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

doi:10.1016/j.cardiores.2007.05.015

Cardiovascular Research 2007 75(2):426-433; doi:10.1016/j.cardiores.2007.05.015

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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 mitochondrialoxidant damage by mobilizing intracellular free zinc (Zn²⁺).

Methods Zn²⁺ levels were determined by imaging enzymaticallyisolated adult rat cardiomyocytes loaded with Newport GreenDCF. Mitochondrial membrane potential ( ${Delta}$ ${Psi}$ _m) was assessed by imagingcardiomyocytes loaded with tetramethylrhodamine ethyl ester(TMRE).

Results S-nitroso-N-acetylpenicillamine (SNAP) dramaticallyincreased Zn²⁺, which was blocked by both ODQ and NS2028, twospecific inhibitors of guanylyl cyclase. The protein kinaseG (PKG) inhibitor KT5823 blocked the effect of SNAP while thePKG activator 8-Br-cGMP mimicked the action of SNAP, indicatingthat 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 K_ATPchannel opening may account for this effect. Since chelationof Zn²⁺ blocked the preventive effect of SNAP on H₂O₂-inducedloss of ${Delta}$ ${Psi}$ _m and exogenous zinc (1 µM ZnCl₂) preventeddissipation of ${Delta}$ ${Psi}$ _m, Zn²⁺ may play a critical role in the protectiveeffect of NO. The MEK (mitogen-activated protein kinase or extracellularsignal-regulated kinase) inhibitor PD98059 blocked the preventiveeffects of SNAP and zinc on ${Delta}$ ${Psi}$ _m, indicating that extracellularsignal-regulated kinase (ERK) mediates the protective effectof both these compounds on mitochondrial oxidant damage. A Westernblot analysis further showed that ZnCl₂ significantly enhancesphosphorylation of ERK, confirming the involvement of ERK inthe action of Zn²⁺.

Conclusions In isolated cardiomyocytes, NO mobilizes endogenouszinc by opening mitochondrial K_ATP channels through the cGMP/PKGpathway. In these cells, Zn²⁺ may be an important mediator ofthe action of NO on the mitochondrial death pathway.

KEYWORDS Nitric oxide; Mitochondria; Protein kinase G

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