Nox1 is involved in angiotensin II-mediated hypertension: a study in Nox1-deficient mice.
BACKGROUND
Increased production of reactive oxygen species (ROSs) by angiotensin II (Ang II) is involved in the initiation and progression of cardiovascular diseases. NADPH oxidase is a major source of superoxide generated in vascular tissues. Although Nox1 has been identified in vascular smooth muscle cells as a new homolog of gp91phox (Nox2), a catalytic subunit of NADPH oxidase, the pathophysiological function of Nox1-derived ROSs has not been fully elucidated. To clarify the role of Nox1 in Ang II-mediated hypertension, we generated Nox1-deficient (-/Y) mice.


RESULTS
No difference in the baseline blood pressure was observed between Nox1(+/Y) and Nox1(-/Y). Infusion of Ang II induced a significant increase in mean blood pressure, accompanied by augmented expression of Nox1 mRNA and superoxide production in the aorta of Nox1(+/Y), whereas the elevation in blood pressure and production of superoxide were significantly blunted in Nox1(-/Y). Conversely, the infusion of pressor as well as subpressor doses of Ang II did elicit marked hypertrophy in the thoracic aorta of Nox1(-/Y) similar to Nox1(+/Y). Administration of a nitric oxide synthase inhibitor (L-NAME) to Nox1(+/Y) did not affect the Ang II-mediated increase in blood pressure, but it abolished the suppressed pressor response to Ang II in Nox1(-/Y). Finally, endothelium-dependent relaxation and the level of cGMP in the isolated aorta were preserved in Nox1(-/Y) infused with Ang II.


CONCLUSIONS
A pivotal role for ROSs derived from Nox1/NADPH oxidase was suggested in the pressor response to Ang II by reducing the bioavailability of nitric oxide.
Matsuno
Kuniharu
K
Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Yamada
Hiroyuki
H
Iwata
Kazumi
K
Jin
Denan
D
Katsuyama
Masato
M
Matsuki
Masato
M
Takai
Shinji
S
Yamanishi
Kiyofumi
K
Miyazaki
Mizuo
M
Matsubara
Hiroaki
H
Yabe-Nishimura
Chihiro
C
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D000074624:NADPH Oxidase 1; D009569:Nitric Oxide / Q000493:pharmacokinetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D000804:Angiotensin II; D009569:Nitric Oxide; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse