Detalle Publicación

Activated protein C beta-glycoform promotes enhanced noncanonical PAR1 proteolysis and superior resistance to ischemic injury

Autores: Gleeson, E. M. ; Dichiara, M. G.; Salicio Castillo, Agustina; Quinn, L. M. ; Drakeford, C.; Russell, S.E.; Walsh, P. T.; Orbe Lopategui, Josune; Hermida Santos, José María; Smith, O. P. ; O'Donnell, J. S. ; Montes, R.; Preston, R. J. S. (Autor de correspondencia)
Título de la revista: BLOOD
ISSN: 0006-4971
Volumen: 126
Número: 7
Páginas: 915 - 919
Fecha de publicación: 2015
Activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. In this study, a recombinant APC variant (APC(N329Q)) mimicking the naturally occurring APC-beta plasma glycoform was found to exhibit superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling. APC(N329Q) also enhanced integrin alpha(M)beta(2)-dependent PAR1 proteolysis to exert significantly improved antiinflammatory activity on macrophages compared with wild-type APC. Recent therapeutic applications of recombinant APC in ischemic stroke models have used APC variants with limited anticoagulant activity to negate potential bleeding side effects. Using a mouse model of ischemic stroke and late t-PA intervention, the neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPC(PS)) was compared with an identical APC variant except for the absence of glycosylation at the APC-beta sequon (mAPC(PS/N329Q)). Remarkably, mAPC(PS/N329Q) limited cerebral ischemic injury and reduced brain lesion volume significantly more effectively than mAPC(PS). Collectively, this study reveals the importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC and demonstrates the potential of novel APC variants with superior cytoprotective signaling function as enhanced therapeutic agents for the treatment of ischemic stroke.