Peptide-agonist of protease-activated receptor (PAR1) stimulates keratinocyte proliferation and epithelial layer wound healing similarly to activated protein C

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.

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Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside

International Journal of Molecular Sciences ◽

10.3390/ijms20040903 ◽

2019 ◽

Vol 20 (4) ◽

pp. 903 ◽

Cited By ~ 5

Author(s):

Ruilong Zhao ◽

Haiyan Lin ◽

Lara Bereza-Malcolm ◽

Elizabeth Clarke ◽

Christopher Jackson ◽

...

Keyword(s):

Wound Healing ◽

Clinical Studies ◽

Protein C ◽

Activated Protein C ◽

Epithelial Barrier ◽

Cutaneous Wound Healing ◽

Cutaneous Wound ◽

Beneficial Effects ◽

The Past ◽

Complex Process

Independent of its well-known anticoagulation effects, activated protein C (APC) exhibits pleiotropic cytoprotective properties. These include anti-inflammatory actions, anti-apoptosis, and endothelial and epithelial barrier stabilisation. Such beneficial effects have made APC an attractive target of research in a plethora of physiological and pathophysiological processes. Of note, the past decade or so has seen the emergence of its roles in cutaneous wound healing—a complex process involving inflammation, proliferation and remodelling. This review will highlight APC’s functions and mechanisms, and detail its pre-clinical and clinical studies on cutaneous wound healing.

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Hemostasis and Thrombosis in Trauma Patients

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0034-1398378 ◽

2015 ◽

Vol 41 (01) ◽

pp. 026-034 ◽

Cited By ~ 14

Author(s):

Satoshi Gando

Keyword(s):

Wound Healing ◽

Protein C ◽

Activated Protein C ◽

Fat Embolism ◽

Whole Body ◽

Severe Bleeding ◽

Trauma Patients ◽

Embolism Syndrome ◽

Acute Coagulopathy Of Trauma ◽

Pathological Reaction

Hemostasis and thrombosis in trauma patients consist of physiological hemostasis for wound healing and the pathological reaction of disseminated intravascular coagulation (DIC). Whole body trauma, isolated brain injury, and fat embolism syndrome, if extremely severe, can cause DIC and affect a patient's prognosis. Shock-induced hyperfibrinolysis causes DIC with the fibrinolytic phenotype, contributing to oozing-type severe bleeding. If uncontrolled, this phenotype progresses to thrombotic phenotype at the late stage of trauma, followed by microvascular thrombosis, leading to organ dysfunction. Another type of pathological hemostatic change is acute coagulopathy of trauma shock (ACOTS), which gives rise to activated protein C–mediated systemic hypocoagulation, resulting in bleeding. ACOTS occurs only in trauma associated with shock-induced hypoperfusion and there is nothing to suggest DIC in this phenomenon. This review will provide information about the recent advances in hemostasis and thrombosis in trauma and will clarify the pathogeneses of the pathological processes observed in trauma patients.

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