Effects of plasminogen activator inhibitor-1 on ischemic brain injury in permanent and thrombotic middle cerebral artery occlusion models in mice.
OBJECTIVE
Tissue plasminogen activator (t-PA) improves the outcome of ischemic stroke by recanalization of occluded vessels, but has neurotoxic side effects in experimental stroke models. Here, the effect of plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of t-PA, on ischemic infarct volume was studied.


METHODS
After either permanent ligation or thrombotic occlusion of the middle cerebral artery (MCA), infarct volume, spontaneous reperfusion of thrombosed MCA, t-PA/PAI-1 complex level, and blood-brain barrier (BBB) permeability in the ischemic region was studied in transgenic mice with overexpression of PAI-1 and wild-type littermate controls and in mice with intracerebroventricular injection of human PAI-1.


RESULTS
Infarct volume was smaller in PAI-1 transgenic mice (2.9 +/- 3.7 mm3, mean +/- SD) than in controls (8.9 +/- 5.0 mm3, P < 0.05) after permanent MCA ligation (plasma PAI-1 level 39 +/- 23 ng mL(-1) in transgenic mice vs. 1.5 +/- 0.6 ng mL(-1) in controls), whereas after MCA thrombosis it was larger in transgenics (13.1 +/- 3.1 mm3) than in controls (8.0 +/- 3.2 mm3, P < 0.05). Spontaneous reperfusion of the thrombosed MCA was significantly delayed in transgenic vs. control mice. In the ligation model, t-PA/PAI-1 complex levels were higher and BBB disruption was more pronounced in the ischemic region. Human PAI-1 injection reduced infarct volume by about 50% in wild-type mice but not in t-PA gene deficient mice.


CONCLUSIONS
High PAI-1 levels reduced infarct volume in the permanent MCA ligation model, but enhanced it in the MCA thrombosis model.
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. nobuo.nagai@med.kuleuven.be
N
N
Nagai
Y
Y
Suzuki
B
B
Van Hoef
H R
HR
Lijnen
D
D
Collen
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D002536:Cerebral Arteries / Q000473:pathology*; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000628:therapy*; D007511:Ischemia; D008027:Light; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010539:Permeability; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015427:Reperfusion Injury; D013927:Thrombosis; D013997:Time Factors
D017395:Plasminogen Activator Inhibitor 1; D011994:Recombinant Proteins