Published Online
on March 1, 2004

A more recent version of this article appeared on March 16, 2004

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Submitted on February 13, 2003
Revised on October 30, 2003
Accepted on October 31, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: ajay.shah{at}kcl.ac.uk.

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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