CKD712 promotes wound closure by producing VEGF through AMPK‐dependent HO‐1 induction

Abstract

Given the importance of vascular endothelial growth factor (VEGF) and heme oxygenase (HO)‐1 in wound healing, the present study was tested our hypothesis that CKD712, a strong HO‐1 inducer, produces VEGF through HO‐1 induction for stimulating wound healing. Results indicated that CKD712 significantly increased VEGF production and accelerated migration of human dermal fibroblast (HDF) where addition of anti‐VEGF antibody antagonized the effect of promoting cell migration. Both AMPK inhibitor (compound C) and HO‐1 inhibitor (SnPPIX) but not inhibitors of MAPKs, PI3K, and PKC significantly reduced the production of VEGF by CKD712. Interestingly, SnPPIX inhibited HO‐1 expression but not p‐AMPK by CKD712. By contrast, compound C inhibited both p‐AMPK and HO‐1 induction by CKD712, indicating that AMPK controls HO‐1 induction. Moreover, CKD712 decreased HO‐1 induction without affecting the expression of p‐AMPK in siHO‐1 transfection but it failed to induce HO‐1 induction in siAMPKƒÑ1‐ transfected cells, supporting that AMPK is involved in HO‐1 induction by CKD712. In addition, administration of CKD712 significantly shortened the time of wound closure in SnPP IX‐sensitive manner in full‐thickness skin wound mice model. Taken together, we concluded that CKD712 accelerates cutaneous wound healing, at least, by production of VEGF through AMPK‐dependent HO‐1 induction.Grant Funding Source: NRF (03‐2010‐0298)