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Br J Pharmacol 2013, PMID: 23088309

(S)-1-╬▒-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712), promotes wound closure by producing VEGF through HO-1 induction in human dermal fibroblasts and mouse skin.

Jang, Hwa Jin; Tsoyi, Konstantin; Kim, Young Min; Park, Eun Jung; Park, Sang Won; Kim, Hye Jung; Lee, Jae Heun; Chang, Ki Churl

OBJECTIVE

Given the importance of VEGF and haem oxygenase (HO)-1 in wound healing, the present study tested the hypothesis that CKD712, a synthetic tetrahydroisoquinoline alkaloid, activated VEGF production through the induction of HO-1 in human dermal fibroblasts (HDFs) and in mouse skin to stimulate wound healing.

METHODS

Using HDFs, the effects of CKD712 on the production of VEGF and migration were evaluated. The mechanisms responsible were investigated using various signal inhibitors and small interfering RNA techniques. The ability of CKD712 to promote wound healing was also investigated in full-thickness skin-wounded mice.

RESULTS

CKD712 treatment of HDFs increased VEGF production and accelerated migration, which was antagonized by anti-VEGF antibodies. Both an AMPK inhibitor (compound C) and a HO-1 activity inhibitor (SnPPIX) but not inhibitors of MAPKs, PI3K and PKC reduced the production of VEGF by CKD712. Interestingly, SnPPIX inhibited HO-1 expression but not p-AMPK, whereas compound C inhibited both p-AMPK and HO-1 induction by CKD712. Moreover, CKD712 decreased HO-1 expression without affecting the expression of p-AMPK by siHO-1 transfection, but it failed to induce HO-1 in siAMPK╬▒1-transfected cells, suggesting that AMPK is involved in HO-1 induction by CKD712 in HDFs. Also, CKD712 shortened the time of wound closure in an SnPPIX-sensitive manner in a full-thickness skin-wounded mouse model.

CONCLUSIONS

CKD712 accelerated cutaneous wound healing, at least in part, by the production of VEGF through HO-1 induction in HDFs and mouse skin.

Diseases/Pathways annotated by Medline MESH: Wounds, Penetrating
Document information provided by NCBI PubMed

Text Mining Data

VEGF → HO-1: " Both an AMPK inhibitor ( compound C ) anda HO-1 activity inhibitor ( SnPPIX ) but not inhibitors of MAPKs, PI3K and PKC reduced the production of VEGF by CKD712 "

VEGF → PI3K: " Both an AMPK inhibitor ( compound C ) anda HO-1 activity inhibitor ( SnPPIX ) but not inhibitors of MAPKs, PI3K and PKC reduced the production of VEGF by CKD712 "

VEGF → PI3K: " Both an AMPK inhibitor ( compound C ) anda HO-1 activity inhibitor ( SnPPIX ) but not inhibitors of MAPKs, PI3K and PKC reduced the production of VEGF by CKD712 "

VEGF → AMPK: " Both an AMPK inhibitor ( compound C ) anda HO-1 activity inhibitor ( SnPPIX ) but not inhibitors of MAPKs, PI3K and PKC reduced the production of VEGF by CKD712 "

HO-1 → AMPK: " Moreover, CKD712 decreased HO-1 expression without affecting the expression of p-AMPK by siHO-1 transfection, but it failed to induce HO-1 in siAMPKa1 transfected cells, suggesting that AMPK is involved in HO-1 induction by CKD712 in HDFs "

Manually curated Databases

No curated data.