title: [Peptide-agonist of protease-activated receptor (PAR 1), similar to activated protein C, promotes proliferation in keratinocytes and wound healing of epithelial layer].
abstract: Activated protein C (APC) is serine protease hemostasis, independent of its anticoagulant activity, exhibits anti-inflammatory and anti-apoptotic properties that determine the possibility of the protective effects of APC in different diseases, including sepsis and chronic wound healing. APC, binding of endothelial protein C receptor (EPCR) and specifically cleaving PAR1 receptor and releasing peptide agonist PAR1 stabilizes not only endothelial cells, but also many others, including epidermal keratinocytes of the skin. We develop the hypothesis that the cytoprotective effect of APC on the cells, involved in wound healing, seem to imitate peptide - analogous of PAR1 "tethered ligand" that activate PAR1. In our work, we synthesized a peptide (AP9) - analogue of PAR1 tethered ligand, released by APC, and firstly showed that peptide AP9 (0.1-10 мM), like to APC (0.01-100 nM), stimulates the proliferative activity of human primary keratinocytes. Using a model of the formation of epithelial wounds in vitro we found that peptide AP9, as well as protease APC, accelerates wound healing. Using specific antibodies to the receptor PAR1 and EPCR was studied the receptor mechanism of AP9 action in wound healing compared with the action of APС. The necessity of both receptors - PAR1 and EPСR, for proliferative activity of agonists was revealed. Identified in our work imitation by peptide AP9 - PAR1 ligand, APC acts on keratinocytes suggests the possibility of using a peptide AP9 to stimulate tissue repair.
authors.affiliation: Koltzov Institute of Developmental Biology RAS.
authors.forename: E V
authors.initials: EV
authors.lastname: Kiseleva
authors.affiliation: Russian Cardiology Research and Production Complex, Moscow, Russia.
authors.forename: M V
authors.initials: MV
authors.lastname: Sidorova
authors.affiliation: Lomonosov Moscow State University, Moscow, Russia; Pirogov Russian National Research Medical University, Moscow, Russia.
authors.forename: L R
authors.initials: LR
authors.lastname: Gorbacheva
authors.affiliation: Lomonosov Moscow State University, Moscow, Russia.
authors.forename: S M
authors.initials: SM
authors.lastname: Strukova
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019610:Cytoprotection; D000074283:Endothelial Protein C Receptor; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008024:Ligands; D008954:Models, Biological; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D061251:Primary Cell Culture; D011486:Protein C / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D008024:Ligands; C478370:PROCR protein, human; D010455:Peptides; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface
keywords: keratinocytes; peptide agonist; protease-activated receptor; protein C; wound healing