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VASCULAR BIOLOGY

A role for proteinase-activated receptor 2 and PKC- in thrombin-mediated induction of decay-accelerating factor on human endothelial cells

¹British Heart Foundation Cardiovascular Medicine Unit, Eric Bywaters Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom; ²Institute of Molecular Oncology, Showa University, Tokyo, Japan; and ³Cardiovascular Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois

Submitted 13 October 2004 ; accepted in final form 2 August 2005

Thrombin, an important mediator of thrombosis and inflammation, may also enhance vascular cytoprotection. Thus thrombin induces expression of the complement-inhibitory protein decay-accelerating factor (DAF) in human umbilical vein endothelial cells (HUVECs), thus increasing protection against complement-mediated injury. Using PKC isozyme-specific peptide antagonists and adenoviral constructs, we have shown in the present study that PKC- is the primary isozyme involved in DAF induction by thrombin. Experiments with proteinase-activated receptor-1 (PAR₁) and PAR₂ activating peptides (APs) showed that DAF expression induced by PAR₁-AP was PKC--dependent; in contrast, PAR₂-AP induction of DAF required activation of PKC-. PAR₁-AP and PAR₂-AP in combination exerted an additive effect on DAF protein expression, which was equivalent to that observed with thrombin alone. These data implied a specific role for PAR₂ in DAF induction, which was supported by the observation that upregulation of endothelial cell (EC) PAR₂-enhanced DAF induction by thrombin. ERK1/2, p38, and JNK MAPK were also involved in thrombin-induced DAF upregulation, with evidence of interdependence between ERK1/2 and JNK. A role for transactivation of PAR₂ by PAR₁ was suggested by partial inhibition of thrombin-induced DAF expression by the PAR₁ signaling antagonists BMS-200261 and SCH79797, whereas inhibition of thrombin-induced cleavage of PAR₁ by specific MAbs or hirudin completely abrogated the response. Together, these data imply that the predominant pathway for thrombin-induced DAF expression involves transactivation of PAR₂ by PAR₁ and signaling via PKC-/MAPK. This may represent an important, novel pathway for endothelial cytoprotection during inflammation and angiogenesis and suggests that PAR₂ may play a central role in some thrombin-induced responses.

cytoprotection; proteinase-activated receptor 1

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