Published Online
on January 22, 2007

A more recent version of this article appeared on February 6, 2007

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Submitted on August 9, 2006
Accepted on November 8, 2006

Overweight and Obese Humans Demonstrate Increased Vascular Endothelial NAD(P)H Oxidase-p47^phox Expression and Evidence of Endothelial Oxidative Stress

Annemarie E. Silver PhD, Stacy D. Beske PhD, Demetra D. Christou PhD, Anthony J. Donato PhD, Kerrie L. Moreau PhD, Iratxe Eskurza MD, PhD, Phillip E. Gates PhD, and Douglas R. Seals PhD^*

From the Department of Integrative Physiology (A.E.S., S.D.B., D.D.C., A.J.D., K.L.M., I.E., P.E.G., D.R.S.), University of Colorado, Boulder; and Department of Medicine (D.R.S., K.L.M.), Divisions of Cardiology and Geriatric Medicine, University of Colorado Health Sciences Center, Denver.

^* To whom correspondence should be addressed. E-mail: seals{at}colorado.edu.

Background--Obesity may alter vascular endothelial cell protein expression (VECPE) of molecules that influence susceptibility to atherosclerosis.

Methods and Results--Quantitative immunofluorescence was performed on vascular endothelial cells collected from 108 men and women free of clinical disease who varied widely in adiposity (body mass index 18.4 to 36.7 kg/m²; total body fat 5.8 to 55.0 kg; waist circumference: 63.0 to 122.9 cm). All 3 expressions of adiposity were positively associated with VECPE of the oxidant enzyme subunit NAD(P)H oxidase-p47^phox (part correlation coefficient [r_part] 0.22 to 0.24, all P<0.05) and the antioxidant enzyme catalase (r_part=0.71 to 0.75, all P<0.001). Total body fat was positively associated with VECPE of nitrotyrosine (r_part=0.36, P=0.003), a marker of protein oxidation, and, in men, with Ser1177-phosphorylated endothelial nitric oxide synthase (r_part=0.46, P=0.02), an activated form of endothelial nitric oxide synthase. Overweight/obese subjects (body mass index 25 kg/m²) had 35% to 130% higher VECPE of NAD(P)H oxidase-p47^phox, nitrotyrosine, catalase, and the cytosolic antioxidant CuZn superoxide dismutase (all P<0.05), as well as a 56% greater VECPE of the potent local vasoconstrictor endothelin-1 (P=0.05) than normal-weight subjects (body mass index <25 kg/m²). Nuclear factor-B protein expression was 60% to 100% greater in the most obese adults than in the leanest adults (P0.01). These relations were independent of sex but were selectively reduced after accounting for the influence of plasma C-reactive protein, fasting glucose-insulin metabolism, or serum triglycerides.

Conclusions--Compared with their normal-weight peers, overweight and obese adults demonstrate increased vascular endothelial expression of NAD(P)H oxidase-p47^phox and evidence of endothelial oxidative stress, with selective compensatory upregulation of antioxidant enzymes and Ser1177-phosphorylated endothelial nitric oxide synthase. Endothelin-1 and nuclear factor-B protein expression also appear to be elevated in obese compared with lean adults. These findings may provide novel insight into the molecular mechanisms linking obesity to increased risk of clinical atherosclerotic diseases in humans.

Key words: endothelium • obesity • endothelin • free radicals • antioxidants • atherosclerosis

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