Protective Role of Intracellular Zinc in Myocardial Ischemia/Reperfusion Is Associated with Preservation of Protein Kinase C Isoforms

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, ␦ and , 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.

Intracellular zinc release-activated ERK-dependent GSK-3β–p53 and Noxa–Mcl-1 signaling are both involved in cardiac ischemic-reperfusion injury

“…TSQ is a non-acetoxymethyl ester Zn 2 þ indicator. Although it is a very sensitive Zn 2 þ probe (Kd ¼ 10 nM), 10 it does not depend on cleavage of an acetoxymethyl ester group for uptake and fluorescence, so intracellular TSQ leaks out within a few minutes and it is not possible to measure sequential fluorescent changes. 30 The rest of recording detail, please see Supplemental Methods.…”

“…7,8 When a non-acetoxymethyl ester Zn 2 þ indicator, TSQ, is applied to the heart tissues, reperfusion induces a decrease, rather than an increase, in [Zn 2 þ ] i levels. 9,10 When a mixture of Zn 2 þ and the Zn 2 þ ionophore pyrithione is added to the reperfusion solution for 20-30 min, cardioprotection occurs, and two mechanisms have been suggested, namely preservation of protein kinase C (PKC) isoforms and inhibition of mitochondrial metabolism. 9,10 The molecular mechanism for the effect of the [Zn 2 þ ] i increase on cell survival is therefore still debatable.…”

From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation

“…Others have also reported a Zn 2+ supplement to be cardioprotective in mice with streptozocin-induced diabetic cardiomyopathy, in rat hearts with ischemia/reperfusion injury or following isoproterenol administration. 62,[90][91][92] Coupled Ca 2+ and Zn 2+ dyshomeostasis. The dyshomeostasis of extra-and intracellular Ca 2+ and Zn 2+ that accompanies ALDOST contributes to a deleterious, but reversible disequilibrium between pro-and antioxidants.…”

Morphine prevents the mitochondrial permeability transition pore opening through NO/cGMP/PKG/Zn2+/GSK-3β signal pathway in cardiomyocytes

“…Zn 2ϩ has been demonstrated to prevent apoptosis both in vitro and in vivo models (28,41). Recently, it has been reported that the treatment of isolated rat hearts at reperfusion with Zn 2ϩ ionophore pyrithione induces cardioprotection against ischemiareperfusion injury (23). Recent studies from our laboratory have shown that Zn 2ϩ modulates oxidant-induced mPTP opening in isolated rat cardiomyocytes (20) and prevents reperfusion injury by targeting mPTP in cardiac H9c2 cells (4).…”