Low concentration of 4-hydroxy hexenal increases heme oxygenase-1 expression through activation of Nrf2 and antioxidative activity in vascular endothelial cells

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• 作者：Atsushi Ishikado ; Yoshihiko Nishio ; Katsutaro Morino ; Satoshi Ugi ; Hajime Kondo ; Taketoshi Makino ; Atsunori Kashiwagi ; Hiroshi Maegawa
• 关键词：4-hydroxy hexenal ; 4-hydroxy nonenal ; n-3 polyunsaturated fatty acid ; Peroxidation ; Oxidative stress
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2010
• 出版时间：5 November 2010
• 年：2010
• 卷：402
• 期：1
• 页码：99-104
• 全文大小：449 K

文摘

Large-scale clinical studies have shown that n-3 polyunsaturated fatty acids (n-3 PUFAs) such as eicosapentaenoic and docosahexaenoic acids reduce cardiovascular events without improving classical risk factors for atherosclerosis. Recent studies have proposed that direct actions of n-3 PUFAs themselves, or of their enzymatic metabolites, have antioxidative and anti-inflammatory effects on vascular cells. Although a recent study showed that plasma 4-hydroxy hexenal (4-HHE), a peroxidation product of n-3 PUFA, increased after supplementation of docosahexaenoic acid, the antiatherogenic effects of 4-HHE in vascular cells remain unclear.

In the present study, we tested the hypothesis that 4-HHE induces the antioxidative enzyme heme oxygenase-1 (HO-1) through activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulatory transcriptional factor, and prevents oxidative stress-induced cytotoxicity in vascular endothelial cells. This mechanism could partly explain the cardioprotective effects of n-3 PUFAs.

Human umbilical vein endothelial cells were stimulated with 1–10 μM 4-HHE or 4-hydroxy nonenal (4-HNE), a peroxidation product of n-6 PUFAs. Both 4-HHE and 4-HNE dose-dependently increased HO-1 mRNA and protein expression, and intranuclear expression and DNA binding of Nrf2 at 5 μM. Small interfering RNA for Nrf2 significantly reduced 4-HHE- or 4-HNE-induced HO-1 mRNA and protein expression. Furthermore, pretreatment with 4-HHE or 4-HNE prevented tert-butyl hydroperoxide-induced cytotoxicity.

In conclusion, 4-HHE, a peroxidation product of n-3 PUFAs, stimulated expression of the antioxidant enzyme HO-1 through the activation of Nrf2 in vascular endothelial cells. This resulted in prevention of oxidative stress-induced cytotoxicity, and may represent a possible mechanism to partly explain the cardioprotective effects of n-3 PUFAs.