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Evidence that nitric oxide inhibits vascular inflammation and superoxide production via a p47phox-dependent mechanism in mice.
Clin Exp Pharmacol Physiol. 2010 Apr; 37(4):429-34.CE

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, Monash University, Melbourne, Victoria, Australia.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19843095

Citation

Harrison, Craig B., et al. "Evidence That Nitric Oxide Inhibits Vascular Inflammation and Superoxide Production Via a P47phox-dependent Mechanism in Mice." Clinical and Experimental Pharmacology & Physiology, vol. 37, no. 4, 2010, pp. 429-34.
Harrison CB, Drummond GR, Sobey CG, et al. Evidence that nitric oxide inhibits vascular inflammation and superoxide production via a p47phox-dependent mechanism in mice. Clin Exp Pharmacol Physiol. 2010;37(4):429-34.
Harrison, C. B., Drummond, G. R., Sobey, C. G., & Selemidis, S. (2010). Evidence that nitric oxide inhibits vascular inflammation and superoxide production via a p47phox-dependent mechanism in mice. Clinical and Experimental Pharmacology & Physiology, 37(4), 429-34. https://doi.org/10.1111/j.1440-1681.2009.05317.x
Harrison CB, et al. Evidence That Nitric Oxide Inhibits Vascular Inflammation and Superoxide Production Via a P47phox-dependent Mechanism in Mice. Clin Exp Pharmacol Physiol. 2010;37(4):429-34. PubMed PMID: 19843095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evidence that nitric oxide inhibits vascular inflammation and superoxide production via a p47phox-dependent mechanism in mice. AU - Harrison,Craig B, AU - Drummond,Grant R, AU - Sobey,Christopher G, AU - Selemidis,Stavros, Y1 - 2009/10/16/ PY - 2009/10/22/entrez PY - 2009/10/22/pubmed PY - 2010/8/7/medline SP - 429 EP - 34 JF - Clinical and experimental pharmacology & physiology JO - Clin Exp Pharmacol Physiol VL - 37 IS - 4 N2 - 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. SN - 1440-1681 UR - https://www.unboundmedicine.com/medline/citation/19843095/Evidence_that_nitric_oxide_inhibits_vascular_inflammation_and_superoxide_production_via_a_p47phox_dependent_mechanism_in_mice_ L2 - https://doi.org/10.1111/j.1440-1681.2009.05317.x DB - PRIME DP - Unbound Medicine ER -