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- Title
Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity.
- Authors
Jiong Hu; Bibli, Sofia-Iris; Wittig, Janina; Zukunft, Sven; Jihong Lin; Hammes, Hans-Peter; Popp, Rüdiger; Fleming, Ingrid; Hu, Jiong; Lin, Jihong
- 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.
- Subjects
EPOXIDE hydrolase; POLY ADP ribose; RETROLENTAL fibroplasia; ADP-ribosyltransferases; UNSATURATED fatty acids; DOCOSAHEXAENOIC acid; DNA metabolism; TYROSINE metabolism; OXYGEN metabolism; ANIMAL experimentation; ANIMAL populations; APOPTOSIS; CELL physiology; CELLS; COMPARATIVE studies; DNA; EPITHELIAL cells; HYDROLASES; RESEARCH methodology; MEDICAL cooperation; MICE; MITOCHONDRIA; NEOVASCULARIZATION; RESEARCH; RETINA; PHENOTYPES; EVALUATION research; HYPEROXIA
- Publication
Journal of Clinical Investigation, 2019, Vol 129, Issue 12, p5204
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI123835