Chemical Proteomics Reveals Soluble Epoxide Hydrolase as a Therapeutic Target for Ocular Neovascularization

Sulaiman, Rania S.; Park, Bomina; Pasha, Sheik Pran Babu Sardar; Si, Yubing; Kharwadkar, Rakshin; Mitter, Sayak K.; Lee, Bit; Sun, Wei; Qi, Xiaoping; Boulton, Michael E.; Meroueh, Samy O.; Xiang, Fenfen; Seo, Seung‐Yong; Corson, Timothy W.

doi:10.1021/acschembio.7b00854

Cited by 28 publications

(47 citation statements)

References 33 publications

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“…Frozen sections were cut at 15 µm on a cryostat (Leica Biosystems, Buffalo Grove, IL, USA), mounted on superfrost plus slides (Fisher Scientific, Pittsburgh, PA, USA), and stored at −80°C until use. Immunohistochemistry was performed using standard protocols 23,39,44 . Cryosections were pretreated with PBS and DNase antigen retrieval, followed by 1 hour in blocking solution (5% of bovine serum albumin (BSA) in 0.3% of Triton‐X 100‐PBS).…”

Section: Methodsmentioning

confidence: 99%

Ferrochelatase regulates retinal neovascularization

2020

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Ferrochelatase (FECH) is the terminal enzyme in heme biosynthesis. We previously showed that FECH is required for endothelial cell growth in vitro and choroidal neovascularization in vivo. But FECH has not been explored in retinal neovascularization, which underlies diseases like proliferative diabetic retinopathy and retinopathy of prematurity. Here, we investigated the inhibition of FECH using genetic and chemical approaches in the oxygen‐induced retinopathy (OIR) mouse model. In OIR mice, FECH expression is upregulated and co‐localized with neovascular tufts. Partial loss‐of‐function Fechm1Pas mutant mice showed reduced retinal neovascularization and endothelial cell proliferation in OIR. An intravitreal injection of the FECH inhibitor N‐methyl protoporphyrin had similar effects. Griseofulvin is an antifungal drug that inhibits FECH as an off‐target effect. Strikingly, intravitreal griseofulvin decreased both pathological tuft formation and areas of vasoobliteration compared to vehicle, suggesting potential as a FECH‐targeting therapy. Ocular toxicity studies revealed that intravitreal injection of griseofulvin in adult mice does not disrupt retinal vasculature, function, or morphology. In sum, mutation and chemical inhibition of Fech reduces retinal neovascularization and promotes physiological angiogenesis, suggesting a dual effect on vascular repair upon FECH inhibition, without ocular toxicity. These findings suggest that FECH inhibitors could be repurposed to treat retinal neovascularization.

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Section: Methodsmentioning

confidence: 99%

Ferrochelatase regulates retinal neovascularization

2020

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“…The role of CYP4V2 in xenobiotic metabolism of NCE has not been explored in depth. Additionally, soluble epoxide hydrolases and CYP2C8 were overexpressed in murine choroidal neovascularization models and consequently identified as research areas of interest (Hasegawa et al, 2017;Sulaiman et al, 2018).…”

Section: Models Of Ocular Drug Disposition and Toxicitymentioning

confidence: 99%

Models and Approaches Describing the Metabolism, Transport, and Toxicity of Drugs Administered by the Ocular Route

et al. 2018

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The eye is a complex organ with a series of anatomic barriers that provide protection from physical and chemical injury while maintaining homeostasis and function. The physiology of the eye is multifaceted, with dynamic flows and clearance mechanisms. This review highlights that in vitro ocular transport and metabolism models are confined by the availability of clinically relevant absorption, distribution, metabolism, and excretion (ADME) data. In vitro ocular transport models used for pharmacology and toxicity poorly predict ocular exposure. Although ocular cell lines cannot replicate in vivo conditions, these models can help rank-order new chemical entities in discovery. Historic ocular metabolism of small molecules was assumed to be inconsequential or assessed using authentic standards. While various in vitro models have been cited, no single system is perfect, and many must be used in combination. Several studies document the use of laboratory animals for the prediction of ocular pharmacokinetics in humans. This review focuses on the use of human-relevant and human-derived models which can be utilized in discovery and development to understand ocular disposition of new chemical entities. The benefits and caveats of each model are discussed. Furthermore, ADME case studies are summarized retrospectively and capture the ADME data collected for health authorities in the absence of definitive guidelines. Finally, we discuss the novel technologies and a hypothesis-driven ocular drug classification system to provide a holistic perspective on the ADME properties of drugs administered by the ocular route.

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“…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).…”

Section: Discussionmentioning

confidence: 99%