title: Tissue plasminogen activator prevents restoration of tight junction proteins through upregulation of angiopoietin-2.
abstract: We examined the temporal profiles of changes in the expressions of tight junction proteins (TJPs; namely, claudin-5, occludin, and ZO-1) after focal cerebral ischemia/reperfusion in mice. We also examined the effects of delayed treatment with tissue plasminogen activator (tPA) on the expressions of TJPs and angiopoietin (Ang) -1/2/Tie2. Mice subjected to a 6-h filamental middle cerebral artery (MCA) occlusion were treated with tPA (10 mg/kg, intravenously, just after the start of reperfusion) or vehicle. The expressions of TJPs were significantly decreased in the early phase of ischemia/reperfusion, and then gradually recovered. A delayed treatment with tPA decreased the expressions of TJPs when examined at 42 h after reperfusion. In contrast, delayed tPA treatment markedly increased Ang-2, but not Ang-1 expression, when examined at 30 h after reperfusion. Treatment with tPA at 300 μg/ml also significantly decreased Ang- 2, but not Tie2 expression, in an in vitro monolayer model generated using human brain microvascular endothelial cells subjected to serum-deprivation. These findings suggest that delayed tPA treatment prevents recovery of TJPs following focal cerebral ischemia/reperfusion, partially via upregulation of Ang-2.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Mishiro
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Yukiya
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism*; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D062793:Occludin / Q000235:genetics / Q000378:metabolism*; D015424:Reperfusion; D015427:Reperfusion Injury / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D042702:Angiopoietin-2; D062507:Claudin-5; D005343:Fibrinolytic Agents; D062793:Occludin; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D010959:Tissue Plasminogen Activator