The effects of omega-3 PUFA on vascular function

• Project/Area Number: 23591336
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kagoshima University
• Principal Investigator: NISHIO Yoshihiko 鹿児島大学, 医歯(薬)学総合研究科, 教授 (40281084)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 酸化ストレス / 血管内皮 / n-3 多価不飽和脂肪酸 / 魚油 / Nrf2 / 抗酸化

Research Abstract

We tested whether n-3 PUFAs showed antioxidant activity through the activation of Nrf2, a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2-/- mice were fed a fish-oil diet. 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 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 DHA rather than that in 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. Furthermore, DHA prevented oxidant-induced cellular damage and this effect was disappeared by the siRNA of Nrf2.

Research Products

• [Journal Article] A fish-based diet intervention improves endothelial function in postmenopausal women with type 2 diabetes mellitus : A randomized crossover trial (2014)
  • Author(s): Kondo K, Morino K, Nishio Y, Kondo M, Nakao K, Nakagawa F, Ishikado A, Sekine O, Yoshizaki T, Kashiwagi A, Ugi S, Maegawa H
  • Journal Title: Metabolism Volume: (In press)
  • Peer Reviewed
• [Journal Article] 4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs (2014)
  • Author(s): Nakagawa F, Morino K, Ugi S, Ishikado A, Kondo K, Sato D, Konno S, Nemoto K, Kusunoki C, Sekine O, Sunagawa A, Kawamura M, Inoue N, Nishio Y, Maegawa H
  • Journal Title: Biochem Biophys Res Commun Volume: 443(3) Pages: 991-6
  • Peer Reviewed
• [Journal Article] 4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation (2013)
  • Author(s): 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
  • Journal Title: PLoS One Volume: 8(7)
  • Peer Reviewed
• [Journal Article] Ezetimibe prevents hepatic steatosis induced by a high-fat but not a high-fructose diet (2013)
  • Author(s): Ushio M, Nishio Y, Sekine O, Nagai Y, Maeno Y, Ugi S, Yoshizaki T, Morino K, Kume S, Kashiwagi A, Maegawa H
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 305(2)
  • Peer Reviewed
• [Journal Article] Omega-3 polyunsaturated fatty acid has an anti-oxidant effect via the Nrf-2/HO-1 pathway in 3T3-L1 adipocytes (2013)
  • Author(s): Kusunoki C, Yang L, Yoshizaki T, Nakagawa F, Ishikado A, Kondo M, Morino K, Sekine O, Ugi S, Nishio Y, Kashiwagi A, Maegawa H
  • Journal Title: Biochem Biophys Res Commun Volume: 430(1) Pages: 225-30
  • Peer Reviewed
• [Journal Article] 4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs. (2013)
  • Author(s): Nakagawa F, Morino K, Ugi S, Ishikado A, Kondo K, Sato D, Konno S, Nemoto K, Kusunoki C, Sekine O, Sunagawa A, Kawamura M, Inoue N, Nishio Y, Maegawa H
  • Journal Title: Biochem Biophys Res Commun Volume: 443 Pages: 991-6
  • Peer Reviewed
• [Journal Article] 4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation. (2013)
  • Author(s): 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
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] Ezetimibe prevents hepatic steatosis induced by a high-fat but not a high-fructose diet. (2013)
  • Author(s): Ushio M, Nishio Y, Sekine O, Nagai Y, Maeno Y, Ugi S, Yoshizaki T, Morino K, Kume S, Kashiwagi A, Maegawa H
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 305
  • Peer Reviewed
• [Journal Article] Ethnic difference in liver fat content: a cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States (2013)
  • Author(s): Azuma K, Curb JD, Kadowaki T, Edmundowicz D, Kadowaki S, Masaki KH, El-Saed A, Nishio Y, Seto TB, Okamura T, Cetinel C, Kadota A, Sutton-Tyrrell K, Miura K, Evans RW, Takamiya T, Maegawa H, Miljkovic I, Kuller LH, Ueshima H, Kelley DE, Sekikawa A
  • Journal Title: Obes Res Clin Pract Volume: 7
  • Peer Reviewed
• [Journal Article] Omega-3 polyunsaturated fatty acid has an anti-oxidant effect via the Nrf-2/HO-1 pathway in 3T3-L1 adipocytes (2013)
  • Author(s): Kusunoki C, Yang L, Yoshizaki T, Nakagawa F, Ishikado A, Kondo M, Morino K, Sekine O, Ugi S, Nishio Y, Kashiwagi A, Maegawa H
  • Journal Title: Biochem Biophys Res Commun Volume: 430 Pages: 225-230
  • Peer Reviewed
• [Journal Article] Intraepidermal nerve fiber density and nerve conduction study parameters correlate with clinical staging of diabetic polyneuropathy (2013)
