Absence of glutathione peroxidase-1 exacerbates cerebral ischemia-reperfusion injury by reducing post-ischemic microvascular perfusion.
Mice deficient in the anti-oxidant enzyme glutathione peroxidase-1 (Gpx1) have a greater susceptibility to cerebral injury following a localized ischemic event. Much of the response to ischemia-reperfusion is caused by aberrant responses within the microvasculature, including inflammation, diminished endothelial barrier function (increased vascular permeability), endothelial activation, and reduced microvascular perfusion. However, the role of Gpx1 in regulating these responses has not been investigated. Wild-type and Gpx1-/- mice underwent focal cerebral ischemia via mid-cerebral artery occlusion followed by measurement of cerebral perfusion via laser Doppler and intravital microscopy. Post-ischemic brains in wild-type mice displayed significant deficit in microvascular perfusion. However, in Gpx1-/- mice, the deficit in cerebral blood flow was significantly greater than that in wild-type mice, and this was associated with significant increase in infarct size and increased vascular permeability. Ischemia-reperfusion also resulted in expression of matrix metalloproteinase-9 (MMP-9) in endothelial cells. The absence of Gpx1 was associated with marked increase in pro-MMP-9 expression as well as potentiated MMP-9 activity. Pre-treatment of Gpx1-/- mice with the anti-oxidant ebselen restored microvascular perfusion, limited the induction and activation of MMP-9, and attenuated the increases in infarct size and vascular permeability. These findings demonstrate that the anti-oxidant function of Gpx1 plays a critical role in protecting the cerebral microvasculature against ischemia-reperfusion injury by preserving microvascular perfusion and inhibiting MMP-9 expression.
Wong
Connie H Y
CH
Centre for Functional Genomics and Human Disease, Monash Institute of Medical Research, Monash University, Victoria, Australia.
Bozinovski
Steven
S
Hertzog
Paul J
PJ
Hickey
Michael J
MJ
Crack
Peter J
PJ
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D002536:Cerebral Arteries / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000235:genetics*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D054833:Isoindoles; D017078:Laser-Doppler Flowmetry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology; D016566:Organoselenium Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D014463:Ultrasonography; D020293:Vasculitis, Central Nervous System / Q000201:enzymology / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D005979:Glutathione Peroxidase; D020780:Matrix Metalloproteinase 9; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse