Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat Accelerates Wound Healing in a Mouse Hind limb Lymphedema Model.

Abstract

Objective: Drugs regulating hypoxia-inducible factor (HIF)-1α have not been investigated for wound healing in lymphedema. Therefore, we examined the effects of drug modulation of HIF-1α activity for wound healing in our previously developed mouse model of nonirradiated hind limb lymphedema. Approach: Mouse hind limb lymphedema models (n = 17) and a sham group (n = 6) were created using 8- to 10-week-old male C57BL/6N mice. Mice with hind limb lymphedema were randomized into experimental groups receiving roxadustat, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), or dimethyl sulfoxide and were given intraperitoneal injections every 2 days for up to 2 weeks. Four days after the surgery, an 8-mm diameter full-thickness skin wound was created in the hind limb. The number of days required for wound closure and the percentage of wounds closed were measured. Skin samples taken at wound creation were evaluated by histological and molecular analysis. Results: Administration of roxadustat accelerated wound healing, whereas YC-1 delayed it, with a significant decrease and increase in skin thickness, respectively. The relative mRNA expression of Hif1α, matrix metalloproteinase-3, and interleukin-6 was significantly higher in the roxadustat group and that of metalloproteinase-9 was significantly lower in the roxadustat group compared with the control group. Innovation: This study is the first to demonstrate delayed wound healing in a mouse model of hind limb lymphedema and the first to demonstrate the promotion of significant wound healing through the use of roxadustat. Conclusion: Roxadustat exerts wound-healing effects and may promote the regulation of extracellular matrix remodeling via gene expression in hind limb lymphedema wound models.