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

Article

关键词: HUMAN PLASMA;    E-SELECTIN;    ENDOTHELIAL DYSFUNCTION;    OXIDATIVE STRESS;    GLUTATHIONE;    ATHEROSCLEROSIS;    ICAM-1;    ASSAY;    ASSOCIATION;    ACTIVATION;   

DOI  :  10.1161/CIRCULATIONAHA.104.515155

来源: SCIE

【 摘 要 】

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-kappa 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.

【 授权许可】

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