4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation

• Published in: PloS one Vol. 8; no. 7; p. e69415
• Main Authors: Ishikado, Atsushi, Morino, Katsutaro, Nishio, Yoshihiko, Nakagawa, Fumiyuki, Mukose, Atsushi, Sono, Yoko, Yoshioka, Nagisa, Kondo, Keiko, Sekine, Osamu, Yoshizaki, Takeshi, Ugi, Satoshi, Uzu, Takashi, Kawai, Hiromichi, Makino, Taketoshi, Okamura, Tomio, Yamamoto, Masayuki, Kashiwagi, Atsunori, Maegawa, Hiroshi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.07.2013; Public Library of Science (PLoS)
• Subjects: Activation; Adaptor Proteins, Signal Transducing - metabolism; Aldehydes - metabolism; Aldehydes - pharmacology; Animals; Antioxidants; Antioxidants (Nutrients); Antioxidants - pharmacology; Aorta; Aorta - drug effects; Aorta - physiology; Atherosclerosis; Bioassays; Biological assays; Biology; Body Weight - drug effects; Cellular manufacture; Cytoprotection - drug effects; Damage prevention; Deoxyribonucleic acid; Diabetes; Diet; DNA; DNA Damage; Docosahexaenoic acid; Docosahexaenoic Acids - chemistry; Eicosapentaenoic acid; Eicosapentaenoic Acid - chemistry; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Enzymes; Fatty acids; Fish oils; Gene expression; Gene Expression Regulation - drug effects; Genes; Glutamate-Cysteine Ligase - metabolism; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - metabolism; House mouse; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - enzymology; Humans; Inflammation; Laboratories; Lipid Peroxidation - drug effects; Male; Medicine; Metabolism; Metabolites; Mice; Molecular modelling; NF-E2-Related Factor 2 - metabolism; Oils & fats; Omega 3 fatty acids; Oxidation; Oxidation-Reduction - drug effects; Oxidative Stress - drug effects; Oxygen; Oxygenase; Peroxidation; Polyunsaturated fatty acids; R&D; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research & development; Rodents; Science; Sequestosome-1 Protein; siRNA; Studies; Transcription (Genetics); Umbilical vein; Unsaturated fatty acids; Vascular tissue; Vasodilation; Vasodilation - drug effects; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069415

Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra-aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra-vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA.