Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity

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

doi:10.1172/jci123835

Cited by 19 publications

(14 citation statements)

References 50 publications

(75 reference statements)

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“…3 Experimental studies on oxygen-induced retinopathy that used a rodent ROP model reported the protective benefits of DHA-derived oxidized metabolites for sprouting angiogenesis and astrocyte survival. 4,5 With the current neonatal care, extremely preterm infants accumulate substantial deficits in AA and DHA, which could be factors in neonatal morbidities, including ROP. 3,[6][7][8] The requirement for AA supplementation in preterm infants remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants

et al. 2021

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IMPORTANCE Supplementing preterm infants with long-chain polyunsaturated fatty acids (LC-PUFA) has been inconsistent in reducing the severity and incidence of retinopathy of prematurity (ROP). Furthermore, few studies have measured the long-term serum lipid levels after supplementation.OBJECTIVE To assess whether ROP severity is associated with serum levels of LC-PUFA, especially docosahexaenoic acid (DHA) and arachidonic acid (AA), during the first 28 postnatal days. DESIGN, SETTING, AND PARTICIPANTSThis cohort study analyzed the Mega Donna Mega study, a randomized clinical trial that provided enteral fatty acid supplementation at 3 neonatal intensive care units in Sweden. Infants included in this cohort study were born at a gestational age of less than 28

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Section: Introductionmentioning

confidence: 99%

Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants

et al. 2021

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“…We have previously used cell-specific sEH knockout models to show the expression of the sEH in the murine retina is highest in Müller cells but that astrocytes also express the enzyme. While the Müller cell sEH had the most impact on physiological angiogenesis and diabetic retinopathy astrocyte-derived products of the sEH can affect the retinal vascular phenotype in a model of retinopathy of prematurity 56 . In the PKD rat the most marked changes in sEH expression were in cell that spanned the entire retina and thus more closely correspond to Müller cells, however we cannot exclude that the expression of the sEH in the PKD rat was also increased in astrocytes.…”

Section: Discussionmentioning

confidence: 97%

“…However, there was no evidence of retinal capillary pericyte overgrowth under physiological conditions. Rather, by comparing the consequences of sEH expression and 19,20-DHDP on physiological angiogenesis and in diabetic retinopathy it seems that low concentrations of the DHA-derived diol promotes angiogenesis and vascular development, while higher concentrations do the opposite and interfere with cholesterol-binding proteins in membranes to promote pericyte loss and vasoregression 62 . Altered Notch signaling results in microglial activation 63 , implying that the same signaling pathway can concomitantly regulate microglia activity and vasoregression.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of Soluble Epoxide Hydrolase Inhibition in Retinal Vasculopathy associated with Polycystic Kidney Disease

Lin¹,

Hu²,

Schlotterer³

et al. 2020

Theranostics

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Rationale: Vasoregression secondary to glial activation develops in various retinal diseases, including retinal degeneration and diabetic retinopathy. Photoreceptor degeneration and subsequent retinal vasoregression, characterized by pericyte loss and acellular capillary formation in the absence diabetes, are also seen in transgenic rats expressing the polycystic kidney disease (PKD) gene. Activated Müller glia contributes to retinal vasodegeneration, at least in part via the expression of the soluble epoxide hydrolase (sEH). Given that an increase in sEH expression triggered vascular destabilization in diabetes, and that vasoregression is similar in diabetic mice and PKD rats, the aim of the present study was to determine whether sEH inhibition could prevent retinal vasoregression in the PKD rat. Methods: One-month old male homozygous transgenic PKD rats were randomly allocated to receive vehicle or a sEH inhibitor (sEH-I; Sar5399, 30 mg/kg) for four weeks. Wild-type Sprague-Dawley (SD) littermates received vehicle as controls. Retinal sEH expression and activity were measured by Western blotting and LC-MS, and vasoregression was quantified in retinal digestion preparations. Microglial activation and immune response cytokines were assessed by immunofluorescence and quantitative PCR, respectively. 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) mediated Notch signaling, microglial activation and migration were assessed in vivo and in vitro . Results: This study demonstrates that sEH expression and activity were increased in PKD retinae, which led to elevated production of 19,20-DHDP and the depression of Notch signaling. The latter changes elicited pericyte loss and the recruitment of CD11b + /CD74 + microglia to the perivascular region. Microglial activation increased the expression of immune-response cytokines, and reduced levels of Notch3 and delta-like ligand 4 (Dll4). Treatment with Sar5399 decreased 19,20-DHDP generation and increased Notch3 expression. Sar5399 also prevented vasoregression by reducing pericyte loss and suppressed microglial activation as well as the expression of immune-response cytokines. Mechanistically, the activation of Notch signaling by Dll4 maintained a quiescent microglial cell phenotype, i.e. reduced both the surface presentation of CD74 and microglial migration. In contrast, in retinal explants, 19,20-DHDP and Notch inhibition both promoted CD74 expression and reversed the Dll4-induced decrease in migration. Conclusions: Our data indicate that 19,20-DHDP-induced alterations in Notch-signaling result in microglia activation and pericyte loss and contribute to retinal vasoregression in polycystic kidney disease. Moreover, sEH inhibition can ameliorate vasoregression through reduced activity of inflammatory microglia. sEH inhibition is thus an attractive new therapeutic approach to prevent retinal vas...

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“…Yu et al used TDP-43 transgenic mice to demonstrate that TDP-43 can invade mitochondria and release mtDNA through permeability transition pores [ 75 ]; TDP-43 has also been shown to induce astrocyte inflammation [ 76 ]. Hu found that hypoxia-induced mtDNA damage could lead to apoptosis in mouse astrocytes [ 77 ]. Ignatenko et al used replicative mtDNA decapping enzyme Twinkle (TwKO) inactivation to induce mtDNA depletion in mouse neurons and astrocytes and found that mtDNA deletion caused astrocyte overactivation to induce early onset neurological disease [ 78 ].…”

Section: Ros-induced Mitochondrial Dysfunction Promotes Neurodegeneration Through the Release Of Mtdnamentioning

confidence: 99%

ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression

Zhao

Liu

et al. 2021

Antioxidants

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One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis, is microglia-mediated and astrocyte-mediated neuroinflammation. Although inhibitions of both harmful proteins and aggregation are major treatments for neurodegenerative diseases, whether the phenomenon of non-normal protein or peptide aggregation is causally related to neuronal loss and synaptic damage is still controversial. Currently, excessive production of reactive oxygen species (ROS), which induces mitochondrial dysfunction in neurons that may play a key role in the regulation of immune cells, is proposed as a regulator in neurological disorders. In this review, we propose that mitochondrial DNA (mtDNA) release due to ROS may act on microglia and astrocytes adjacent to neurons to induce inflammation through activation of innate immune responses (such as cGAS/STING). Elucidating the relationship between mtDNA and the formation of a pro-inflammatory microenvironment could contribute to a better understanding of the mechanism of crosstalk between neuronal and peripheral immune cells and lead to the development of novel therapeutic approaches to neurodegenerative diseases.

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Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity

Cited by 19 publications

References 50 publications

Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants

Association of Docosahexaenoic Acid and Arachidonic Acid Serum Levels With Retinopathy of Prematurity in Preterm Infants

Protective effect of Soluble Epoxide Hydrolase Inhibition in Retinal Vasculopathy associated with Polycystic Kidney Disease

ROS-Induced mtDNA Release: The Emerging Messenger for Communication between Neurons and Innate Immune Cells during Neurodegenerative Disorder Progression

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