This Article Full Text Full Text (PDF) All Versions of this Article: 111/22/2973    most recent CIRCULATIONAHA.104.515155v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Go, Y.-M. Articles by Jones, D. P. Search for Related Content PubMed PubMed Citation Articles by Go, Y.-M. Articles by Jones, D. P. Related Collections Cell signalling/signal transduction Other arteriosclerosis Other Vascular biology

(Circulation. 2005;111:2973-2980.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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

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

Correspondence to Dr Dean P. Jones, Department of Medicine, 205 Whitehead Research Center, Emory University, Atlanta, GA 30322. E-mail dpjones{at}emory.edu

Received July 2, 2004; de novo received October 18, 2004; revision received January 13, 2005; accepted January 20, 2005.

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

This article has been cited by other articles:

				J. M. Kleinhenz, D. J. Kleinhenz, S. You, J. D. Ritzenthaler, J. M. Hansen, D. R. Archer, R. L. Sutliff, and C. M. Hart Disruption of endothelial peroxisome proliferator-activated receptor-{gamma} reduces vascular nitric oxide production Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1647 - H1654. [Abstract] [Full Text] [PDF]

				T. Seefeldt, Y. Zhao, W. Chen, A. S. Raza, L. Carlson, J. Herman, A. Stoebner, S. Hanson, R. Foll, and X. Guan Characterization of a Novel Dithiocarbamate Glutathione Reductase Inhibitor and Its Use as a Tool to Modulate Intracellular Glutathione J. Biol. Chem., January 30, 2009; 284(5): 2729 - 2737. [Abstract] [Full Text] [PDF]

				S. S. Iyer, D. P. Jones, K. L. Brigham, and M. Rojas Oxidation of Plasma Cysteine/Cystine Redox State in Endotoxin-Induced Lung Injury Am. J. Respir. Cell Mol. Biol., January 1, 2009; 40(1): 90 - 98. [Abstract] [Full Text] [PDF]

				S. S. Iyer, A. M. Ramirez, J. D. Ritzenthaler, E. Torres-Gonzalez, S. Roser-Page, A. L. Mora, K. L. Brigham, D. P. Jones, J. Roman, and M. Rojas Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L37 - L45. [Abstract] [Full Text] [PDF]

				D. P. Jones Radical-free biology of oxidative stress Am J Physiol Cell Physiol, October 1, 2008; 295(4): C849 - C868. [Abstract] [Full Text] [PDF]

				S. Ashfaq, J. L. Abramson, D. P. Jones, S. D. Rhodes, W. S. Weintraub, W. C. Hooper, V. Vaccarino, R. W. Alexander, D. G. Harrison, and A. A. Quyyumi Endothelial Function and Aminothiol Biomarkers of Oxidative Stress in Healthy Adults Hypertension, July 1, 2008; 52(1): 80 - 85. [Abstract] [Full Text] [PDF]

				J. Zhu, S. Li, Z. M. Marshall, and A. R. Whorton A cystine-cysteine shuttle mediated by xCT facilitates cellular responses to S-nitrosoalbumin Am J Physiol Cell Physiol, April 1, 2008; 294(4): C1012 - C1020. [Abstract] [Full Text] [PDF]

				P. Giral, N. Jacob, C. Dourmap, B. Hansel, A. Carrie, E. Bruckert, X. Girerd, and M. J. Chapman Elevated Gamma-Glutamyltransferase Activity and Perturbed Thiol Profile Are Associated With Features of Metabolic Syndrome Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 587 - 593. [Abstract] [Full Text] [PDF]

				Y.-M. Go, P. J. Halvey, J. M. Hansen, M. Reed, J. Pohl, and D. P. Jones Reactive Aldehyde Modification of Thioredoxin-1 Activates Early Steps of Inflammation and Cell Adhesion Am. J. Pathol., November 1, 2007; 171(5): 1670 - 1681. [Abstract] [Full Text] [PDF]

				R. A Blanco, T. R Ziegler, B. A Carlson, P.-Y. Cheng, Y. Park, G. A Cotsonis, C. J. Accardi, and D. P Jones Diurnal variation in glutathione and cysteine redox states in human plasma Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1016 - 1023. [Abstract] [Full Text] [PDF]

				A. Ramirez, B. Ramadan, J. D. Ritzenthaler, H. N. Rivera, D. P. Jones, and J. Roman Extracellular cysteine/cystine redox potential controls lung fibroblast proliferation and matrix expression through upregulation of transforming growth factor-beta Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L972 - L981. [Abstract] [Full Text] [PDF]

				C. L. Anderson, S. S. Iyer, T. R. Ziegler, and D. P. Jones Control of extracellular cysteine/cystine redox state by HT-29 cells is independent of cellular glutathione Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1069 - R1075. [Abstract] [Full Text] [PDF]

				M. Y. Yeh, E. L. Burnham, M. Moss, and L. A. S. Brown Chronic Alcoholism Alters Systemic and Pulmonary Glutathione Redox Status Am. J. Respir. Crit. Care Med., August 1, 2007; 176(3): 270 - 276. [Abstract] [Full Text] [PDF]

				D. Giustarini, I. Dalle-Donne, S. Lorenzini, A. Milzani, and R. Rossi Age-related influence on thiol, disulfide, and protein-mixed disulfide levels in human plasma. J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2006; 61(10): 1030 - 1038. [Abstract] [Full Text] [PDF]

				S. Ashfaq, J. L. Abramson, D. P. Jones, S. D. Rhodes, W. S. Weintraub, W. C. Hooper, V. Vaccarino, D. G. Harrison, and A. A. Quyyumi The Relationship Between Plasma Levels of Oxidized and Reduced Thiols and Early Atherosclerosis in Healthy Adults J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1005 - 1011. [Abstract] [Full Text] [PDF]