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REVIEW: A New Concept of Action of Hemostatic Proteases on Inflammation, Neurotoxicity, and Tissue Regeneration

L. R. Gorbacheva1,2, E. V. Kiseleva2,3, I. G. Savinkova2, and S. M. Strukova1*

1Lomonosov Moscow State University, Faculty of Biology, 119991 Moscow, Russia; E-mail: sstrukova@yahoo.com

2Pirogov Russian National Research Medical University, 117997 Moscow, Russia

3Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia

* To whom correspondence should be addressed.

Received February 9, 2017; Revision received April 5, 2017
Key hemostatic serine proteases such as thrombin and activated protein C (APC) are signaling molecules controlling blood coagulation and inflammation, tissue regeneration, neurodegeneration, and some other processes. By interacting with protease-activated receptors (PARs), these enzymes cleave a receptor exodomain and liberate new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signaling pathways and cell responses. Among four PAR family members, APC and thrombin mainly act via PAR1, and they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective activity, whereas thrombin is a protease with procoagulant and proinflammatory effects. Hallmark features of APC-induced effects result from acting via different pathways: limited proteolysis of PAR1 localized in membrane caveolae with coreceptor (endothelial protein C receptor) as well as its targeted proteolytic action at a receptor exodomain site differing from the canonical thrombin cleavage site. Hence, a new noncanonical tethered PAR1 agonist peptide (PAR1-AP) is formed, whose effects are poorly investigated in inflammation, tissue regeneration, and neurotoxicity. In this review, a concept about a role of biased agonism in effects exerted by APC and PAR1-AP via PAR1 on cells involved in inflammation and related processes is developed. New evidence showing a role for a biased agonism in activating PAR1 both by APC and PAR1-AP as well as induction of antiinflammatory and cytoprotective cellular responses in experimental inflammation, wound healing, and excitotoxicity is presented. It seems that synthetic PAR1 peptide-agonists may compete with APC in controlling some inflammatory and neurodegenerative diseases.
KEY WORDS: thrombin, activated protein C, protease-activated receptors, biased agonism, inflammation, tissue regeneration

DOI: 10.1134/S0006297917070033