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Evidence that nitric oxide inhibits vascular inflammation and superoxide production via a p47 phox ‐dependent mechanism in mice
Author(s) -
Harrison Craig B,
Drummond Grant R,
Sobey Christopher G,
Selemidis Stavros
Publication year - 2010
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2009.05317.x
Subject(s) - superoxide , nadph oxidase , nitric oxide , angiotensin ii , medicine , endocrinology , lucigenin , reactive oxygen species , chemistry , oxidase test , nitric oxide synthase , nox4 , biochemistry , blood pressure , enzyme
Summary 1. Regulation of vascular Nox2‐containing NADPH oxidase by p47 phox plays a pivotal role in the development of atherosclerotic lesions through the generation of superoxide. Reduced vascular nitric oxide (NO) bioavailability is a major contributing factor in the initiation of atherosclerosis because it leads to an increase in adhesion molecule expression for inflammatory cell recruitment into the vessel wall. 2. The aim of the present study was to examine whether the anti‐oxidant and anti‐inflammatory effects of endogenous NO involve inhibition of NADPH oxidase‐dependent superoxide production. 3. To inhibit endogenous NO production, male C57Bl/6 wild‐type (WT) mice or age‐matched p47 phox −/− mice were treated with N G ‐nitro‐ l‐ arginine methyl ester ( l ‐NAME; 100 mg/kg per day for 4 weeks). Blood pressure was measured weekly via the tail‐cuff method. Basal and phorbol dibutyrate (PDB)‐stimulated aortic superoxide production was detected using lucigenin‐ and L‐012‐enhanced chemiluminescence, respectively. Aortic Nox2, p47 phox and vascular cell adhesion molecule (VCAM)‐1 expression were measured with western blotting. Plasma angiotensin (Ang) II levels were determined by radioimmunoassay. 4. Compared with vehicle (tap water)‐treated WT mice ( n = 4), l ‐NAME‐treated WT mice had significantly higher systolic blood pressure (SBP; n = 6; P < 0.05) and basal and stimulated aortic extracellular superoxide production ( n = 6–8; P < 0.05), but lower plasma AngII levels ( P < 0.05). There was no change in Nox2 expression following l ‐NAME treatment of WT mice ( n = 6); however, significant increases in both aortic p47 phox ( n = 6; P < 0.05) and VCAM‐1 expression ( n = 6; P < 0.05) were observed. In p47 phox −/− mice, l ‐NAME treatment significantly increased SBP ( n = 3–4; P < 0.05), but failed to increase aortic superoxide production and VCAM‐1 expression. 5. In conclusion, endogenous NO suppresses vascular inflammation, via inhibition of p47 phox expression, leading to attenuation of NADPH oxidase‐dependent superoxide production.