Research on mechanisms for vascular action of adrenomedullin

肾上腺髓质素血管作用机制研究

• 批准号: 10218202
• 负责人: HIRATA Yasunobu
• 金额: $ 42.05万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10218202/
• 关键词: adrenomedullin; nitric oxide; endothelium; PI3-K; Akt; vasodilation; knockout mice; ischemia; アドレノメデュリン; cGMP; cAMP; アポトーシス; 低酸素; 遺伝子; 尿細管; 血管平滑筋細胞

Adrenomedullin is a vasodilatory peptide and major source of circulating adrenomedullin is the vascular wall. The vascular action of adrenomedullin was at first considered to solely due elevated cAMP production, I. e., endothelium-independent vasodilation. However, we found that endothelial denudation substantially reduced the vasodilatory action of adrenomedullin in rodent aortic rings. Furthermore, this adrenomedullin-induced endothelium-dependent vasorelaxation is exerted mostly through activation of the phosphatydil inositol 3-kinase (PI3-K)/Akt pathway. It has been well established that this pathway is involved in various important actions such as anti-apoptosis and tissue protection as well as activation of endothelial nitric oxide synthase (eNOS).Furthermore, we have reported that expression of the adrenomedullin gene is upregulated by hypoxia. Adrenomedullin abrogates ischemia/reperfusion renal injury. Studies using adrenomedullin gene knockout mice revealed that adrenomedullin plays an important role in vascular formation in embryos. Adrenomedullin transgenic mice were resistant to ischemia/reperfusion renal injury and adrenomedullin knockout mice vice versa. These findings suggest that endogenous adrenomedullin may play an important role as a tissue survival factor.

肾上腺髓质素是一种血管舒张肽，其主要来源是血管壁。肾上腺髓质素的血管作用最初被认为仅仅是由于cAMP的产生升高，即内皮非依赖性血管舒张。然而，我们发现内皮剥脱大大降低了肾上腺髓质素在啮齿动物主动脉环中的血管舒张作用。此外，这种肾上腺髓质素诱导的内皮依赖性血管松弛主要是通过激活磷酸二醇肌醇3-激酶(PI3-K)/Akt通路来实现的。已证实该通路参与多种重要作用，如抗凋亡和组织保护以及内皮型一氧化氮合酶（eNOS）的激活。此外，我们已经报道了缺氧会上调肾上腺髓质素基因的表达。肾上腺髓质素消除肾缺血/再灌注损伤。对肾上腺髓质素基因敲除小鼠的研究表明，肾上腺髓质素在胚胎血管形成中起重要作用。肾上腺髓质素转基因小鼠对缺血/再灌注肾损伤具有抵抗性，而肾上腺髓质素敲除小鼠对缺血/再灌注肾损伤具有抵抗性。这些发现提示内源性肾上腺髓质素可能作为组织存活因子发挥重要作用。

项目成果

Nishimatsu H, Suzuki E, Nagata D, Moriyama N, Satonaka H, Walsh K, Sata M, Kangawa K, Matsuo H, Goto A, Kitamura T, Hirata Y: "Adrenomedullin induces endothelium-dependent vasorelaxation via the phosphatidylinositol 3 kinase/akt-dependent pathway in rat a

Nishimatsu H、Suzuki E、Nagata D、Moriyama N、Satonaka H、Walsh K、Sata M、Kangawa K、Matsuo H、Goto A、Kitamura T、Hirata Y：“肾上腺髓质素通过磷脂酰肌醇 3 激酶/akt 诱导内皮依赖性血管舒张

Kakoki M,Hirata Y, et al.: "Effects of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure."J Am Soc Nephrol. 11. 301-309 (2000)

Kakoki M、Hirata Y 等人：“四氢生物蝶呤对缺血性急性肾衰竭大鼠内皮功能障碍的影响。”J Am Soc Nephrol。

Suzuki E,Hirata Y, et al.: "Reentry into the cell cycle of contact-inhibited vascular endothelial cells by a phosphatase inhibitor : possible involvement of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase."J Biol Chem. 275. 3637-36

Suzuki E、Hirata Y 等人：“通过磷酸酶抑制剂重新进入接触抑制的血管内皮细胞的细胞周期：可能涉及细胞外信号调节激酶和磷脂酰肌醇 3-激酶。”J Biol Chem。

Nishimatsu H, Hirata Y, Hayakawa H, Nagata D, Satonaka H, Suzuki E, Horie S, Takeuchi T, Ohta N, Homma Y, Minowada S, Nagai R, Kawabe K, Kitamura T: "Effects of intracavemous administration of adrenomedullin on erectile function in rats"Peptides. 22. 1913

Nishimatsu H、Hirata Y、Hayakawa H、Nagata D、Satonaka H、Suzuki E、Horie S、Takeuchi T、Ohta N、Homma Y、Minowada S、Nagai R、Kawabe K、Kitamura T：“肾上腺髓质素的海绵体内给药对

Sata M, Hirata Y et al.: "Hematopoietic stem cells differentiate into vascular cells that particiate in the pathogenesis of atherosclerosis"Nature Med. 8. 403-409 (2002)

Sata M、Hirata Y 等人：“造血干细胞分化为参与动脉粥样硬化发病机制的血管细胞”Nature Med。