Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension.
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 beta-galactosidase (beta-gal) reporter gene (5x10(10) 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 ETA 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 beta-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 ETA receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D003900:Desoxycorticosterone; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009154:Mutation; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000378:metabolism*; D014161:Transduction, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D019010:Vascular Cell Adhesion Molecule-1; D013481:Superoxides; D003900:Desoxycorticosterone; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein