Abstract
The recent discovery of zinc signals and their essential role in the redox signaling network implies that zinc homeostasis and the function of zinc-containing proteins are probably altered as a result of oxidative stress, suggesting new targets for pharmacological intervention. We hypothesized that the level of intracellular labile zinc is changed in hearts subjected to ischemia/reperfusion (I/R) and investigated whether the maintenance of myocardial zinc status protected heart functions. Using fluorescent imaging, we demonstrated decreased levels of labile zinc in the I/R hearts. Phorbol 12-myristate 13-acetate, a known trigger of zinc release, liberated zinc ions in control hearts but failed to produce any increase in zinc levels in the I/R rat hearts. Adding the zinc ionophore pyrithione at reperfusion improved myocardial recovery up to 100% and reduced the incidence of arrhythmias more than 2-fold. This effect was dose-dependent, and high concentrations of zinc were toxic. Adding membrane-impermeable zinc chloride was ineffective. Hearts from rats receiving zinc pyrithione supplements in their diet fully recovered from I/R. The recovery was associated with the prevention of degradation of the two protein kinase C isoforms, δ and ϵ, during I/R. In conclusion, our results suggest a protective role of intracellular zinc in myocardial recovery from oxidative stress imposed by I/R. The data support the potential clinical use of zinc ionophores in the settings of acute redox stress in the heart.
Footnotes
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This study was supported by the National Institutes of Health (Grants RO1 HL77390-01 to I.K. and RO1 HL-077494 to M.B.) and by a Veterans Administration Merit grant (to M.B.).
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This study was presented in abstract form at the Third Annual Symposium of the American Heart Association Council on Basic Cardiovascular Sciences: Translation of Basic Insights into Clinical Practice, 2006 Jul 31–Aug 3; Keystone, CO [Karagulova G, Yankun Yue, Boutjdr M, Moreyra AE, and Korichneva I (2006) Intracellular Zn protects isolated rat hearts from ischemia/reperfusion injury: involvement of protein kinase C. Circ Res99:136].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.119644.
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ABBREVIATIONS: MT, metallothionein; PKC, protein kinase C; PMA, phorbol-12myristate-13acetate; I/R, ischemia/reperfusion; TSQ, N-(6-methoxy)-8-quinolyl-toluenesulfonamide; TPEN, N,N,N′,N′-tetrakis-(2-pyridylmethyl)ethylenediamine; LVDP, left ventricular developed pressure; HR, heart rate; dP/dT, maximal time rate of change of pressure; LVDP × HR, rate pressure product; VF, ventricular fibrillation; VT, ventricular tachycardia; OCT, optimal cutting temperature; RPP, rate pressure product.
- The American Society for Pharmacology and Experimental Therapeutics
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