  • Author(s): Arimura A, Deguchi T, Sugimoto K, Uto T, Nakamura T, Arimura Y, Arimura K, Yagihashi S, Nishio Y, Takashima H
  • Journal Title: Diabetes Res Clin Pract Volume: 99 Pages: 24-29
  • Peer Reviewed
• [Journal Article] MicroRNA-494 regulates mitochondrial biogenesis in skeletal muscle through mitochondrial transcription factor A and Forkhead box j3 (2012)
  • Author(s): Yamamoto H, Morino K, Nishio Y, Ugi S, Yoshizaki T, Kashiwagi A, Maegawa H
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 303(12)
  • Peer Reviewed
• [Journal Article] Japanese Elderly Intervention Trial Research Group. Factors associated with progression of diabetic nephropathy in Japanese elderly patients with type 2 diabetes: sub-analysis of the Japanese Elderly Diabetes Intervention Trial (2012)
  • Author(s): Araki S, Nishio Y, Araki A, Umegaki H, Sakurai T, Iimuro S, Ohashi Y, Uzu T, Maegawa H, Kashiwagi A, Ito H
  • Journal Title: Geriatr Gerontol Int Volume: Suppl 1 Pages: 127-133
• [Journal Article] Autophagy regulates inflammation in adipocytes (2012)
  • Author(s): Yoshizaki T, Kusunoki C, Kondo M, Yasuda M, Kume S, Morino K, Sekine O, Ugi S, Uzu T, Nishio Y, Kashiwagi A, Maegawa H
  • Journal Title: Biochem Biophys Res Commun Volume: 417 Pages: 352-7
  • Peer Reviewed
• [Journal Article] GW501516, a PPARδ agonist, ameliorates tubulointerstitial inflammation in proteinuric kidney disease via inhibition of TAK1-NFκB pathway in mice. (2011)
  • Author(s): Yang X, Kume S, Tanaka Y, Isshiki K, Araki S, Chin-Kanasaki M, Sugimoto T, Koya D, Haneda M, Sugaya T, Li D, Han P, Nishio Y, Kashiwagi A, Maegawa H, Uzu T
  • Journal Title: PLoS One Volume: 6
  • Peer Reviewed
• [Journal Article] Differential association of docosahexaenoic and eicosapentaenoic acids with carotid intima-media thickness. (2011)
  • Author(s): Sekikawa A, Kadowaki T, El-Saed A, Okamura T, Sutton-Tyrrell K, Nakamura Y, Evans RW, Mitsunami K, Edmundowicz D, Nishio Y, et al
  • Journal Title: Stroke Volume: 42 Pages: 2538-43
  • Peer Reviewed
• [Journal Article] Postprandial activation of protein kinase Cμ regulates the expression of adipocytokines via the transcription factor AP-2β. (2011)
  • Author(s): Kondo M, Ugi S, Morino K, Fuke T, Obata T, Yoshizaki T, Nishio Y, Maeda S, Kashiwagi A, Maegawa H
  • Journal Title: Int J Mol Med Volume: 28 Pages: 95-100
  • Peer Reviewed
• [Journal Article] Association between serum soluble TNFα receptors and renal dysfunction in type 2 diabetic patients without proteinuria. (2011)
  • Author(s): Miyazawa I, Araki S, Obata T, Yoshizaki T, Morino K, Kadota A, Ugi S, Kawai H, Uzu T, Nishio Y, Koya D, Haneda M, Kashiwagi A, Maegawa H.
  • Journal Title: Diabetes Res Clin Pract Volume: 92 Pages: 174-80
  • Peer Reviewed
• [Presentation] 血管内皮細胞機能改善をめざした治療戦略 (2013)
  • Author(s): 西尾善彦
  • Organizer: 第23回日本糖尿病合併症学会シンポジウム3
  • Place of Presentation: 旭川
  • Year and Date: 2013-09-13
• [Presentation] The effects of omega-3 PUFA on vascular function (2013)
  • Author(s): 西尾善彦
  • Organizer: 第56回日本糖尿病学会Symposium 15 (Diabetes and Macrovascular Complications)
  • Place of Presentation: 熊本
  • Year and Date: 2013-05-18
• [Presentation] A high-fiber diet improves M1/M2 phenotype as well as the vascular function in the patients with type 2 diabetes mellitus (2012)
  • Author(s): Keiko Kondo, Yoshihiko Nishio, Atsushi Ishikado et al.
  • Organizer: 72nd scientific sessions of American diabetes association
  • Place of Presentation: Philadelphia
• [Presentation] 多価不飽和脂肪酸による血管内皮での酸化ストレス抑制作用 (2011)
  • Author(s): 西尾善彦、石角篤、柏木厚典、前川聡
  • Organizer: 第４３回日本動脈硬化学会(招待講演)
  • Place of Presentation: 札幌
• [Presentation] HA Increases HO-1 Expression and Antioxidative Activity through the Activation of Nrf2 in Vascular Endothelial Cells. (2011)
  • Author(s): Atsushi Ishikado, Yoshihiko Nishio, Katsutaro Morino, Atsushi Mukose, Satoshi Ugi, Hajime Kondo, Yoko Murakami, Taketoshi Makino, Atsunori Kashiwagi, Hiroshi Maegawa
  • Organizer: 71st Scientific Sessions-American Diabetes Association
  • Place of Presentation: San Diego, CA, USA
• [Presentation] ω３不飽和脂肪酸による抗酸化治療
  • Author(s): 西尾善彦、石角篤、前川聡、柏木厚典
  • Organizer: 第２７回日本糖尿病合併症学会 シンポジウム４
  • Place of Presentation: 福岡市
  • Invited