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Cardiovascular Research 2007 75(2):426-433; doi:10.1016/j.cardiores.2007.05.015
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Copyright © 2007, European Society of Cardiology

NO mobilizes intracellular Zn2+ via cGMP/PKG signaling pathway and prevents mitochondrial oxidant damage in cardiomyocytes

Youngho Jang, Huihua Wang, Jinkun Xi, Robert A. Mueller, Edward A. Norfleet and Zhelong Xu*

Department of Anesthesiology, CB#7010 University of North Carolina at Chapel Hill Chapel Hill, NC 27599-7010, United States

* Corresponding author. Tel.: +1 919 843 4174; fax: +1 919 843 3805. zxu{at}aims.unc.edu

Objective Our aim was to determine if NO prevents mitochondrial oxidant damage by mobilizing intracellular free zinc (Zn2+).

Methods Zn2+ levels were determined by imaging enzymatically isolated adult rat cardiomyocytes loaded with Newport Green DCF. Mitochondrial membrane potential ({Delta}{Psi}m) was assessed by imaging cardiomyocytes loaded with tetramethylrhodamine ethyl ester (TMRE).

Results S-nitroso-N-acetylpenicillamine (SNAP) dramatically increased Zn2+, which was blocked by both ODQ and NS2028, two specific inhibitors of guanylyl cyclase. The protein kinase G (PKG) inhibitor KT5823 blocked the effect of SNAP while the PKG activator 8-Br-cGMP mimicked the action of SNAP, indicating that the cGMP/PKG pathway is responsible for the effect of SNAP. The increased Zn2+ was prevented by 5-hydroxydecanoate (5HD) but was mimicked by diazoxide, implying that mitochondrial KATP channel opening may account for this effect. Since chelation of Zn2+ blocked the preventive effect of SNAP on H2O2-induced loss of {Delta}{Psi}m and exogenous zinc (1 µM ZnCl2) prevented dissipation of {Delta}{Psi}m, Zn2+ may play a critical role in the protective effect of NO. The MEK (mitogen-activated protein kinase or extracellular signal-regulated kinase) inhibitor PD98059 blocked the preventive effects of SNAP and zinc on {Delta}{Psi}m, indicating that extracellular signal-regulated kinase (ERK) mediates the protective effect of both these compounds on mitochondrial oxidant damage. A Western blot analysis further showed that ZnCl2 significantly enhances phosphorylation of ERK, confirming the involvement of ERK in the action of Zn2+.

Conclusions In isolated cardiomyocytes, NO mobilizes endogenous zinc by opening mitochondrial KATP channels through the cGMP/PKG pathway. In these cells, Zn2+ may be an important mediator of the action of NO on the mitochondrial death pathway.

KEYWORDS Nitric oxide; Mitochondria; Protein kinase G


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