Protective role of intracellular zinc in myocardial ischemia/reperfusion is associated with preservation of protein kinase C isoforms.
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, delta and epsilon, 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.
Karagulova
Gulnura
G
Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08903, and Molecular and Cellular Cardiology Program, Veterans Administration New York Harbor Healthcare System, New York, NY, USA.
Yue
Yuankun
Y
Moreyra
Abel
A
Boutjdir
Mohamed
M
Korichneva
Irina
I
D000818:Animals; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000737:chemistry; D051745:Protein Kinase C-delta / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015032:Zinc / Q000032:analysis / Q000502:physiology*
D008668:Metallothionein; C497260:Prkcd protein, rat; C497257:Prkce protein, rat; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D015032:Zinc; D013755:Tetradecanoylphorbol Acetate