title: Intracellular zinc release-activated ERK-dependent GSK-3β-p53 and Noxa-Mcl-1 signaling are both involved in cardiac ischemic-reperfusion injury.
abstract: Oxidative stress and nitrosative stress are both suggested to be involved in cardiac ischemia-reperfusion (I/R) injury. Using time-lapse confocal microscopy of cardiomyocytes and high-affinity O(2)(-•) and Zn(2+) probes, this study is the first to show that I/R, reactive oxygen species (ROS), and reactive nitrogen species (RNS) all cause a marked increase in the [O(2)(-•)](i), resulting in cytosolic and mitochondrial Zn(2+) release. Exposure to a cell-penetrating, high-affinity Zn(2+)(i) chelator, TPEN, largely abolished the Zn(2+)(i) release and markedly protected myocytes from I/R-, ROS-, RNS-, or Zn(2+)/K(+) (Zn(2+)(i) supplementation)-induced myocyte apoptosis for at least 24 h after TPEN removal. Flavonoids and U0126 (a MEK1/2 inhibitor) largely inhibited the myocyte apoptosis and the TPEN-sensitive I/R- or Zn(2+)(i) supplement-induced persistent extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, dephosphorylation of p-Ser9 on glycogen synthase kinase 3β (GSK-3β), and the translocation into and accumulation of p-Tyr216 GSK-3β and p53 in, the nucleus. Silencing of GSK-3β or p53 expression was cardioprotective, indicating that activation of the ERK-GSK-3β-p53 signaling pathway is involved in Zn(2+)-sensitive myocyte death. Moreover, the ERK-dependent Noxa-myeloid cell leukemia-1 (Mcl-1) pathway is also involved, as silencing of Noxa expression was cardioprotective and U0126 abolished both the increase in Noxa expression and in Mcl-1 degradation. Thus, acute upstream Zn(2+)(i) chelation at the start of reperfusion and the use of natural products, that is, flavonoids, may be beneficial in the treatment of cardiac I/R injury.
authors.affiliation: Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Lin
authors.forename: H-C
authors.initials: HC
authors.lastname: Tseng
authors.forename: R-F
authors.initials: RF
authors.lastname: Chen
authors.forename: W-P
authors.initials: WP
authors.lastname: Chen
authors.forename: M-J
authors.initials: MJ
authors.lastname: Su
authors.forename: K-M
authors.initials: KM
authors.lastname: Fang
authors.forename: M-L
authors.initials: ML
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002070:Butadienes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009570:Nitriles; C539472:Pmaip1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C113580:U 0126; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D015032:Zinc