Biopterin regulation and its association with NOS activity in vascular endothelial cells

生物蝶呤调节及其与血管内皮细胞NOS活性的关系

• 批准号: 12670689
• 负责人: HATTORI Yoshiyuki
• 金额: $ 1.79万
• 依托单位: Dokkyo University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670689/
• 关键词: tetrahydrobiopterin; NO synthase; statin; テトラヒドロビオプテリン; 一酸化窒素合成酵素; 血管内皮細胞; 一酸化窒素; ビオプテリン; 酸化ストレス

Statin increased cellular biopterin by inducing GTPCH gene expression. This seems to enhance formation of NO and reudce uncoupling of NOS leading to NOS-mediated reduction of oxygen and formation of superoxide anions and hydrogen peroxide. Statin therefore increase eNOS activity by not only inducing eNOS itself but also increasing available BH4. This study indicates that statin increased stability of eNOS mRNA but not that of GTPCH mRNA, suggesting that upregulation of GTPCH mRNA by statin is induced by transcriptional activatoin.NO producibility was investigated in VSMC, in which BH4 synthesis is able only via salvage pathway but de novo pathway is disable, using 2,4-diamino-6-hydroxypyrimidine (DAHP), a, selective inhibitor of GTPCH. The present data shows that BH4, BH2, and sepiapterin dose- dependently increased NO production and increased intracellular biopterin levels. NO producibility as a functon of concentrations was BH4 << BH2 < sepiapterin, and similarly intracellular biopterin concentration was BH4 << BH2 < sepiapterin.

他汀类药物通过诱导GTPCH基因表达增加细胞生物喋呤。这似乎增强了NO的形成并导致NOS解偶联，从而导致NOS介导的氧还原以及超氧阴离子和过氧化氢的形成。因此，他汀类药物不仅通过诱导eNOS本身，而且还通过增加可利用的BH 4来增加eNOS活性。本研究用GTPCH选择性抑制剂2，4-diamino-6-hydroxypyrimidine（DAHP），观察了仅能通过补救途径合成BH_4而不能通过从头途径合成BH_4的VSMC产生NO的情况。本数据显示，BH 4、BH 2和墨蝶呤剂量依赖性地增加NO产生并增加细胞内生物蝶呤水平。NO生成量随浓度的变化规律为BH_4 <<BH_2 < sepiapterin，细胞内生物蝶呤浓度随浓度的变化规律为BH_4 <<BH_2 < sepiapterin。