Inhibition of Soluble Epoxide Hydrolase 2 Ameliorates Diabetic Keratopathy and Impaired Wound Healing in Mouse Corneas

Abstract

EPHX2 (encoding soluble epoxide hydrolase [sEH]) converts biologically active epoxyeicosatrienoic acids (EETs), anti-inflammatory and profibrinolytic effectors, into the less biologically active metabolites, dihydroxyeicostrienoic acids. We sought to characterize the expression and the function of EPHX2 in diabetic corneas and during wound healing. The expression of EPHX2 at both mRNA and protein levels, as well as sEH enzymatic activity, was markedly upregulated in the tissues/cells, including corneal epithelial cells as well as the retina of human type 2 and mouse type 1 (streptozotocin [STZ] induced) and/or type 2 diabetes. depletion had no detectable effects on STZ-induced hyperglycemia but prevented the development of tear deficiency. mice showed an acceleration of hyperglycemia-delayed epithelium wound healing. Moreover, inhibition of sEH increased the rate of epithelium wound closure and restored hyperglycemia-suppressed STAT3 activation and heme oxygenase-1 (HO-1) expression in the diabetic corneas. Treatment of diabetic corneas with cobalt protoporphyrin, a well-known HO-1 inducer, restored wound-induced HO-1 upregulation and accelerated delayed wound healing. Finally, depletion enhanced sensory innervation and regeneration in diabetic corneas at 1 month after epithelial debridement. Our data suggest that increased sEH activity may be a contributing factor for diabetic corneal complications; targeting sEH pharmacologically or supplementing EETs may represent a new, adjunctive therapy for treating diabetic keratopathy.

Impact of a weight loss and fitness intervention on exercise‐associated plasma oxylipin patterns in obese, insulin‐resistant, sedentary women

“…While a complete understanding of the role that sEH plays in glucose homeostasis has yet to emerge, sEH ablation increases pancreatic islet size and insulin signaling in high fat fed mice (Luria et al, 2011). Conversely, overexpression of this enzyme is associated with diabetes‐associated comorbidities including diabetic retinopathy and impaired wound healing (Hu et al, 2017; Sun et al, 2018). Despite the possibility that changes in sEH activity play a role in pre‐ versus post‐intervention OxL differences in our cohort, the sEH product/precursor ratios (diols:epoxides) for 9,10‐DiHODE, 12,13‐DiHODE, and 9,10‐DiHOME were not convincingly altered (~4%, 12%, 11% reductions, respectively).…”

Static Magnetic Field Accelerates Diabetic Wound Healing by Facilitating Resolution of Inflammation

“…Accumulating studies have reported that the alteration in the JAK/STAT pathway may result in impaired wound healing in a diabetes model and promotes alternative activation of macrophage [39–44]. Activated STAT3 induces the upregulation of iNOS expression, increases NO production in keratinocytes, and promotes angiogenesis in the wound tissue [45].…”

Soluble Epoxide Hydrolase Inhibition for Ocular Diseases: Vision for the Future

“…The loss of sEH also restored wound-induced STAT3 signaling and heme oxygenase-1 (HO-1) expression that were downregulated by hyperglycemic conditions. Similarly, sEH inhibition with subconjunctival 10 nM t -AUCB or clinical candidate inhibitor GSK2256294A (Table 1) promoted epithelial wound healing and restored HO-1 expression in diabetic mouse corneas (Sun et al, 2018).…”

“…Diabetic keratopathy is characterized by delayed corneal epithelial wound healing and epithelial erosion, resulting in a compromised defense system against corneal injury and infective agents (Kaji, 2005). sEH is a potential therapeutic target for diabetic keratopathy, as tested in a mouse model where corneal erosions develop upon a single corneal debridement wound (Sun et al, 2018). The expression and enzymatic activity of sEH were increased in the corneal epithelial cells of streptozotocin-induced diabetic epithelial unwounded and wounded mice compared to control mice.…”