title: Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage.
abstract: Brain hemorrhage is a serious complication of tissue plasminogen activator (tPA) therapy for ischemic stroke. Here we report that activated protein C (APC), a plasma serine protease with systemic anticoagulant, anti-inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, blocks tPA-mediated brain hemorrhage after transient brain ischemia and embolic stroke in rodents. We show that APC inhibits a pro-hemorrhagic tPA-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1. The present findings suggest that APC may improve thrombolytic therapy for stroke, in part, by reducing tPA-mediated hemorrhage.
authors.affiliation: Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Cheng
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Petraglia
authors.forename: Zhang
authors.initials: Z
authors.lastname: Li
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Thiyagarajan
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zhong
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Wu
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Maggirwar
authors.forename: Rashid
authors.initials: R
authors.lastname: Deane
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.forename: Barbra
authors.initials: B
authors.lastname: LaRue
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000818:Animals; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D011486:Protein C; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9