Activated protein C inhibits tissue plasminogen activator–induced brain hemorrhage

Tong Cheng^1, 5, Anthony L Petraglia^1, 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

¹  Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York 14642, USA.

²  Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.

³  Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA.

⁴  Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.

⁵  These authors contributed equally to this work.

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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