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CLINICAL RESEARCH: ATHEROSCLEROSIS

The Relationship Between Plasma Levels of Oxidized and Reduced Thiols and Early Atherosclerosis in Healthy Adults

Salman Ashfaq, MD, FACC^_*, Jerome L. Abramson, PhD, Dean P. Jones, PhD, Steven D. Rhodes, RN, William S. Weintraub, MD, FACC, W. Craig Hooper, PhD, Viola Vaccarino, MD, PhD, David G. Harrison, MD, FACC and Arshed A. Quyyumi, MD, FACC^,_*

^_* Division of Cardiology, University of Kansas School of Medicine, Wichita, Kansas
Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia
Centers for Disease Control and Prevention, Atlanta, Georgia

Manuscript received March 31, 2005; revised manuscript received September 13, 2005, accepted September 26, 2005.

^_* Reprint requests and correspondence: Dr. Arshed A. Quyyumi, Emory University School of Medicine, 1364 Clifton Road NE, Suite F606, Atlanta, Georgia 30322. (Email: aquyyum{at}emory.edu).

OBJECTIVES: The study investigated the relationship between biomarkers of oxidative stress and early atherosclerosis.

BACKGROUND: Oxidative stress is an important etiologic factor in the pathogenesis of vascular disease. We hypothesized that oxidative stress would predict early atherosclerosis in a relatively healthy population.

METHODS: One hundred fourteen healthy non-smokers, without known clinical atherosclerosis, had carotid intima-media thickness (IMT) measured using ultrasound. Oxidative stress was estimated by measuring plasma levels of: 1) glutathione (GSH), an important intracellular antioxidant thiol, its oxidized disulfide form (GSSG), and their redox state (E_h GSH/GSSG), and 2) cysteine (Cys), an important extracellular antioxidant thiol, its oxidized disulfide form cystine (CySS), and their redox state (E_hCys/CySS).

RESULTS: The univariate predictors of IMT were age, body mass index, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol, high-sensitivity C-reactive protein (hs-CRP), and Framingham risk score. Intima-media thickness was also higher in males and hypertensive subjects. Among the oxidative stress markers, GSH (r = –0.39, p < 0.0001), CySS (r = 0.18, p = 0.049), and E_h GSH/GSSG (r = 0.34, p < 0.0002) correlated with IMT. After adjusting for traditional risk factors and hs-CRP, only E_h GSH/GSSG remained an independent predictor of IMT. E_h GSH/GSSG predicted IMT in a manner that was both independent of and additive to Framingham risk score.

CONCLUSIONS: Glutathione redox state (E_h GSH/GSSG), an in vivo measure of intracellular oxidative stress, is an independent predictor for the presence of early atherosclerosis in an otherwise healthy population. This finding supports a role for oxidative stress in the pathogenesis of premature atherosclerosis, and its measurement may help in the early identification of asymptomatic subjects at risk of atherosclerotic disease.

Abbreviations and Acronyms   BMI = body mass index   CAD = coronary artery disease   Cys = cysteine   CySS = cystine   Eh Cys/CySS = cysteine redox state   Eh GSH/GSSG = glutathione redox state   GPx-1 = glutathione peroxidase 1   GSH = glutathione   GSSG = oxidized form of glutathione   hs-CRP = high-sensitivity C-reactive protein   IMT = intima-media thickness

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