title: Protease activated receptor-2 mediates activated protein C-induced cutaneous wound healing via inhibition of p38.
abstract: Activated protein C (APC) is a natural anticoagulant that exerts anti-inflammatory and cytoprotective properties mediated through the protease activated receptor (PAR)-1. APC can also proteolytically cleave PAR-2, although subsequent function is unknown. On the basis of recent evidence that APC promotes wound healing, the aim of this study was to determine whether APC acts through PARs to heal murine excisional wounds or to regulate human cultured keratinocyte function and to determine the signaling mechanisms. Topical administration of APC accelerated wound healing in wild-type mice and, unexpectedly, in PAR-1 knockout mice. PAR-2 knockout mice healed significantly slower than wild-type mice, and healing was not altered by adding APC, indicating that APC acts through PAR-2 to heal wounds. In cultured human primary keratinocytes, APC enhanced PAR-2, stimulated proliferation, activated phosphatidylinositol 3-kinase/Src/Akt, and inhibited phosphorylated (P)-p38. Inhibiting PAR-1 or PAR-2, by small-interfering RNA or blocking antibody, reversed APC-induced keratinocyte proliferation and Akt activation. Blocking PAR-2, but not PAR-1, reversed the inhibition of P-p38 by APC. Furthermore, inhibition of P-p38 accelerated wound healing in wild-type mice. In summary, although APC acts through both PAR-1 and PAR-2 to activate Akt and to increase keratinocyte proliferation, APC-induced murine wound healing depends on PAR-2 activity and inhibition of P-p38.
authors: Sutton Arthritis Research Laboratories, Institute of Bone and Joint Research, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, Australia.
authors: Sohel M
authors: SM
authors: Julovi
authors: Meilang
authors: M
authors: Xue
authors: Suat
authors: S
authors: Dervish
authors: Philip N
authors: PN
authors: Sambrook
authors: Lyn
authors: L
authors: March
authors: Christopher John
authors: CJ
authors: Jackson
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology; D044464:Receptor, PAR-2 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D012867:Skin / Q000201:enzymology* / Q000293:injuries; D014945:Wound Healing / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D011486:Protein C; D034741:RNA, Small Interfering; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases