Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

Abstract

Diabetic retinopathy is an important cause of blindness in the adult population1,2 and is characterized by a progressive loss of vascular cells and slow dissolution of inter-vascular junctions resulting in vascular leak and retinal edema3. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization4,5. Here we identify the soluble epoxide hydrolase (sEH) as a key enzyme that initiates the pericyte “drop off” and loss of endothelial barrier function by generating a diol from docosahexaenoic acid (DHA) i.e. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). The expression of the sEH and the accumulation of 19,20-DHDP were elevated in diabetic murine and human retinas as well as in human vitreous. Mechanistically, the diol targeted the cell membrane to alter the localisation of cholesterol-binding proteins, and interfered with the association of presenilin 1 (PS1) with N-cadherin and VE-cadherin to compromise pericyte-endothelial cell as well as inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Overexpression of the sEH in the retinal Müller glial cells of non-diabetic mice, on the other hand, resulted in vessel abnormalities similar to those seen in diabetic animals with retinopathy. Thus, increased expression of the sEH is a determinant event in the pathogenesis of diabetic retinopathy and sEH inhibition can prevent the progression of the disease.

Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity

“…The deletion or inhibition of sEH in the postnatal retina impedes angiogenesis and retinal vascularization (15), as well as the revascularization described herein. In adults, however, markedly increased expression of sEH, such as that detected in diabetes, is associated with a pronounced increase in 19,20-DHDP production that has been linked to the dissolution of intracellular junctions and the vascular destabilization associated with diabetic retinopathy (25) and possibly also wet age-related macular degeneration (36). The overexpression of sEH in retinal Müller cells was sufficient to elicit retinopathy in nondiabetic WT mice (25).…”

“…Astrocytes from sEH -/mice were more susceptible to hyperoxia-induced changes in the mitochondrial membrane potential than astrocytes from WT littermates, a phenomenon that was reversed following the addition of 19,20 DHDP but not 19,20-EDP ( Figure 8A). Little is known about the effects of PUFA diols on organelle membrane integrity, but our previous observations (15,25) indicated that 19,20-DHDP can influence membrane cholesterol distribution. This finding was relevant inasmuch as increased mitochondrial membrane cholesterol results in mitochondrial damage and death (26).…”

“…19,20-DHDP, but not 19,20-EDP, decreased cholesterol levels in the mitochondrial membrane and partially prevented the reduction in membrane potential triggered by cholesterol. The cholesterol-interacting protein, PS-1, was previously characterized as a target of 19,20-DHDP (15,25) and was of interest, as it has also been attributed to γ-secretase-dependent and -independent proapoptotic effects in mitochondria (27,28). Given the lack of effect of DAPT on astrocyte loss in the mouse model, work focused on γ-secretase-independent actions of PS-1, which are mainly mediated by its interaction with the PS-1-associated protein (PSAP; also known as mitochondrial carrier homolog 1) (28).…”

Chiral lipidomics of monoepoxy and monohydroxy metabolites derived from long-chain polyunsaturated fatty acids

“…Moreover, we observed that the fold-change was much more pronounced with the enantiomers than with the total levels of the corresponding regioisomers. This shift in enantiomeric composition has not been analyzed before, but might have significantly contributed to the beneficial effects of genetic or pharmacological sEH inhibition as observed in various animal models of cardiovascular and inflammatory diseases (24,25,39,40). Also, the enantioselectivity of mEH may provide a novel clue for understanding the role of this enzyme in human diseases (41,42).…”

Endocannabinoid Virodhamine Is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase

“…16,20,24–26 These metabolites are targets of both FAAH and soluble epoxide hydrolase (sEH) which degrades CYP epoxygenase-derived eCB metabolites to yield the corresponding diol product, which is a current target for the development of anti-inflammatory drugs. 5,14,27,28 …”