4-Hydroxy Hexenal Derived from Docosahexaenoic Acid Protects Endothelial Cells via Nrf2 Activation

Atsushi Ishikado, Katsutaro Morino, Yoshihiko Nishio, Fumiyuki Nakagawa, Atsushi Mukose, Yoko Sono, Nagisa Yoshioka, Keiko Kondo, Osamu Sekine, Takeshi Yoshizaki, Satoshi Ugi, Takashi Uzu, Hiromichi Kawai, Taketoshi Makino, Tomio Okamura, Masayuki Yamamoto, Atsunori Kashiwagi, Hiroshi Maegawa

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69 Citations (Scopus)


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.

Original languageEnglish
Article numbere69415
JournalPloS one
Issue number7
Publication statusPublished - 2013 Jul 23

ASJC Scopus subject areas

  • General


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