title: Endothelial HO-1 induction by model TG-rich lipoproteins is regulated through a NOX4-Nrf2 pathway.
abstract: Circulating levels of chylomicron remnants (CMRs) increase postprandially and their composition directly reflects dietary lipid intake. These TG-rich lipoproteins likely contribute to the development of endothelial dysfunction, albeit via unknown mechanisms. Here, we investigated how the FA composition of CMRs influences their actions on human aortic endothelial cells (HAECs) by comparing the effects of model CMRs-artificial TG-rich CMR-like particles (A-CRLPs)-containing TGs extracted from fish, DHA-rich algal, corn, or palm oils. HAECs responded with distinct transcriptional programs according to A-CRLP TG content and oxidation status, with genes involved in antioxidant defense and cytoprotection most prominently affected by n-3 PUFA-containing A-CRLPs. These particles were significantly more efficacious inducers of heme oxygenase-1 (HO-1) than n-6 PUFA corn or saturated FA-rich palm CRLPs. Mechanistically, HO-1 induction by all CRLPs requires NADPH oxidase 4, with PUFA-containing particles additionally dependent upon mitochondrial reactive oxygen species. Activation of both p38 MAPK and PPARβ/δ culminates in increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression/nuclear translocation and HO-1 induction. These studies define new molecular pathways coupling endothelial cell activation by model CMRs with adaptive regulation of Nrf2-dependent HO-1 expression and may represent key mechanisms through which dietary FAs differentially impact progression of endothelial dysfunction.
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, United Kingdom.
authors.forename: Sally H
authors.initials: SH
authors.lastname: Latham Birt
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Purcell
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, United Kingdom.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Botham
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, United Kingdom cwheeler@rvc.ac.uk.
authors.forename: Caroline P D
authors.initials: CP
authors.lastname: Wheeler-Jones
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D053298:Chylomicron Remnants / Q000097:blood; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015525:Fatty Acids, Omega-3 / Q000097:blood; D005786:Gene Expression Regulation / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000097:blood / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008074:Lipoproteins / Q000097:blood; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000097:blood / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000097:blood / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D053298:Chylomicron Remnants; D015525:Fatty Acids, Omega-3; D008074:Lipoproteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D014280:Triglycerides; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human
keywords: artificial chylomicron remnant-like particles; cell signaling; endothelial cells; fatty acid; heme oxygenase-1; lipids/oxidation; nuclear factor erythroid 2-related factor 2; omega-3 fatty acids; reduced nicotinamide adenine dinucleotide phosphate oxidase 4; triglyceride