Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during hypercholesterolemia

Miller, A. A. , De Silva, T. M., Judkins, C. P., Diep, H., Drummond, G. R. and Sobey, C. G. (2010) Augmented superoxide production by Nox2-containing NADPH oxidase causes cerebral artery dysfunction during hypercholesterolemia. Stroke, 41(4), pp. 784-789. (doi: 10.1161/STROKEAHA.109.575365) (PMID:20167907)

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Abstract

Background and Purpose— We tested the hypothesis that elevated superoxide production by Nox2-NADPH oxidase occurs in cerebral arteries during hypercholesterolemia and causes decreased nitric oxide function. Methods— Wild-type (WT), apolipoprotein E-deficient (ApoE−/−) and Nox2−/−/ApoE−/− mice were fed a high-fat diet for 7 to 14 weeks. Basal superoxide production by cerebral arteries was measured using L-012 (100 μmol/L)-enhanced chemiluminescence. Nitric oxide function was assessed in isolated middle cerebral arteries through the constrictor response to Nω-nitro-L-arginine methyl ester (L-NAME; 100 μmol/L). Western blotting was used to measure protein expression of Nox2, p47phox, endothelial nitric oxide synthase, and superoxide dismutases (1–3). Results— Morphology of cerebral arteries was similar in WT and ApoE−/− mice. In ApoE−/−, but not Nox2−/−/ApoE−/− mice, superoxide production by cerebral arteries was approximately 50% greater than in WT mice (P<0.05). Moreover, the magnitude of L-NAME-induced contractions of isolated middle cerebral arteries from ApoE−/− mice was <50% of that in WT mice (P<0.05), whereas in Nox2−/−/ApoE−/− mice, the contractile response was comparable to WT responses. In the presence of the superoxide scavenger, tempol (1 mmol/L), L-NAME-induced contractions of middle cerebral arteries were similar between WT and ApoE−/− mice. Expression of p47phox was approximately 2-fold higher in ApoE−/− versus WT mice, whereas Nox2, endothelial nitric oxide synthase, and superoxide dismutase isoforms were unchanged. Conclusions— Elevated superoxide production and reduced basal nitric oxide-mediated relaxation occur in cerebral arteries of hypercholesterolemic mice even in the absence of lesions. These changes appear to be exclusively due to increased activity of Nox2-NADPH oxidase, possibly through increased expression of its regulatory subunit p47phox.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Dr Alyson
Authors: Miller, A. A., De Silva, T. M., Judkins, C. P., Diep, H., Drummond, G. R., and Sobey, C. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Stroke
Publisher:American Heart Association
ISSN:0039-2499
ISSN (Online):1524-4628

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