Intracellular Proatherogenic Events and Cell Adhesion Modulated by Extracellular Thiol/Disulfide Redox State
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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 (Eh) 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 Eh according to the Nernst equation. Eh 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 Eh from −150 mV (most reduced) to 0 mV (most oxidized). Compared with more reduced Eh, oxidized Eh of Cys/CySS stimulated H2O2 but not nitric oxide production, activated nuclear factor-κB, 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 Eh regulated thiol/disulfide redox states of extracellular membrane proteins and H2O2 production, indicating that variation in extracellular Eh is detected and signaled at the cell surface.
Conclusions— The extracellular thiol/disulfide Eh 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.
Received July 2, 2004; de novo received October 18, 2004; revision received January 13, 2005; accepted January 20, 2005.