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Letter to the editor: “Zinc and cardioprotection: the missing link”

2008; American Physical Society; Volume: 296; Issue: 1 Linguagem: Inglês

10.1152/ajpheart.00985.2008

1522-1539

Mihaela Mocanu, Derek M. Yellon,

Neuroscience and Neuropharmacology Research

LETTERS TO THE EDITORLetter to the editor: “Zinc and cardioprotection: the missing link”Mihaela M. Mocanu and Derek M. YellonMihaela M. Mocanu and Derek M. YellonPublished Online:01 Jan 2009https://doi.org/10.1152/ajpheart.00985.2008MoreFiguresReferencesRelatedInformationPDF (113 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: Zinc is an essential heavy metal with multiple pleiotropic roles in biological systems. With regard to cell survival, it has been shown that zinc can have an antiapoptotic effect, acting either as an inorganic ion or as a key cofactor of many organic molecules (4). There are a number of zinc transporter systems in all cell membranes (10). Recently, a putative zinc receptor has been suggested (5) that may play an important role in cell survival by activating a number of prosurvival kinases (5). Furthermore, the addition of zinc ions to ischemic tissue seems to increase survival and improve recovery in different organs (1, 9).In a recent issue of the American Journal of Physiology-Heart and Circulatory Physiology, Chanoit et al. (3) have demonstrated for the first time that the administration of ZnCl2 at the onset of reoxygenation, following a period of ischemia in H9C2 cells, resulted in a significant reduction of the ischemia-reperfusion injury. They further investigated the mechanism of this protection, and their data support the hypothesis that cardioprotection is due to increased Akt activation, which in turn phosphorylates GSK-3β. Phosphorylated GSK-3β is incapable of inducing cell death since the opening of the mitochondrial permeability transition pore (mPTP) will be prevented. Although the relationship between Akt-Gsk3β-mPTP and cardioprotection has been previously established (6, 8), a significant question remains unanswered in this study, i.e., what is the missing link between zinc and Akt? In other words, how can this inorganic molecule increase Akt phosphorylation and prevent cell death? In this regard, there is strong evidence that zinc acts directly on the initiation of the phosphatidylinositol 3-kinase (PI3K)-Akt signaling cascade by inhibiting the negative regulators of this pathway, namely the protein tyrosine phosphatases (PTPases). Zinc ions are known to modify the activity of PTPases by reacting with specific cysteine residues localized in the active site of these enzymes. This reaction inactivates the phosphatase and can trigger the process of ubiquitination and proteosomal degradation (2). The most important PTPase in the downregulation of the PI3K/Akt pathway is the phosphatase and tensin homolog on chromosome 10 (PTEN) (7). Interestingly, it has already been shown in human airway epithelial cells and rat lungs that treatment with zinc results in a significant reduction of the levels of PTEN, parallel with an increased Akt phosphorylation (11). In addition to PTEN, but to a lesser extent, other tyrosine protein phosphatases (e.g., Src homology 2-containing inositol phosphatase 2) or protein phosphatases (e.g., PH domain leucine-rich repeat protein phosphatase and protein phosphatase 2A) can modulate the activity of the PI3K/Akt pathway, a pathway that needs strict regulation to avoid initiating uncontrolled tissue growth (Fig. 1).It seems very likely that the protective effect of zinc on the PI3K/Akt pathway may be a result of the inhibition of regulatory phosphatases. In this respect, the cardioprotective role of zinc warrants further investigation. Fig. 1.Possible mechanism responsible for the activation of phosphatidylinositol 3-kinase (PI3K)/Akt by zinc. PI3K phosphorylates (activates) Akt, which, in turn, phosphorylates (inactivates) GSK-3β, and the mitochondrial