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(Circulation. 2005;112:2677-2685.)
© 2005 American Heart Association, Inc.

Hypertension

Nox1 Is Involved in Angiotensin II–Mediated Hypertension

A Study in Nox1-Deficient Mice

Kuniharu Matsuno, MS; Hiroyuki Yamada, MD, PhD; Kazumi Iwata, MS; Denan Jin, MD, PhD; Masato Katsuyama, PhD; Masato Matsuki, MD, PhD; Shinji Takai, PhD; Kiyofumi Yamanishi, MD, PhD; Mizuo Miyazaki, MD, PhD; Hiroaki Matsubara, MD, PhD; Chihiro Yabe-Nishimura, MD, PhD

From the Department of Pharmacology (K.M., K.I., M.K., C.Y.-N.), Department of Cardiovascular Medicine (H.Y., H.M.), and Department of Dermatology (M. Matsuki, K.Y.), Kyoto Prefectural University of Medicine, Kyoto; and the Department of Pharmacology, Osaka Medical College (D.J., S.T., M. Miyazaki), Osaka, Japan. Drs Matsuki and Yamanishi are now at the Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Japan.

Correspondence to Chihiro Yabe-Nishimura, MD, PhD, Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. E-mail nchihiro{at}koto.kpu-m.ac.jp

Received July 6, 2005; revision received August 17, 2005; accepted August 18, 2005.

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.

Methods and 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.

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