4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation.
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.
Department of Medicine, Shiga University of Medical Science, Shiga, Japan.
Atsushi
A
Ishikado
Katsutaro
K
Morino
Yoshihiko
Y
Nishio
Fumiyuki
F
Nakagawa
Atsushi
A
Mukose
Yoko
Y
Sono
Nagisa
N
Yoshioka
Keiko
K
Kondo
Osamu
O
Sekine
Takeshi
T
Yoshizaki
Satoshi
S
Ugi
Takashi
T
Uzu
Hiromichi
H
Kawai
Taketoshi
T
Makino
Tomio
T
Okamura
Masayuki
M
Yamamoto
Atsunori
A
Kashiwagi
Hiroshi
H
Maegawa
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D004249:DNA Damage; D004032:Diet; D004281:Docosahexaenoic Acids / Q000737:chemistry*; D015118:Eicosapentaenoic Acid / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D014664:Vasodilation / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C063409:4-hydroxyhexenal; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D051547:Heme Oxygenase-1; C546365:GCLM protein, human; D005721:Glutamate-Cysteine Ligase; C027576:4-hydroxy-2-nonenal