Role of dihydrofolate reductase in the regulation of endothelial function

• Project/Area Number: 15K08238
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: University of the Ryukyus
• Principal Investigator: Noguchi Katsuhiko 琉球大学, 医学部, 非常勤講師 (70156181)
• Co-Investigator(Kenkyū-buntansha): 筒井 正人 琉球大学, 医学(系)研究科(研究院), 教授 (70309962)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 一酸化窒素 / 血管内皮細胞機能 / ジヒドロビオプテリン / テトラヒドロビオプテリン / ジヒドロ葉酸還元酵素 / 酸化ストレス / 血管内皮細胞 / 血管内皮機能 / dihydrofolate reductase / 遺伝子導入マウス

Outline of Final Research Achievements

An elevation of oxidized forms of tetrahydrobiopterin (BH4), especially dihydrobiopterin (BH2), has been reported in the setting of oxidative stress, such as atherosclerotic disorders, where eNOS is dysfunctional, but a role of dihydrofolate reductase (DHFR), an enzyme catalyzing intracellular conversion of BH2 to BH4, in the regulation of endothelial function in vivo remains to be clarified. To this end, we generated novel mice with endothelium-specific deficiency of Dhfr gene, endothelium-specific and temporal deficiency of the gene and with endothelium-specific expression of DHFR transgene, and we examined characteristics of phenotypes of these mice.

Research Products

• [Journal Article] Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice. (2017)
  • Author(s): Kina-Tanada M, Sakanashi M, Tanimoto A, Kaname T, Matsuzaki T, Noguchi K, Uchida T, Nakasone J, Kozuka C, Ishida M, Kubota H, Taira Y, Totsuka Y, Kina SI, Sunakawa H, Omura J, Satoh K, Shimokawa H, Yanagihara N, Maeda S, Ohya Y, Matsushita M, Masuzaki H, Arasaki A, Tsutsui M.
  • Journal Title: Diabetologia. Volume: 60 Issue: 6 Pages: 1138-1152
  • DOI: 10.1007/s00125-017-4259-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Deleterious effect of all nitric oxide synthases in cerebral infarction in male mice: involvements of sex difference and testosterone. (2017)
  • Author(s): Tsutsui M, Kubota H, Noguchi K, Matsuzaki T, Sakanashi M, Nakasone J, Shimokawa H, Ohya Y, Sugahara K, Kakinohana M.
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Long-term dietary nitrite and nitrate deficiency causes metabolic syndrome, endothelial dysfunction, and cardiovascular death in mice. (2017)
  • Author(s): Tsutsui M, Kina-Tanada M, Kubota H, Sakanashi M, Matsuzaki T, Noguchi K, Nakasone J, Shimokawa H, Ohya Y, Arasaki A.
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Sex difference in sudden death of 2/3 nephrectomized triple nitric oxide synthases-deficient mice. (2017)
  • Author(s): Tsutsui M, Sakanashi M, Taira Y, Matsuzaki T, Noguchi K, Nakasone J, Ohya Y, Shimokawa H.
  • Organizer: IGM Congress 2017, The 8th Congress of the International Society for Gender Medicine.
  • Int'l Joint Research
• [Presentation] 脳梗塞におけるNO合成酵素の有害な作用：性差およびテストステロンの関与 (2017)
  • Author(s): 久保田陽秋、野口克彦、坂梨まゆ子、松崎俊博、仲宗根淳子、下川宏明、須加原一博、垣花 学、筒井正人
  • Organizer: 第46回日本心脈管作動物質学会