title: Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke.
abstract: Matrix metalloproteinase-9 (MMP-9) and NADPH oxidase contribute to blood-brain barrier (BBB) disruption after ischemic stroke. We have previously shown that normobaric hyperoxia (NBO) treatment reduces MMP-9 and oxygen free radical generation in ischemic brain. In this study, we tested the hypothesis that NBO protects the BBB through inhibiting NADPH oxidase-mediated MMP-9 induction in transient focal cerebral ischemia. Male Sprague-Dawley rats (n = 69) were given NBO (95% O2) or normoxia (21% O2) during 90-min filament occlusion of the middle cerebral artery. Cerebral microvessels were isolated for analyzing MMP-9 and NADPH oxidase. BBB damage was non-invasively quantified with magnetic resonance imaging. In normoxic rats, both NADPH oxidase catalytic subunit gp91(phox) and MMP-9 expression were up-regulated in ischemic hemispheric microvessels after 90-min middle cerebral artery occlusion with 22.5 h reperfusion. Inhibition of NADPH oxidase with apocynin reduced the MMP-9 increase, indicating a causal link between NADPH oxidase-derived superoxide and MMP-9 induction. NBO treatment inhibited gp91(phox) expression, NADPH oxidase activity, and MMP-9 induction, which led to significantly less BBB damage and brain edema in the ischemic brain. These results suggest that gp91(phox) containing NADPH oxidase plays an important role in MMP-9 induction in ischemic BBB microvasculature, and that NBO treatment may attenuate MMP-9 induction and brain edema through inhibiting NADPH oxidase after transient cerebral ischemia.
authors.affiliation: College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
authors.forename: Wenlan
authors.initials: W
authors.lastname: Liu
authors.forename: Rohit
authors.initials: R
authors.lastname: Sood
authors.forename: Qingchuan
authors.initials: Q
authors.lastname: Chen
authors.forename: Unal
authors.initials: U
authors.lastname: Sakoglu
authors.forename: Jill
authors.initials: J
authors.lastname: Hendren
authors.forename: Ozdemir
authors.initials: O
authors.lastname: Cetin
authors.forename: Minoru
authors.initials: M
authors.lastname: Miyake
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002540:Cerebral Cortex / Q000098:blood supply; D062507:Claudin-5; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018496:Hyperoxia / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D013997:Time Factors
chemical_list: D000098:Acetophenones; D062507:Claudin-5; C491510:Cldn5 protein, rat; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C056165:acetovanillone; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9; D010100:Oxygen
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