Published Online
on May 31, 2005

A more recent version of this article appeared on June 7, 2005

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Submitted on July 2, 2004
Revised on January 13, 2005
Accepted on January 20, 2005

Intracellular Proatherogenic Events and Cell Adhesion Modulated by Extracellular Thiol/Disulfide Redox State

Young-Mi Go PhD and Dean P. Jones PhD^*

From the Department of Medicine, Divisions of Cardiology and Pulmonary, Emory University, Atlanta, Ga.

^* To whom correspondence should be addressed. E-mail: dpjones{at}emory.edu.

Background--Oxidative stress, a contributing factor to atherosclerosis, causes oxidation of biological thiols, which can be quantified in terms of the thiol/disulfide redox. The major thiol/disulfide redox couple in human plasma is cysteine (Cys) and its disulfide, cystine (CySS). Although atherosclerosis has previously been associated with Cys/CySS oxidation, whether oxidation of Cys/CySS contributes in a causal way to atherosclerosis development is not known. We examined the function of extracellular Cys/CySS redox potential (E_h) in the regulation of early events of atherosclerosis using cultured aortic endothelial cells and monocytes as a vascular model system.

Methods and Results--To determine the range of thiol/disulfide redox state in human plasma, we analyzed levels of Cys, CySS, glutathione (GSH), and glutathione disulfide (GSSG) and calculated E_h according to the Nernst equation. E_h of Cys/CySS and GSH/GSSG was -120 to -20 and -200 to -50 mV, respectively. To approximate this range, endothelial cells were exposed to initial E_h from -150 mV (most reduced) to 0 mV (most oxidized). Compared with more reduced E_h, oxidized E_h of Cys/CySS stimulated H₂O₂ but not nitric oxide production, activated nuclear factor-B, increased expression of adhesion molecules (intercellular adhesion molecule-1, platelet endothelial cell adhesion molecule-1, P-selectin), and stimulated monocytes binding to endothelial cells. Extracellular E_h regulated thiol/disulfide redox states of extracellular membrane proteins and H₂O₂ production, indicating that variation in extracellular E_h is detected and signaled at the cell surface.

Conclusions--The extracellular thiol/disulfide E_h of the Cys/CySS couple plays a key role in regulating early events of atherosclerosis and could be useful as a potential marker for vascular disease risk.

Key words: atherosclerosis • cell adhesion molecules • endothelium • inflammation • plasma

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