1. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3.
- Author
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Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernández JA, Griffin JH, and Zlokovic BV
- Subjects
- Animals, Apoptosis drug effects, Apoptosis Inducing Factor, Caspases drug effects, Caspases metabolism, Cells, Cultured, Cerebral Cortex cytology, Cerebral Cortex drug effects, Cerebral Cortex enzymology, Fetus, Flavoproteins drug effects, Flavoproteins metabolism, Male, Membrane Proteins drug effects, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, N-Methylaspartate pharmacology, Neurodegenerative Diseases enzymology, Neurons cytology, Neurons drug effects, Protein C pharmacology, Receptor, PAR-1 antagonists & inhibitors, Receptor, PAR-1 genetics, Receptors, Thrombin antagonists & inhibitors, Receptors, Thrombin genetics, Staurosporine pharmacology, Tumor Suppressor Protein p53 drug effects, Tumor Suppressor Protein p53 metabolism, Apoptosis physiology, Neurons enzymology, Protein C metabolism, Receptor, PAR-1 metabolism, Receptors, Thrombin metabolism
- Abstract
Activated protein C (APC), a serine protease with anticoagulant and anti-inflammatory activities, exerts direct cytoprotective effects on endothelium via endothelial protein C receptor-dependent activation of protease activated receptor 1 (PAR1). Here, we report that APC protects mouse cortical neurons from two divergent inducers of apoptosis, N-methyl-D-aspartate (NMDA) and staurosporine. APC blocked several steps in NMDA-induced apoptosis downstream to nitric oxide, i.e., caspase-3 activation, nuclear translocation of apoptosis-inducing factor (AIF), and induction of p53, and prevented staurosporine-induced apoptosis by blocking caspase-8 activation upstream of caspase-3 activation and AIF nuclear translocation. Intracerebral APC infusion dose dependently reduced NMDA excitotoxicity in mice. By using different anti-PARs antibodies and mice with single PAR1, PAR3, or PAR4 deletion, we demonstrated that direct neuronal protective effects of APC in vitro and in vivo require PAR1 and PAR3. Thus, PAR1 and PAR3 mediate anti-apoptotic signaling by APC in neurons, which may suggest novel treatments for neurodegenerative disorders.
- Published
- 2004
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