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.


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.
Go
Young-Mi
YM
Department of Medicine, Divisions of Cardiology and Pulmonary, Emory University, Atlanta, Ga 30322, USA.
Jones
Dean P
DP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000032:analysis; D002417:Cattle; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002478:Cells, Cultured; D018920:Coculture Techniques; D003545:Cysteine / Q000032:analysis / Q000378:metabolism*; D003553:Cystine / Q000032:analysis / Q000378:metabolism*; D004563:Electrochemistry; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012306:Risk; D013438:Sulfhydryl Compounds / Q000032:analysis; D015854:Up-Regulation
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D013438:Sulfhydryl Compounds; D003553:Cystine; D003545:Cysteine