Evaluation of the role of dihydrobiopterin in the regulation of endothelial function in the normal and pathological states

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590324
• 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(系)研究科(研究院), 准教授 (70156181)
• Co-Investigator(Kenkyū-buntansha): TSUTSUI Masato 琉球大学, 大学院医学研究科, 教授 (70309962)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 心血管 / 一酸化窒素 / 血管内皮細胞機能 / 酸化ストレス / 動脈硬化 / ジヒドロビオプテリン / テトラヒドロビオプテリン / dihydrofolate reductase

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 endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH2 in the regulation of endothelial function in vivo remains to be clarified. This study was conducted to evaluate the effect of pharmacologically increased levels of BH2 on development of atherosclerotic lesion using a mouse arteriosclerotic model. Two-week treatment with sepiapterin and methotrexate increased aortic levels of BH2 doubly, but exacerbation of atherosclerotic lesion was not clearly found probably because of unspecific drug actions. Thus, to clarify the role of dihydrofolate reductase (DHFR), an enzyme catalyzing intracellular conversion of BH2 to BH4, in the regulation of endothelial function in vivo, we have been generating a novel mouse model with endothelial cell-specific deletion of DHFR gene.

Free Research Field

循環器薬理学