The goal of this proposal is to elucidate the subcellular signaling pathways through which myocardium acutely adapts to ischemic stress. Such adaptation (termed ischemic preconditioning; IP) occurs in response to short, non-lethal episodes of myocardial ischemia and is manifest by a marked reduction in infarct size resulting from a subsequent lethal episode of ischemia. Thus, characterization of the underlying mechanisms of this adaptation will enhance understanding of irreversible myocyte injury and may lead to new and innovative clinical strategies in the therapy of acute myocardial infarction. Recent studies have implicated activation of protein kinases as important in adaptation to ischemic stress. However, to date, further analysis of these subcellular signaling pathways has been limited due to the complexity of intact animal models. In order to simplify analysis of these signaling pathways, the investigator has developed a model of in vitro ischemia in adult canine isolated ventricular myocytes. This proposal will test the hypothesis that myocardial ischemia initiates a signaling cascade which, working through activation of a sequence of protein kinases, results in cardioprotection through stabilization of the myocyte cytoskeleton. The proposed signaling pathways leading from myocardial ischemia to stabilization of the cytoskeleton will be dissected into a series of sequential events. In addition, the specific cytoskeletal targets stabilized by protein kinase activation will be evaluated. Experimental design will include morphologic, biochemical, and pharmacologic assessment of isolated myocytes subjected to myocardial ischemia.
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 |
Wei, Hongguang; Campbell, Wendy; Vander Heide, Richard S (2006) Heat shock-induced cardioprotection activates cytoskeletal-based cell survival pathways. Am J Physiol Heart Circ Physiol 291:H638-47 |
L'Ecuyer, Thomas; Sanjeev, Sanjeev; Thomas, Ronald et al. (2006) DNA damage is an early event in doxorubicin-induced cardiac myocyte death. Am J Physiol Heart Circ Physiol 291:H1273-80 |
L'Ecuyer, Thomas; Allebban, Zuhair; Thomas, Ronald et al. (2004) Glutathione S-transferase overexpression protects against anthracycline-induced H9C2 cell death. Am J Physiol Heart Circ Physiol 286:H2057-64 |
L'Ecuyer, T; Horenstein, M S; Thomas, R et al. (2001) Anthracycline-induced cardiac injury using a cardiac cell line: potential for gene therapy studies. Mol Genet Metab 74:370-9 |