Key result
Inhibition of CYP with SKF-525a reduced hypoxia-induced VEGF production in astrocytes and inhibited retinal neovascularization in an oxygen-induced retinopathy rat model.
Why the study?
Does CYP inhibition reduce VEGF production and retinal neovascularization in preclinical models of hypoxia-induced angiogenesis?
Does CYP inhibition reduce VEGF production and retinal neovascularization in preclinical models of hypoxia-induced angiogenesis?
Inhibition of cytochrome P450 epoxygenases reduces VEGF production and retinal neovascularization in preclinical models, suggesting a potential therapeutic target for pathologic retinal angiogenesis.
Hypothesis-generating for CYP inhibition in retinal angiogenesis; prospective studies required before any clinical consideration.
PURPOSE: The purpose of this study was to investigate the role(s) of cytochrome P450 epoxygenases (CYPs) and their products, the epoxyeicosatrienoic acids (EETs), in hypoxia-induced VEGF production and pathologic retinal angiogenesis. METHODS: Human retinal astrocytes, Müller cells, and retinal microvascular endothelial cells (HRMEC) were exposed to hypoxia, and relative CYP2C expression was measured by RT-PCR. Astrocyte and Müller cell VEGF production was measured by ELISA after exposure to hypoxia and treatment with the general CYP inhibitor, SKF-525a. Human retinal microvascular endothelial cells were treated with the CYP product, 11,12-epoxyeicosatrienoic acid [EET], or SKF-525a in the presence or absence of VEGF. Proliferation of HRMEC and tube formation were assayed. Oxygen-induced retinopathy (OIR) was induced in newborn rats. Retinal CYP2C11 and CYP2C23 expression were measured by RT-PCR. The OIR rats received SKF-525a by intravitreal injection and preretinal neovascularization (NV) was quantified. Retinal VEGF protein levels were measured by ELISA. RESULTS: Human retinal astrocytes were the only cells to exhibit significant induction of CYP2C8 and CYP2C9 mRNA expression by hypoxia. Astrocytes, but not Müller cells, exhibited reduced hypoxia-induced VEGF production when treated with SKF-525a. 11,12-EET induced HRMEC proliferation and tube formation, and SKF-525a inhibited VEGF-induced proliferation. Oxygen-induced retinopathy induced expression of CYP2C23, but had no effect on CYP2C11. SKF-525a inhibited retinal NV and reduced retinal VEGF levels in OIR rats. CONCLUSIONS: The CYP-derived 11,12-EET may exhibit a proangiogenic biological function in the retina following stimulation by hypoxia in astrocytes. Inhibition of CYP may provide a rational therapy against retinal NV, because it can reduce VEGF production and VEGF-induced angiogenic responses in endothelial cells.
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Capozzi et al. (2014) studied Pathologic retinal angiogenesis and oxygen-induced retinopathy. SKF-525a (CYP inhibitor) and 11,12-EET was evaluated on VEGF production, cell proliferation, tube formation, and preretinal neovascularization. Inhibition of CYP with SKF-525a reduced hypoxia-induced VEGF production in astrocytes and inhibited retinal neovascularization in an oxygen-induced retinopathy rat model.
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