4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation.
4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation.
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源自二十六烯酸酸的4-羟基己烯酸通过NRF2激活保护内皮细胞。
DOI：
10.1371/journal.pone.0069415
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Maegawa H
中科院分区：
文献类型：
--
作者：
Ishikado A;Morino K;Nishio Y;Nakagawa F;Mukose A;Sono Y;Yoshioka N;Kondo K;Sekine O;Yoshizaki T;Ugi S;Uzu T;Kawai H;Makino T;Okamura T;Yamamoto M;Kashiwagi A;Maegawa H
最近的研究提出，n-3 多不饱和脂肪酸（n-3 PUFA）在血管组织中具有直接的抗氧化和抗炎作用，这解释了它们的心脏保护作用。然而，其分子机制尚未完全清楚。我们测试了 n-3 PUFA 是否通过激活核因子红细胞 2 相关因子 2 (Nrf2)（抗氧化基因的主要转录因子）而显示出抗氧化活性。 C57BL/6 或 Nrf2−/− 小鼠用鱼油饮食喂养 3 周。鱼油饮食显着增加了 C57BL/6 小鼠主动脉中血红素加氧酶-1 (HO-1) 的表达和内皮依赖性血管舒张，但在 Nrf2−/− 小鼠中则不然。此外，我们观察到，n-3 PUFA 过氧化的终产物 4-羟基己烯醛 (4-HHE) 在 C57BL/6 小鼠主动脉中显着增加，同时主动脉内二十二碳六烯酸 (DHA) 而非二十碳五烯酸 (EPA) 主要增加。将人脐静脉内皮细胞与 DHA 或 EPA 一起孵育。我们发现 DHA（而非 EPA）显着增加细胞内 4-HHE、Nrf2 的核表达和 DNA 结合。 DHA和4-HHE都增加了Nrf2靶基因（包括HO-1）的表达，而Nrf2的siRNA消除了这些作用。此外，DHA 可以防止氧化剂引起的细胞损伤或活性氧的产生，而这些作用可以被 HO-1 抑制剂或 Nrf2 的 siRNA 消除。因此，我们发现DHA通过血管组织中的Nrf2激活而发挥保护作用，并伴随血管内4-HHE的增加，这可能解释了DHA的心脏保护作用的机制。
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.
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影响因子：
20.1
作者：
Dai, Guohao;Vaughn, Saran;Gimbrone, Michael A., Jr.
通讯作者：
Gimbrone, Michael A., Jr.
影响因子：
3.6
作者：
Gladine, Cecile;Roy, Nicole C.;Comte, Blandine
通讯作者：
Comte, Blandine
影响因子：
37.8
作者：
Mori, TA;Watts, GF;Beilin, LJ
通讯作者：
Beilin, LJ
影响因子：
5.3
作者：
Calzada, Catherine;Colas, Romain;Lagarde, Michel
通讯作者：
Lagarde, Michel
影响因子：
158.5
作者：
KROMHOUT, D;BOSSCHIETER, EB;COULANDER, CD
通讯作者：
COULANDER, CD