Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective

Tong Cheng, Dong Liu, John H. Griffin, José A. Fernández, Francis Castellino, Elliot D. Rosen, Kenji Fukudome, Berislav V. Zlokovic

Research output: Contribution to journalArticle

486 Scopus citations

Abstract

Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor1-3. 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 anticoagulant and anti-inflammatory effects1-3. 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.

Original languageEnglish (US)
Pages (from-to)338-342
Number of pages5
JournalNature Medicine
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective'. Together they form a unique fingerprint.

  • Cite this

    Cheng, T., Liu, D., Griffin, J. H., Fernández, J. A., Castellino, F., Rosen, E. D., Fukudome, K., & Zlokovic, B. V. (2003). Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nature Medicine, 9(3), 338-342. https://doi.org/10.1038/nm826