Elucidation of roles of Na^+-driven cation transporter in blood pressure control and arterial lesions

阐明Na^驱动的阳离子转运蛋白在血压控制和动脉病变中的作用

• 批准号: 14570097
• 负责人: IWAMOTO Takahiro
• 金额: $ 2.37万
• 依托单位: Fukuoka University (2003)National Cardiovascular Center Research Institute (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570097/
• 关键词: Na^+; Ca^<2+> exchanger; Hypertension; Calcium ion; Salt-sensitivity; Vasodilation; トランスジェニックマウス; 食塩感受性高血圧; 心肥大; 血管肥厚; 腎臓障害; 血管拡張

Excessive salt intake is a major risk factor for hypertension Here we identify the role of Na^+/Ca^<2+> exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor for Ca^<2+> entry via NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in normotensive rats or other types of hypertensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increases arterial blood flow indicating peripheral vasodilation. SEA0400 reverses ouabain-induced cytosolic Ca^<2+> elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deflcient mice have low salt-sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt SEA0400 significantly lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca^<2+> entry via NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.

过量的盐摄入是高血压的主要危险因素，我们确定了使用SEA0400的Na^+/Ca^<2+>交换器类型1（NCX1）在盐敏感的高血压中的作用，SEA0400是通过NCX1进行CA^<2+>进入的特异性抑制剂，以及基因工程的小鼠。 SEA0400降低了依赖盐的高血压大鼠模型中的动脉血压，但在正常的大鼠或其他类型的高血压大鼠中降低了动脉血压。在盐依赖性高血压大鼠中将SEA0400输注到股动脉中增加了动脉血流，表明周围血管舒张。 SEA0400逆转了Ouabain引起的胞质Ca^<2+>升高和血管收缩的动脉。 Furthermore, heterozygous NCX1-deflcient mice have low salt-sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt SEA0400 significantly lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants.这些发现表明，对盐敏感的高血压是由Ca^<2+>通过NCX1进入动脉平滑肌的触发的，并建议NCX1抑制剂在治疗上可能是有用的。

项目成果

Iwamoto, T.: "Functional analysis of Na^+/Ca^<2+> exchanger using novel drugs and genetically engineered mice."Folia Pharmacol.Jpn.. 120-Suppl1. 91-93 (2002)

Iwamoto, T.：“使用新型药物和基因工程小鼠对Na ^ /Ca ^ 2 交换器进行功能分析。”Folia Pharmacol.Jpn.. 120-Suppl1。

Wakimoto, K.: "Na^+/Ca^<2+> exchanger-deficient mice have disorganized myofibrils and swollen mitochondria in cardiomyocytes."Comp.Biochem.Physiol.B.Biochem.Mol.Biol.. 135-1. 9-15 (2003)

Wakimoto，K.：“Na ^ /Ca ^ 2 交换器缺陷小鼠的心肌细胞中的肌原纤维紊乱和线粒体肿胀。”Comp.Biochem.Physiol.B.Biochem.Mol.Biol.. 135-1。

Iwamoto, T.: "Development and application of Na^+/Ca^<2+> exchange inhibitors"Mol.Cell.Biochem.. 259・1-2. 157-161 (2004)

Iwamoto, T.：“Na^+/Ca^<2+>交换抑制剂的开发和应用”Mol.Cell.Biochem.. 259・1-2(2004)。

Iwamoto, T.: "Na^+/Ca^<2+> exchanger and ischemia/reperfusion injury."Heart View. 7-12. 126-131 (2003)

Iwamoto, T.：“Na^/Ca^<2>交换器和缺血/再灌注损伤。”心脏视图。

Iwamoto, T.: "Molecular determinants of Na^+/Ca^<2+> exchanger (NCX1) inhibition by SEA0400."J.Biol.Chem.. 279・9. 187-198 (2004)

Iwamoto, T.：“SEA0400 抑制 Na^+/Ca^2+> 交换器 (NCX1) 的分子决定因素。J.Biol.Chem.. 187-198 (2004)”