Am J Physiol Heart Circ Physiol 296: H233–H234, 2009;
doi:10.1152/ajpheart.00985.2008.
Letters To The Editor
Letter to the editor: “Zinc and cardioprotection: the missing link”
Mihaela M. Mocanu and Derek M. Yellon
The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, United Kingdom
Address 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: [email protected]).
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 leucinerich 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.
REFERENCES
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the liver. Semin Liver Dis 16: 31–38, 1996.
2. 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.
3. 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 inactiva-
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-3␤, 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.
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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 PhysiologyHeart 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 ischemiareperfusion 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-3␤. Phosphorylated GSK-3␤ is incapable of inducing cell death since the opening of the mitochondrial permeability transition pore (mPTP) will be prevented. Although the relationship between Akt-Gsk3␤-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
TO THE EDITOR:
Letters To The Editor
H234
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7.
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effect of zinc aspartate pretreatment on ischemia-reperfusion injury
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AJ. Zinc-induced PTEN protein degradation through the proteasome
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