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(Circulation. 2004;109:1307-1313.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Opposing Roles of p47^phox in Basal Versus Angiotensin II–Stimulated Alterations in Vascular O₂^- Production, Vascular Tone, and Mitogen-Activated Protein Kinase Activation

Jian-Mei Li, MD, PhD; Stephen Wheatcroft, MBBCh, MRCP; Lampson M. Fan; Mark T. Kearney, MD, MRCP; Ajay M. Shah, MD, FRCP

From the Department of Cardiology, Guy’s, King’s, and St Thomas’ School of Medicine, King’s College London, London, UK.

Correspondence to Professor Ajay M. Shah, Department of Cardiology, GKT School of Medicine, Bessemer Road, London SE5 9PJ, UK. E-mail ajay.shah{at}kcl.ac.uk

Received February 13, 2003; de novo received July 14, 2003; revision received October 30, 2003; accepted October 31, 2003.

Background— NADPH oxidase is a major source of vascular superoxide (O₂^-) production and is implicated in angiotensin II (Ang II)–induced oxidant stress. The p47^phox subunit plays an important role in Ang II–induced oxidase activation, but its role in basal oxidase activity and vascular function is unclear.

Methods and Results— Aortae from p47^phox-/- and matched wild-type (WT) mice (n=9/group) were incubated ex vivo with or without Ang II (200 nmol/L, 30 minutes) and then examined for (1) NADPH-dependent O₂^- production, (2) endothelium-dependent and -independent vascular relaxation, and (3) activation of mitogen-activated protein kinases (MAPKs). In the absence of Ang II, p47^phox-/- vessels had slightly but significantly higher (1.3±0.1-fold; P<0.05) NADPH-dependent O₂^- production than WT; impaired relaxation to acetylcholine (maximum 54±4% versus 80±3%; P<0.05), which was normalized to WT levels by the O₂^- scavenger tiron or by Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride, and increased basal phosphorylation of ERK1/2, p38MAPK, and JNK compared with WT. In WT aortae, Ang II increased NADPH-dependent O₂^- production (2.5±0.5-fold; P<0.05), impaired relaxation to acetylcholine (maximum 60±6% versus 80±3%; P<0.05), and increased ERK1/2, p38MAPK, and JNK phosphorylation (P<0.05). In contrast, Ang II failed to increase O₂^- production, impair acetylcholine responses, or increase MAPK activation in p47^phox-/- aortae.

Conclusions— p47^phox plays a complex dual role in the vasculature. It inhibits basal NADPH oxidase activity but is critical for Ang II–induced vascular dysfunction via activation of NADPH oxidase.

Key Words: angiotensin • free radicals • endothelium • vessels • nitric oxide

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