Stimulation of cutaneous wound healing by an FPR2‐specific peptide agonist WKYMVm

Abstract

Diabetes is one of the most common human diseases and 15% of the 200 million diabetics worldwide suffer from diabetic wounds. Development of new therapeutic agents is needed for treatment of diabetic wounds. Wound healing is mediated by multiple steps, including inflammation, epithelialization, neoangiogenesis, and granulation. Formyl peptide receptor 2 has been known to stimulate angiogenesis, which is essential for tissue repair and cutaneous wound healing. In this study, we explored the therapeutic effects of WKYMVm (TrpLys-Tyr-Met-Val-D-Met-NH2), a synthetic peptide agonist of formyl peptide receptor 2, on cutaneous wounds in streptozotocin-induced diabetic rats. Topical application of WKYMVm onto cutaneous wounds stimulated formation of von Willebrand factor-positive capillary and a-smooth muscle actin-positive arteriole with a maximal stimulation on day 6, suggesting WKYMVm-stimulated angiogenesis. Infiltration of immune cells could be detected on early phase during wound healing and WKYMVm treatment acutely augmented infiltration of CD68-positive macrophages. In addition, reepithelialization and granulation tissue formation were accelerated by treatment with WKYMVm. These results suggest that WKYMVm has therapeutic effects on diabetic wounds by stimulating angiogenesis and infiltration of immune cells.Diabetic patients frequently suffer from impaired wound healing, with a lifetime risk of 15% for development of diabetic skin ulcerations. 1 Diabetic ulcers have a poor prognosis, and lead to surgical removal of bone in 15-27% of patients. 2

Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives

“…However, the expression of FPRs in various nonphagocytic cells suggests that these receptors also participate in functions other than innate immunity and may represent unique targets for therapeutic drug design [5–7]. Such drugs may have the potential to treat many inflammatory diseases, including rheumatoid arthritis, asthma, other auto-immune diseases, and stimulate wound healing [6, 8–10]. …”

Structural basis of ligand binding modes at the human formyl peptide receptor 2

“…How FPR2 is able to recognize and bind these ligands and transduce both proinflammatory and anti-inflammatory signals remains a mystery. Some FPR2 ligands have shown therapeutic potential for the treatment of inflammation, diabetic wounds and Alzheimer's disease [7][8][9] . However, the lack of a three-dimensional structure of FPR2 has hampered the understanding of the potential therapeutic mechanism as well as their clinical applications.…”

Biomedical therapy using synthetic WKYMVm hexapeptide

“…15 Recently, Kwon et al identified that the WKYMVm effectively stimulated the healing of a cutaneous wound in streptozotocin-induced diabetic mice. 9 By topical treatment with a small amount of WKYMVm (20 mL of 1 mM in HBSS) on wound sites for 12 days, they found that WKYMVm accelerated re-epithelialization and angiogenesis in dermal tissues. Histological analysis showed WKYMV-m-treated group accelerated re-epithelialization at the early time points compared with the HBSS-treated control group.…”

“…6,7 In addition, several studies showed that WKYMVm improved tissue repair with enhanced neovascularization through promoting homing, proliferation, and tube formation of endothelial colonyforming cells (ECFCs). [8][9][10][11] Furthermore, synthesis of WKYMVm peptides composed of few amino-acids can be easily and quickly performed and cost-effective. With these properties of WKYMVm, recent studies are using these small peptides in various biomedical application fields.…”