title: Role of glycogen synthase kinase-3beta in cardioprotection.
abstract: Limitation of infarct size by ischemic/pharmacological pre- and postconditioning involves activation of a complex set of cell-signaling pathways. Multiple lines of evidence implicate the mitochondrial permeability transition pore (mPTP) as a key end effector of ischemic/pharmacological pre- and postconditioning. Increasing the ROS threshold for mPTP induction enhances the resistance of cardiomyocytes to oxidant stress and results in infarct size reduction. Here, we survey and synthesize the present knowledge about the role of glycogen synthase kinase (GSK)-3beta in cardioprotection, including pre- and postconditioning. Activation of a wide spectrum of cardioprotective signaling pathways is associated with phosphorylation and inhibition of a discrete pool of GSK-3beta relevant to mitochondrial signaling. Therefore, GSK-3beta has emerged as the integration point of many of these pathways and plays a central role in transferring protective signals downstream to target(s) that act at or in proximity to the mPTP. Bcl-2 family proteins and mPTP-regulatory elements, such as adenine nucleotide translocator and cyclophilin D (possibly voltage-dependent anion channel), may be the functional downstream target(s) of GSK-3beta. Gaining a better understanding of these interactions to control and prevent mPTP induction when appropriate will enable us to decrease the negative impact of the reperfusion-induced ROS burst on the fate of mitochondria and perhaps allow us to limit propagation of damage throughout and between cells and consequently, to better limit infarct size.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, Box 13, National Institute on Aging, NIH, Baltimore, Maryland 21224-6825, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Juhaszova
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Zorov
authors.forename: Yael
authors.initials: Y
authors.lastname: Yaniv
authors.forename: H Bradley
authors.initials: HB
authors.lastname: Nuss
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sollott
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D016923:Cell Death; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019194:Ischemic Preconditioning; D008322:Mammals; D008929:Mitochondria, Heart / Q000378:metabolism / Q000502:physiology; D009203:Myocardial Infarction / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology*; D015398:Signal Transduction
chemical_list: D002316:Cardiotonic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3