Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage.
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.
Cheng
Tong
T
Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, USA.
Petraglia
Anthony L
AL
Li
Zhang
Z
Thiyagarajan
Meenakshisundaram
M
Zhong
Zhihui
Z
Wu
Zhenhua
Z
Liu
Dong
D
Maggirwar
Sanjay B
SB
Deane
Rashid
R
Fernández
José A
JA
LaRue
Barbra
B
Griffin
John H
JH
Chopp
Michael
M
Zlokovic
Berislav V
BV
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*
D016328:NF-kappa B; D011486:Protein C; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9