BACKGROUND: Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) possess angiogenic effects. However, the effect of CYP-derived EETs and soluble epoxide hydrolase (sEH) deletion on wound healing in vivo has not been rigorously investigated. In this study, we measured the effect of exogenous CYP-derived EETs and targeted disruption of sEH in an in vivo wound model. MATERIALS AND METHODS: Standardized full-thickness dermal wounds were created on the dorsum of mouse ears. Wound epithelialization was directly viewed and measured using intravital microscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for metalloproteinase (MMP) 2, MMP7, MMP9, tissue inhibitor of metalloproteinases (TIMP) 1, and tumor necrosis factor (TNF) α on days 2, 4, and 12. RESULTS: Treatment with 11,12-EETs, 14,15-EETs, and sEH deletion significantly accelerated wound closure. This effect was attenuated by the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) in sEH(-/-) mice. Neither 11,12- nor 14,15-EETs caused significant alterations in MMP9 expression in wounds. In contrast, MMP2 and MMP7 were significantly upregulated in the EET-treated groups, whereas TIMP1 and TNF-α were downregulated. CONCLUSIONS: Collectively, these data demonstrated that potentiation of the CYP epoxy-genase pathway by either exogenous CYP-derived EETs or sEH deletion significantly accelerated wound epithelialization in vivo. This beneficial effect might be due to downregulation of TNF-α production and, to a lesser degree, to the release of MMPs and could be used as a viable angiogenic therapeutic strategy.
BACKGROUND:Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) possess angiogenic effects. However, the effect of CYP-derived EETs and soluble epoxide hydrolase (sEH) deletion on wound healing in vivo has not been rigorously investigated. In this study, we measured the effect of exogenous CYP-derived EETs and targeted disruption of sEH in an in vivo wound model. MATERIALS AND METHODS: Standardized full-thickness dermal wounds were created on the dorsum of mouse ears. Wound epithelialization was directly viewed and measured using intravital microscopy and computerized planimetry every second day until healing was complete. Wound sections were analyzed by immunostaining for metalloproteinase (MMP) 2, MMP7, MMP9, tissue inhibitor of metalloproteinases (TIMP) 1, and tumor necrosis factor (TNF) α on days 2, 4, and 12. RESULTS: Treatment with 11,12-EETs, 14,15-EETs, and sEH deletion significantly accelerated wound closure. This effect was attenuated by the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) in sEH(-/-) mice. Neither 11,12- nor 14,15-EETs caused significant alterations in MMP9 expression in wounds. In contrast, MMP2 and MMP7 were significantly upregulated in the EET-treated groups, whereas TIMP1 and TNF-α were downregulated. CONCLUSIONS: Collectively, these data demonstrated that potentiation of the CYP epoxy-genase pathway by either exogenous CYP-derived EETs or sEH deletion significantly accelerated wound epithelialization in vivo. This beneficial effect might be due to downregulation of TNF-α production and, to a lesser degree, to the release of MMPs and could be used as a viable angiogenic therapeutic strategy.
Authors: Sung Hee Hwang; Aaron T Wecksler; Guodong Zhang; Christophe Morisseau; Long V Nguyen; Samuel H Fu; Bruce D Hammock Journal: Bioorg Med Chem Lett Date: 2013-05-15 Impact factor: 2.823
Authors: Yan Gong; Zhuo Shao; Zhongjie Fu; Matthew L Edin; Ye Sun; Raffael G Liegl; Zhongxiao Wang; Chi-Hsiu Liu; Samuel B Burnim; Steven S Meng; Fred B Lih; John Paul SanGiovanni; Darryl C Zeldin; Ann Hellström; Lois E H Smith Journal: EBioMedicine Date: 2016-09-30 Impact factor: 8.143
Authors: Dorothy M Supp; Jennifer M Hahn; Kevin L McFarland; Kelly A Combs; Kin Sing Stephen Lee; Bora Inceoglu; Debin Wan; Steven T Boyce; Bruce D Hammock Journal: Plast Reconstr Surg Glob Open Date: 2016-12-20
Authors: Jéssica R Silva; Beatriz Burger; Carolina M C Kühl; Thamiris Candreva; Mariah B P Dos Anjos; Hosana G Rodrigues Journal: Mediators Inflamm Date: 2018-04-12 Impact factor: 4.711