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Cellular and Molecular Mechanisms of Metabolic Adaptation to Myocardial Ischemia .
Maintenance of cardiac energetics requires the precise regulation of energy generating and consuming pathways in the heart and is required for contractile function and cellular viability. Significant alterations in cardiac energetics occur during ischemia-reperfusion and result in injury and apoptosis in the heart. Our laboratory is studying the cellular and molecular mechanisms responsible for the metabolic adaptation to the hypoxic stress associated with myocardial ischemia, recently focusing on the AMP-activated protein kinase (AMPK) signaling pathway. AMPK has emerged as a key regulator of glucose transporter (GLUT4) translocation, cellular metabolism, ion channel activity and cell survival and apoptosis in the heart. Combining physiologic models of ischemia with cellular and molecular techniques, we are interested in the cardio-protective action of AMPK in the heart, the upstream mechanisms of AMPK activation and its downstream interaction with other signaling pathways, as well as the discovery of novel AMPK targets. The use of transgenic mouse models allows us to dissect out the role of AMPK and other signaling pathways in the intact perfused heart and in vivo. The goal of this research is to develop novel strategies to protect the heart against injury during myocardial ischemia.
Recent selected publications:
Coven DL, Hu X, Cong L, Bergeron R, Hardie GH, Shulman GI, Young LH. Physiologic role of AMP-activated protein kinase in the heart: graded activation during exercise. Am J Physiol Endocrinol Metab 2003; 285:E629-E636.
Young LH. Insulin resistance and the effects of thiazolidinediones on cardiac metabolism. Am J Med 2003; 115:75S-80S.
Russell RR, Li J, Coven D, Pypaert M, Zechner C, Palmeri M, Giordano F, Mu J, Birnbaum M, Young LH. AMP-activated protein kinase mediates ischemic glucose uptake and prevents post-ischemic cardiac dysfunction, apoptosis and injury. J Clin Invest 2004; 114:495-503 (featured article with editorial comment).
Li J, Hu X, Selvakumar P, Russell IR, Cushman SW, Holman GD, Young LH. Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol Endocrinol Metab 2004; 287:E834-E841.
Baron S, Li J, Russell RR, Neumann D, Miller EJ, Tuerk R, Wallimann T, Hurley R, Witters LA, Young LH. Dual mechanisms regulating AMPK kinase action in the ischemic heart. Circulation Research 2005; 96:337-345.
Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR, Young LH. AMPK activates p38 MAP kinase by increasing its recruitment to TAB1 in the ischemic heart. Circulation Research 2005; 97:872-879.
Young LH, Li J, Russell RR. AMP-activated protein kinase: a key stress signaling pathway in the heart. Trends in Cardiovascular Medicine 2005; 15:110-118.
Miller EJ, Young LH. AMPK-a pivotal rheostat in the control of cardiac metabolism. Drug Discovery Today: Disease Mechanisms 2005; 2:93-100.
Li J, Coven DL, Miller EJ, Hu X, Young ME, Carling D, Sinusas AJ, Young LH. Activation of AMPK alpha- and gamma- isoform complexes in the intact ischemic rat heart . Am J Physiol Heart Circ Physiol 2006; in press.
lawrence.young@yale.edu
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