title: Oxidative stress and endothelial dysfunction in aortas of aged spontaneously hypertensive rats by NOX1/2 is reversed by NADPH oxidase inhibition.
abstract: Arterial hypertension is associated with increased levels of reactive oxygen species, which may scavenge endothelium-derived NO and thereby diminish its vasorelaxant effects. However, the quantitatively relevant source of reactive oxygen species is unclear. Thus, this potential pathomechanism is not yet pharmacologically targetable. Several enzymatic sources of reactive oxygen species have been suggested: uncoupled endothelial NO synthase, xanthine oxidase, and NADPH oxidases. Here we show that increased reactive oxygen species formation in aortas of 12- to 14-month-old spontaneously hypertensive rats versus age-matched Wistar Kyoto rats is inhibited by the specific NADPH oxidase inhibitor VAS2870 but neither by the xanthine oxidase inhibitor oxypurinol nor the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester. NADPH oxidase activity, as well as protein expression of its catalytic subunits, NOX1 and NOX2, was increased in the aortas of spontaneously hypertensive rats, whereas the expression of NOX4 protein, the most abundant NOX isoform, was not significantly changed. Impaired acetylcholine-induced relaxation of spontaneously hypertensive rat aortas was significantly improved by VAS2870. In conclusion, NOX1 and NOX2 but not NOX4 proteins are increased in aged spontaneously hypertensive rat aortas. Importantly, these NOX isoforms, in particular, ectopic expression of NOX1 in endothelial cells, appear to affect vascular function in an NADPH oxidase inhibitor-reversible manner. NADPH oxidases may, thus, be a novel target for the treatment of systemic hypertension.
authors.affiliation: Department of Pharmacology, Maastricht University, PO Box 616, NL-6200 MD Maastricht, The Netherlands.
authors.forename: Sven
authors.initials: S
authors.lastname: Wind
authors.forename: Knut
authors.initials: K
authors.lastname: Beuerlein
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Armitage
authors.forename: Ashraf
authors.initials: A
authors.lastname: Taye
authors.forename: Arun H S
authors.initials: AH
authors.lastname: Kumar
authors.forename: Daniel
authors.initials: D
authors.lastname: Janowitz
authors.forename: Christina
authors.initials: C
authors.lastname: Neff
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Kirstin
authors.initials: K
authors.lastname: Wingler
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D005455:Fluorescent Antibody Technique; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; D014969:Xanthine Oxidase; D009247:NADH, NADPH Oxidoreductases; C500593:Cybb protein, rat; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C000614712:NOX1 protein, rat; D000109:Acetylcholine