Importance of NOX1 for angiotensin II-induced cerebrovascular superoxide production and cortical infarct volume following ischemic stroke.
Angiotensin II (Ang II) receptor blockade is beneficial in stroke, possibly due to attenuation of vascular oxidative stress. Mice genetically targeted for the superoxide-forming vascular NADPH oxidase subunit, NOX1, have a blunted hypertensive response to Ang II. We therefore hypothesised that NOX1 is mechanistically involved in Ang II-induced superoxide production by cerebral arteries, and potentially in stroke outcome. Superoxide production by cerebral arteries and brains from wild-type (WT) and NOX1 deficient (NOX1-KO) mice was measured using L-012-enhanced chemiluminescence. Ischemic stroke was induced by middle cerebral artery occlusion (MCAO; 0.5 h). Cerebral blood flow was measured using transcranial laser-Doppler flowmetry. After 24 h, neurological assessment was performed, mice were euthanised, and infarct and edema volumes were calculated. Basal superoxide was similar between WT and NOX1-KO in brain and cerebral artery homogenates, and in intact cerebral arteries. However, Ang II-stimulated increases in superoxide were approximately 70% smaller in rings from NOX1-KO versus WT. During MCAO, rCBF decreased by approximately 75% in both WT and NOX1-KO, and increased to similar levels in each strain immediately following reperfusion. No difference in neurological score, total or subcortical cerebral infarct volume or edema volume was observed between WT and NOX1-KO mice. However, cortical infarct volume (which was very modest in WT) was approximately 4-fold greater in brains of NOX1-KO versus WT. Thus, NOX1 is essential for superoxide production in large cerebral arteries in response to Ang II but not under basal conditions. Furthermore, NOX1 does not appear to contribute to stroke size, and it may limit cortical infarct development following cerebral ischemia.
Jackman
Katherine A
KA
Department of Pharmacology, Monash University, Clayton, Melbourne, Victoria 3800, Australia.
Miller
Alyson A
AA
Drummond
Grant R
GR
Sobey
Christopher G
CG
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D020521:Stroke / Q000378:metabolism* / Q000473:pathology; D013481:Superoxides / Q000378:metabolism*
D013481:Superoxides; D000804:Angiotensin II; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse