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Article
Nature Medicine 12, 1278 - 1285 (2006)
Published online: 29 October 2006 | doi:10.1038/nm1498
Activated protein C inhibits tissue plasminogen activator–induced brain hemorrhage
Tong Cheng1,5, Anthony L Petraglia1,5, Zhang Li2, Meenakshisundaram Thiyagarajan1, Zhihui Zhong1, Zhenhua Wu1, Dong Liu1, Sanjay B Maggirwar3, Rashid Deane1, José A Fernández4, Barbra LaRue1, John H Griffin4, Michael Chopp2 & Berislav V Zlokovic1
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-
B–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.
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