Nature Medicine10, 1379 - 1383 (2004)
Published online: 31 October 2004; | doi:10.1038/nm1122
Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C
Dong Liu1, 3, Tong Cheng1, 3, Huang Guo1, 3, José A Fernández2, John H Griffin2, Xiaomei Song1
& Berislav V Zlokovic1
1
Frank P. Smith Laboratory for Neuroscience and Neurosurgical Research, Department of Neurosurgery and Division of Neurovascular Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, Rochester, New York
14642,
2
Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California
92037, USA.
Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity1,
2,
3,
4,
5 is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway6. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities7, which is neuroprotective during transient ischemia8,
9 and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium9,
10,
11 and neurons12, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3−dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.
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