permeability transition pore (mPTP) opening is blocked. Phosphatase and tensin homolog on chromosome 10 (PTEN) is the main negative regulator of this pathway and can be inactivated by the interaction with zinc ions. In addition, SHIP2, PP2A, and PHLPP may also affect this prosurvival pathway but with less impact. There are no data regarding their possible inactivation by zinc. Gray lines, not known impact on PI3K/Akt and cardioprotection; gray dotted lines, hypothetical interactions.Download figureDownload PowerPointAUTHOR NOTESAddress for reprint requests and other correspondence: D. M. Yellon, The Hatter Cardiovascular Inst., 67 Chenies Mews, Univ. College London Hospital and Medical School, London WC1E 6HX, UK (e-mail: d.yellon@ucl.ac.uk) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationREFERENCES1 Arora AS, Gores GJ. The role of metals in ischemia/reperfusion injury of the liver. Semin Liver Dis 16: 31–38, 1996.Crossref | PubMed | ISI | Google Scholar2 Barthel A, Ostrakhovitch EA, Walter PL, Kampkotter A, Klotz LO. Stimulation of phosphoinositide 3-kinase/Akt signaling by copper and zinc ions: mechanisms and consequences. Arch Biochem Biophys 463: 175–182, 2007.Crossref | PubMed | ISI | Google Scholar3 Chanoit G, Lee S, Xi J, Zhu M, McIntosh RA, Mueller RA, Norfleet EA, Xu Z. Exogenous zinc protects cardiac cells from reperfusion injury by targeting mitochondrial permeability transition pore through inactivation of glycogen synthase kinase-3β. Am J Physiol Heart Circ Physiol 295: H1227–H1233, 2008.Link | ISI | Google Scholar4 Chimienti F, Aouffen M, Favier A, Seve M. Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate. Curr Drug Targets 4: 323–338, 2003.Crossref | PubMed | ISI | Google Scholar5 Hershfinkel M, Silverman WF, Sekler I. 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J Biol Chem 278: 28258–28263, 2003.Crossref | PubMed | ISI | Google Scholar Cited ByZinc supplementation in rats impairs hippocampal-dependent memory consolidation and dampens post-traumatic recollection of stressful eventEuropean Neuropsychopharmacology, Vol. 26, No. 6Putative Key Role of Inositol Messengers in Endothelial Cells in PreeclampsiaInternational Journal of Endocrinology, Vol. 2016Increased reactive oxygen species production during reductive stress: The roles of mitochondrial glutathione and thioredoxin reductasesBiochimica et Biophysica Acta (BBA) - Bioenergetics, Vol. 1847, No. 6-7Zinc rescue of Akt2 gene deletion-linked murine cardiac dysfunction and pathological changes is metallothionein-dependentJournal of Molecular and Cellular Cardiology, Vol. 74Renal improvement by zinc in diabetic mice is associated with glucose metabolism signaling mediated by metallothionein and Akt, but not Akt2Free Radical Biology and Medicine, Vol. 68Diabetes-Induced Hepatic Pathogenic Damage, Inflammation, Oxidative Stress, and Insulin Resistance Was Exacerbated in Zinc Deficient Mouse Model12 December 2012 | PLoS ONE, Vol. 7, No. 12Zinc deficiency exacerbates diabetic down-regulation of Akt expression and function in the testis: essential roles of PTEN, PTP1B and TRB3The Journal of Nutritional Biochemistry, Vol. 23, No. 8Molecular mechanism underlying Akt activation in zinc-induced cardioprotectionSungRyul Lee, Guillaume Chanoit, Rachel McIntosh, David A. Zvara, and Zhelong Xu1 August 2009 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 297, No. 2 More from this issue > Volume 296Issue 1January 2009Pages H233-H234 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.00985.2008PubMed19116335History Published online 1 January 2009 Published in print 1 January 2009 Metrics Downloaded 148 times 10 CITATIONS 10 Total citations 0 Recent citations 1.84 Field Citation Ratio n/a Relative Citation Ratio publications10supporting1mentioning4contrasting0Smart Citations10140Citing PublicationsSupportingMentioningContrastingView CitationsSee how this article has been cited at scite.aiscite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.