Normobaric hyperoxia inhibits NADPH oxidase-mediated matrix metalloproteinase-9 induction in cerebral microvessels in experimental stroke.
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.
Liu
Wenlan
W
College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
Sood
Rohit
R
Chen
Qingchuan
Q
Sakoglu
Unal
U
Hendren
Jill
J
Cetin
Ozdemir
O
Miyake
Minoru
M
Liu
Ke Jian
KJ
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
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
J Cereb Blood Flow Metab. 2000 Mar;20(3):452-7
10724108
Blood. 2004 Oct 15;104(8):2385-93
15265790
Circ Res. 2006 Jun 23;98(12):1453-5
16794191
Acta Neuropathol. 1985;68(2):122-9
3907257
Circ Res. 2003 Apr 4;92(6):637-43
12609967
J Cereb Blood Flow Metab. 2001 Dec;21(12):1393-400
11740200
Stroke. 2006 May;37(5):1314-8
16556878
Neurology. 2002 Mar 26;58(6):945-52
11914413
Ann Neurol. 2005 Apr;57(4):571-5
15786465
Brain. 2007 Jun;130(Pt 6):1631-42
17468117
J Cereb Blood Flow Metab. 2008 Feb;28(2):431-8
17700631
Stroke. 1994 Aug;25(8):1658-64; discussion 1664-5
8042219
J Cereb Blood Flow Metab. 2004 Mar;24(3):343-9
15091115
Ann Neurol. 2002 Nov;52(5):566-72
12402253
Stroke. 1997 Nov;28(11):2252-8
9368573
J Cereb Blood Flow Metab. 2006 Oct;26(10):1274-84
16421507
Neurol Res. 2007 Mar;29(2):173-83
17439702
Biochem Biophys Res Commun. 2006 Jan 27;339(4):1197-203
16338221
Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2210-5
16766636
Stroke. 2007 Nov;38(11):3000-6
17916764
J Cereb Blood Flow Metab. 2007 Sep;27(9):1632-42
17311078
Hypertension. 2005 Sep;46(3):555-61
16043662
Free Radic Biol Med. 2005 Jul 1;39(1):71-80
15925279
Circ Res. 2006 Jun 23;98(12):1479-89
16709900
J Neurosci. 2005 Feb 16;25(7):1769-77
15716413
Exp Neurol. 2006 Jul;200(1):38-49
16624294
Nat Med. 2000 Feb;6(2):159-63
10655103
J Cereb Blood Flow Metab. 2002 Jul;22(7):861-8
12142571
J Cereb Blood Flow Metab. 2001 Jan;21(1):2-14
11149664
Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1583-96
16987013
Stroke. 1998 Oct;29(10):2189-95
9756602
J Magn Reson Imaging. 2007 Jan;25(1):39-47
17173307
Circ Res. 2005 Nov 11;97(10):1055-62
16210546
Curr Opin Immunol. 2004 Feb;16(1):42-7
14734109
Stroke. 2008 Jan;39(1):100-4
18063832
Atherosclerosis. 2001 Mar;155(1):45-52
11223425
J Cereb Blood Flow Metab. 2007 Apr;27(4):697-709
16850029
Nature. 1996 Mar 14;380(6570):108-11
8600380
Free Radic Biol Med. 1993 Jul;15(1):97-100
8359713
Stroke. 1987 Mar-Apr;18(2):426-30
3564100
J Neurosci. 2007 Jan 31;27(5):1129-38
17267568
Stroke. 2007 Mar;38(3):1044-9
17272778
Stroke. 1996 Jun;27(6):1124-9
8650725
Brain Res. 2006 May 23;1090(1):182-9
16650838