APC protects against ischemia

Activated protein C blocks p53 and protects brain cells from ischemic injury.

Feb 3, 2003
Tudor Toma

Activated protein C (APC) complements the systemic anticoagulant and anti inflammatory activities of the blood and substantially reduces mortality when administered to patients with severe sepsis. However, its exact mechanisms of action and full potential therapeutic implications have been unclear. In the February 3, Nature Medicine, Tong Cheng and colleagues at the University of Rochester Medical Center, New York, USA, show that activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and confers neuroprotective effects (Nature Medicine, DOI:10.1038/nm826, February 3, 2003).

Cheng et al. used primary human microvascular brain endothelial cells and observed that APC directly prevented apoptosis in hypoxic endothelium. They found that this is effect was mediated by transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling.

In addition, they showed in an in vivo murine model of stroke, cytoprotection of brain endothelium by APC required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1). The in vivo neuroprotective effects of low-dose murine APC was independent of its anti-coagulant activity.

"The present observations contribute to favourable implications for APC in the treatment of cerebral ischemic events and other neurodegenerative disorders, as well as treatment of ischemic injury in the heart, lungs, kidneys and other organs," conclude the authors.