This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 115/5/627    most recent CIRCULATIONAHA.106.657486v1 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 Silver, A. E. Articles by Seals, D. R. Search for Related Content PubMed PubMed Citation Articles by Silver, A. E. Articles by Seals, D. R. Pubmed/NCBI databases Medline Plus Health Information Obesity Related Collections Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Circulation. 2007;115:627-637.)
© 2007 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to Douglas R. Seals, Department of Integrative Physiology, University of Colorado at Boulder, UCB 354, Boulder, CO 80309. E-mail seals{at}colorado.edu

Received August 9, 2006; accepted November 8, 2006.

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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				A. J. Donato, L. B. Gano, I. Eskurza, A. E. Silver, P. E. Gates, K. Jablonski, and D. R. Seals Vascular endothelial dysfunction with aging: endothelin-1 and endothelial nitric oxide synthase Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H425 - H432. [Abstract] [Full Text] [PDF]

				G. L. Pierce, L. A. Lesniewski, B. R. Lawson, S. D. Beske, and D. R. Seals Nuclear Factor-{kappa}B Activation Contributes to Vascular Endothelial Dysfunction via Oxidative Stress in Overweight/Obese Middle-Aged and Older Humans Circulation, March 10, 2009; 119(9): 1284 - 1292. [Abstract] [Full Text] [PDF]

				N. Bashan, J. Kovsan, I. Kachko, H. Ovadia, and A. Rudich Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species Physiol Rev, January 1, 2009; 89(1): 27 - 71. [Abstract] [Full Text] [PDF]

				D. T. Smith, L. J. Carr, C. Dorozynski, and C. Gomashe Internet-delivered lifestyle physical activity intervention: limited inflammation and antioxidant capacity efficacy in overweight adults J Appl Physiol, January 1, 2009; 106(1): 49 - 56. [Abstract] [Full Text] [PDF]

				J. Muller-Ehmsen, D. Braun, T. Schneider, R. Pfister, N. Worm, K. Wielckens, C. Scheid, P. Frommolt, and M. Flesch Decreased number of circulating progenitor cells in obesity: beneficial effects of weight reduction Eur. Heart J., June 2, 2008; 29(12): 1560 - 1568. [Abstract] [Full Text] [PDF]

				S. Jelic, M. Padeletti, S. M. Kawut, C. Higgins, S. M. Canfield, D. Onat, P. C. Colombo, R. C. Basner, P. Factor, and T. H. LeJemtel Inflammation, Oxidative Stress, and Repair Capacity of the Vascular Endothelium in Obstructive Sleep Apnea Circulation, April 29, 2008; 117(17): 2270 - 2278. [Abstract] [Full Text] [PDF]

				G. P. Van Guilder, B. L. Stauffer, J. J. Greiner, and C. A. DeSouza Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1685 - H1692. [Abstract] [Full Text] [PDF]

				D. Gozal and L. Kheirandish-Gozal Cardiovascular Morbidity in Obstructive Sleep Apnea: Oxidative Stress, Inflammation, and Much More Am. J. Respir. Crit. Care Med., February 15, 2008; 177(4): 369 - 375. [Abstract] [Full Text] [PDF]

				D. Onat, S. Jelic, A. M. Schmidt, J. Pile-Spellman, S. Homma, M. Padeletti, Z. Jin, T. H. Le Jemtel, P. C. Colombo, and L. Feng Vascular endothelial sampling and analysis of gene transcripts: a new quantitative approach to monitor vascular inflammation J Appl Physiol, November 1, 2007; 103(5): 1873 - 1878. [Abstract] [Full Text] [PDF]

				A. J. Donato, I. Eskurza, A. E. Silver, A. S. Levy, G. L. Pierce, P. E. Gates, and D. R. Seals Direct Evidence of Endothelial Oxidative Stress With Aging in Humans: Relation to Impaired Endothelium-Dependent Dilation and Upregulation of Nuclear Factor-{kappa}B Circ. Res., June 8, 2007; 100(11): 1659 - 1666. [Abstract] [Full Text] [PDF]