ArticleChemical research in toxicology2018
4-Hydroxy-7-oxo-5-heptenoic Acid Lactone Is a Potent Inducer of the Complement Pathway in Human Retinal Pigmented Epithelial Cells.
Article in Chemical research in toxicology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- (Photo)toxicity of Partially Oxidized Docosahexaenoate and Its Effect on the Formation of Lipofuscin in Cultured Human Retinal Pigment Epithelial Cells.Antioxidants (Basel, Switzerland) · 2024Article
- Complement C3 deficiency alleviates alkylation-induced retinal degeneration in mice.Eye and vision (London, England) · 2022Article
- Complement C3a receptor inactivation attenuates retinal degeneration induced by oxidative damage.Frontiers in neuroscience · 2022Article
- The complement system in age-related macular degeneration.Cellular and molecular life sciences : CMLS · 2021Review
- 4-Hydroxy-7-oxo-5-heptenoic acid (HOHA) lactone induces apoptosis in retinal pigment epithelial cells.Free radical biology & medicine · 2020Article
- Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update.Oxidative medicine and cellular longevity · 2020Review
- Down-regulation of Suv39h1 attenuates neointima formation after carotid artery injury in diabetic rats.Journal of cellular and molecular medicine · 2020Article
- Scavenging of Retinoid Cation Radicals by Urate, Trolox, and α-, β-, γ-, and δ-Tocopherols.International journal of molecular sciences · 2019Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
We previously discovered that oxidative cleavage of docosahexaenoate (DHA), which is especially abundant in the retinal photoreceptor rod outer segments and retinal pigmented endothelial (RPE) cells, generates 4-hydroxy-7-oxo-5-heptenoate (HOHA) lactone, and that HOHA lactone can enter RPE cells that metabolize it through conjugation with glutathione (GSH). The consequent depletion of GSH results in oxidative stress. We now find that HOHA lactone induces upregulation of the antioxidant transcription factor Nrf2 in ARPE-19 cells. This leads to expression of GCLM, HO1, and NQO1, three known Nrf2-responsive antioxidant genes. Besides this protective response, HOHA lactone also triggers a countervailing inflammatory activation of innate immunity. Evidence for a contribution of the complement pathway to age-related macular degeneration (AMD) pathology includes the presence of complement proteins in drusen and Bruch's membrane from AMD donor eyes, and the identification of genetic susceptibility loci for AMD in the complement pathway. In eye tissues from a mouse model of AMD, accumulation of complement protein in Bruch's membrane below the RPE suggested that the complement pathway targets this interface, where lesions occur in the RPE and photoreceptor rod outer segments. In animal models of AMD, intravenous injection of NaIO
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