Nature Medicine
9, 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 neuroprotectiveTong Cheng1, 6, Dong Liu1, 6, John H. Griffin2, José A. Fernández2, Francis Castellino3, Elliot D. Rosen3, Kenji Fukudome4
& Berislav V. Zlokovic1, 51
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.
Correspondence should be addressed to Berislav V. Zlokovic berislav_zlokovic@urmc.rochester.eduActivated 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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