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Megan Capozzi, John Penn; A potential role for cytochrome P450 epoxygenases and their epoxyeicosatrienoic acid products in oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5560.
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© ARVO (1962-2015); The Authors (2016-present)
Epoxyeicosatrienoic acids (EETs) are autocoids derived from arachidonic acid by cytochrome P450 epoxygenase (CYP) enzymes. EETs act by both autocrine and paracrine mechanisms to cause hyperpolarization, promote survival, prevent inflammation, and induce angiogenesis in vascular endothelial cells. Therefore, we investigated the effect of pharmacologic addition of a stable EET analog or inhibition of CYPs on human retinal microvascular endothelial cell (HRMEC) behaviors and on development of neovascularization (NV) in the rat model of oxygen-induced retinopathy (OIR).
Immunohistochemistry was performed to determine the localization of CYP2J2, a well-characterized and potentially relevant CYP. Induction of HRMEC proliferation and tubulogenesis by VEGF were assessed in the presence of CYP inhibitor SKF-525a and synthetic 11,12-EET. The OIR rat model was used to assess the effect of CYP epoxygenase products on development of NV. Dose ranges of SKF-525a and 11,12-EET were intravitreally injected on 0 and 3 days post-oxygen exposure, and retinas were flat-mounted for NV analysis.
CYP2J2 was localized to the vasculature and the inner limiting membrane of the rat retina. CYP inhibition with SKF-525a (5.0μM) reduced VEGF-stimulated proliferation by 40.6% and tube formation by 48%. 11,12-EET (0.5μM) increased proliferation by 55.5% (p=0.0312) and tubulogenesis by 155.7% (p=0.0046). In rat OIR, SKF-525a reduced NV by 48.1% at the highest concentration (5.0μM; p=0.0239), compared to vehicle control.
Preliminary results support the hypothesis that 11,12-EET promotes HRMEC proliferation and tubulogenesis and inhibition of CYPs reduces these behaviors. In the rat model of OIR, CYP inhibition may serve as a therapeutic strategy for reducing subsequent NV.
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