Intracellular proatherogenic events and cell adhesion modulated by extracellular thiol/disulfide redox state.

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-kappaB, 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.