title: Zinc plays a critical role in the cardioprotective effect of postconditioning by enhancing the activation of the RISK pathway in rat hearts.
abstract: This study investigated if zinc plays a role in postconditioning-induced cardioprotection in rat hearts. Isolated rat hearts were subjected to 30 min regional ischemia followed by 2h of reperfusion. Postconditioning was elicited by 6 cycles of 10s reperfusion and 10s ischemia. Cytosolic zinc concentrations were measured with inductively coupled plasma optical emission spectroscopy (ICPOES). Infarct size was assessed by triphenyltetrazolium chloride staining. Cytosolic zinc concentrations were decreased dramatically upon reperfusion in the control hearts. In contrast, postconditioning increased cytosolic zinc levels at reperfusion. The anti-infarct effect of postconditioning was inhibited by the selective zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN). Postconditioning significantly increased phosphorylation levels of the reperfusion injury salvage kinases (RISK) including Akt (Ser(473)), extracellular signal-regulated kinase1/2 (ERK1/2) (Thr(202)/Tyr(204)), and glycogen synthase kinase-3β (GSK-3β) (Ser(9)) at reperfusion, which were nullified by TPEN. Postconditioning decreased the activity of protein phosphatase 2A (PP2A) in a zinc-dependent manner. Knockdown of the zinc transporter Zip2 inhibited the protective effect of postconditioning on hypoxia/reoxygenation injury in H9c2 cells. These results suggest that zinc plays an important role in the cardioprotective effect of postconditioning presumably by enhancing the activation of the RISK pathway. Zip2 and inactivation of PP2A by zinc may, at least in part, account for the activation of the RISK pathway.
authors.affiliation: Department of Physiology & Pathophysiology, Tianjin Medical University, Tianjin 300070, China; Department of Anesthesiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: zxu@tijmu.edu.cn.
authors.forename: Zhelong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Anesthesia and Pain Medicine, Chonnam National University, Guangju, South Korea.
authors.forename: Seokjae
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Anesthesia and Pain Medicine, Seoul National University Boramae Hospital, Seoul, South Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Huh
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002413:Cations, Divalent; D002614:Chelating Agents / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057775:Ischemic Postconditioning; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D027682:Cation Transport Proteins; D002413:Cations, Divalent; D002614:Chelating Agents; D005029:Ethylenediamines; C516872:Slc39a2 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D054648:Protein Phosphatase 2; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Ischemic postconditioning; PP2A; The RISK pathway; Zinc