Nature Medicine9, 338 - 342 (2003)
Published online: 3 February 2003; | doi:10.1038/nm826
Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective
Tong Cheng1, 6, Dong Liu1, 6, John H. Griffin2, José A. Fernández2, Francis Castellino3, Elliot D. Rosen3, Kenji Fukudome4
& Berislav V. Zlokovic1, 5
1
Frank P. Smith Neurosurgical Research Laboratory, Department of Neurosurgery and Center for Aging and Developmental Biology, Division of Neurovascular Biology, University of Rochester Medical Center, Rochester, New York, USA
2
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
3
W.M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
4
Department of Immunology, Saga Medical School, Saga, Japan
5
Socratech Laboratories, Rochester, New York, USA
6
T.C. and D.L. contributed equally to this study.
Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor1,
2,
3. It reduces organ damage in animal models of sepsis, ischemic injury and stroke1,
4,
5 and substantially reduces mortality in patients with severe sepsis6. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect5,
7 is secondary to its anti-coagulant and anti-inflammatory effects1,
2,
3. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells8,
9. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR10. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.
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