu; Terlecky, Stanley R; Vander Heide, Richard S (2011) Targeted intracellular catalase delivery protects neonatal rat myocytes from hypoxia-reoxygenation and ischemia-reperfusion injury. Cardiovasc Pathol 20:272-80|
|Schwartz Longacre, Lisa; Kloner, Robert A; Arai, Andrew E et al. (2011) New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation 124:1172-9|
|Vander Heide, Richard (2011) Clinically useful cardioprotection: ischemic preconditioning then and now. J Cardiovasc Pharmacol Ther 16:251-4|
|Wei, Hongguang; Vander Heide, Richard S (2010) Ischemic preconditioning and heat shock activate Akt via a focal adhesion kinase-mediated pathway in Langendorff-perfused adult rat hearts. Am J Physiol Heart Circ Physiol 298:H152-7|
|Wei, Hongguang; Vander Heide, Richard S (2008) Heat stress activates AKT via focal adhesion kinase-mediated pathway in neonatal rat ventricular myocytes. Am J Physiol Heart Circ Physiol 295:H561-8|