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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 17, 2009; DOI: 10.1124/jpet.108.149997

0022-3565/09/3292-649-656$20.00
JPET 329:649-656, 2009
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CARDIOVASCULAR

Role of Glutaredoxin-Mediated Protein S-Glutathionylation in Cellular Nitroglycerin ToleranceFormula

Pei-Suen Tsou, Vamsi Addanki, Jessica A. Haas, Nathaniel A. Page, and Ho-Leung Fung

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York

We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [35S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to several major observations associated with nitrate tolerance, namely, reduced cGMP accumulation, PSSG formation, superoxide accumulation, and the attenuation of these events by vitamin C. Aortic S-glutathionylated proteins increased approximately 3-fold in rats made tolerant in vivo to NTG and showed significant negative correlation with vascular responsiveness ex vivo. NTG incubation in EA.hy926 endothelial cells and LLC-PK1 cells led to increased S-glutathionylation and activity of p21ras, a known mediator of cellular signaling. These results indicate that the hallmark events of NTG tolerance, such as reduced bioactivation and redox signaling, are associated with GRX-dependent protein deglutathionylation.

Received for publication December 17, 2008
Accepted February 13, 2009.

Address correspondence to: Dr. Ho-Leung Fung, Hochstetter 547, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260-1200. E-mail: hlfung{at}buffalo.edu






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