Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity
Jiong Hu, … , Rüdiger Popp, Ingrid Fleming
Jiong Hu, … , Rüdiger Popp, Ingrid Fleming
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(12):5204-5218. https://doi.org/10.1172/JCI123835.
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Research Article Angiogenesis Ophthalmology

Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity

Abstract

Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). Correspondingly, in a murine model of ROP, sEH–/– mice developed a larger central avascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by sEH deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1–associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss, but also reduced pathological vascular tuft formation in sEH–/– mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.

Authors

Jiong Hu, Sofia-Iris Bibli, Janina Wittig, Sven Zukunft, Jihong Lin, Hans-Peter Hammes, Rüdiger Popp, Ingrid Fleming

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Figure 9

Link between PS-1-PARP1 and mtDNA damage.

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Link between PS-1-PARP1 and mtDNA damage. (A) Immunoblot and densitometr...
(A) Immunoblot and densitometric analysis of PSAP and PS-1 following PS-1 immunoprecipitation from retinas of WT and sEH–/– (–/–) mice exposed to hyperoxia (75% O2) for 24 hours. n = 6 mice/group. (B) Cleaved caspase 3 (red), GFAP (green), and DAPI (blue) in cross sections from WT or sEH–/– retinas after exposure to hyperoxia for 24 hours. n = 6 mice/group. Scale bars: 50 μm. The arrows indicate GFAP+ cleaved caspase 3+ cells. (C) Immunoblot and densitometric analysis of PSAP and PS-1 following immunoprecipitation of PS-1 in astrocytes exposed to hyperoxia for 24 hours. n = 6 independent cell isolations. (D) Immunoblot of PARP1 in retinas from WT and sEH–/– mice. n = 6 mice/group. (E) mtDNA damage in retinas from WT and sEH–/– mice. n = 6–7 mice/group. (F) Immunoblot of PARP1 in astrocytes cultured in the presence of 21% O2 or 75% O2 for 24 hours in the presence of solvent (0.1% DMSO), 19,20-EDP (3 μM), or 19,20-DHDP (3 μM). (G) Fold enrichment of the D-Loop and ND-2 domains of mtDNA bound to the cleaved PARP1 in astrocytes exposed to 21% or 75% O2 for 24 hours. Cells were treated with solvent or EDP/DHDP (3 μM). n = 3 independent cell batches, each in duplicate. (H) mtDNA damage in astrocytes exposed to 21% or 75% O2 for 24 hours in the presence of solvent or EDP/DHDP (3 μM). n = 4 independent cell batches. (A–C) Student’s t test. (D–H) Two-way ANOVA with Tukey’s multiple comparisons test. *P < 0.05, **P < 0.01, and ***P < 0.001.