Published Online
on September 29, 2003

A more recent version of this article appeared on November 1, 2003

This Article Full Text (PDF) All Versions of this Article: 42/5/997    most recent 01.HYP.0000095980.43859.59v1 Alert me when this article is cited Alert me if a correction is posted 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 Li, L. Articles by Chen, A. F. Search for Related Content PubMed PubMed Citation Articles by Li, L. Articles by Chen, A. F. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information High Blood Pressure Related Collections Pathophysiology Gene expression Hypertension - basic studies Gene therapy Oxidant stress Mechanism of atherosclerosis/growth factors

Submitted on July 16, 2003
Revised on August 6, 2003

Endothelin-1 Stimulates Arterial VCAM-1 Expression Via NADPH Oxidase-Derived Superoxide in Mineralocorticoid Hypertension

Lixin Li; Yi Chu; Gregory D. Fink; John F. Engelhardt; Donald D. Heistad; and Alex F. Chen^*

From the Department of Pharmacology and Toxicology and the Neuroscience Program (L.L, G.D.F., A.F.C.), Michigan State University, East Lansing; and the Departments of Medicine (Y.C., J.F.E., D.D.H.) and Anatomy and Cell Biology (J.F.E.), University of Iowa, Iowa City.

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

Abstract--Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O₂^-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or -galactosidase (-gal) reporter gene (5x10¹⁰ plaque formation units [pfu]/mL), and the effect of transgene expression on O₂^- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ET_A receptor antagonist ABT-627 (3x10^-8 mol/L), NADPH oxidase inhibitor apocynin (10^-4 mol/L), or dominant negative Rac1 gene transfer. The levels of O₂^- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not -gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O₂^- from an ET_A receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.

Key words: endothelin • atherosclerosis • hypertension, mineralocorticoid • oxidative stress

This article has been cited by other articles:

				L. Li and B. Frei Prolonged Exposure to LPS Increases Iron, Heme, and p22phox Levels and NADPH Oxidase Activity in Human Aortic Endothelial Cells: Inhibition by Desferrioxamine Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 732 - 738. [Abstract] [Full Text] [PDF]

				A. E. Vendrov, Z. S. Hakim, N. R. Madamanchi, M. Rojas, C. Madamanchi, and M. S. Runge Atherosclerosis Is Attenuated by Limiting Superoxide Generation in Both Macrophages and Vessel Wall Cells Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2714 - 2721. [Abstract] [Full Text] [PDF]

				S. Bien, A. Riad, C. A. Ritter, M. Gratz, F. Olshausen, D. Westermann, M. Grube, T. Krieg, S. Ciecholewski, S. B. Felix, et al. The Endothelin Receptor Blocker Bosentan Inhibits Doxorubicin-Induced Cardiomyopathy Cancer Res., November 1, 2007; 67(21): 10428 - 10435. [Abstract] [Full Text] [PDF]

				K. A. Nath, L. V. d'Uscio, J. P. Juncos, A. J. Croatt, M. C. Manriquez, S. T. Pittock, and Z. S. Katusic An analysis of the DOCA-salt model of hypertension in HO-1-/- mice and the Gunn rat Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H333 - H342. [Abstract] [Full Text] [PDF]

				L. Li and B. Frei Iron Chelation Inhibits NF-{kappa}B-Mediated Adhesion Molecule Expression by Inhibiting p22phox Protein Expression and NADPH Oxidase Activity Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2638 - 2643. [Abstract] [Full Text] [PDF]

				D.-D. Chen and A. F. Chen CuZn Superoxide Dismutase Deficiency: Culprit of Accelerated Vascular Aging Process Hypertension, December 1, 2006; 48(6): 1026 - 1028. [Full Text] [PDF]

				Y. Sun, R. A. Ahokas, S. K. Bhattacharya, I. C. Gerling, L. D. Carbone, and K. T. Weber Oxidative stress in aldosteronism Cardiovasc Res, July 15, 2006; 71(2): 300 - 309. [Abstract] [Full Text] [PDF]

				Y. Zhou, S. Mitra, S. Varadharaj, N. Parinandi, J. L. Zweier, and N. A. Flavahan Increased Expression of Cyclooxygenase-2 Mediates Enhanced Contraction to Endothelin ETA Receptor Stimulation in Endothelial Nitric Oxide Synthase Knockout Mice Circ. Res., June 9, 2006; 98(11): 1439 - 1445. [Abstract] [Full Text] [PDF]

				D. M. Pollock Endothelin, Angiotensin, and Oxidative Stress in Hypertension Hypertension, April 1, 2005; 45(4): 477 - 480. [Full Text] [PDF]