Role of apoptosis of vascular endothelial cells In atherosclerosis

血管内皮细胞凋亡在动脉粥样硬化中的作用

• 批准号: 13470141
• 负责人: HIRATA Yasunobu
• 金额: $ 7.1万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470141/
• 关键词: calcineurin; arteriosclerosis; MCP-I; adenovirus; VSMC; macrophage; apoptosis; アンジオテンシンII; 細胞内シグナル; NFAT3; calcineurin; MEF2A

Although the role of the calcineurin-dependent pathway in the development of cardiac hypertrophy has been intensively studied little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To help elucidate the role of calcineurin in vascular inflammation, we infected cultured vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a constitutively active mutant of calcineurin, and examined its effect on the expression of monocyte chemoattractant protein-1 (MCP-1). We also examined the role of calcineurin in vivo using a transluminal wire injury model of the rat femoral artery. Forced activation of calcineurin significantly increased the expression of MCP-1 both at the transcriptional and protein levels, Angiotensin II (Ang II) also significantly stimulated MCP-1 expression, and this increase was significantly inhibited by cyclosporin A (CyA). Constitutive activation of calcineurin stabilized MCP-1 mRNA without enhancing MCP-1 promoter activity. In accordance with the results, Ang II-induced increase of MCP-1 promoter activity was not suppressed by CyA. Ang II stabilized MCP-1 mRNA, and this effect of Ang II was diminished by CyA. CyA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. CyA also inhibited macrophage Infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that calcineurin mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophage infiltration.

虽然钙调神经磷酸酶依赖性通路在心肌肥厚发展中的作用已被深入研究，但其在血管炎性疾病如动脉粥样硬化和血管成形术后再狭窄中的作用知之甚少。为了帮助阐明钙调神经磷酸酶在血管炎症中的作用，我们用表达钙调神经磷酸酶组成型活性突变体的腺病毒构建体感染培养的血管平滑肌细胞（VSMCs），并研究其对单核细胞趋化蛋白-1（MCP-1）表达的影响。我们还研究了钙调神经磷酸酶在体内使用的大鼠股动脉的经腔线损伤模型的作用。钙调神经磷酸酶的强制激活显著增加MCP-1在转录和蛋白水平的表达，血管紧张素II（Ang II）也显著刺激MCP-1的表达，这种增加被环孢菌素A（CyA）显著抑制。钙调神经磷酸酶的组成性激活稳定了MCP-1 mRNA，而不增强MCP-1启动子活性。根据结果，Ang II诱导的MCP-1启动子活性的增加不被CyA抑制。Ang Ⅱ稳定MCP-1 mRNA的表达，而CyA可减弱Ang Ⅱ的这种作用。CyA抑制经腔机械损伤后股动脉MCP-1的表达。CyA还抑制了丝损伤的股动脉中的巨噬细胞浸润和新生内膜形成。这些结果表明，钙调神经磷酸酶介导的血管炎症，通过刺激MCP-1的表达在VSMCs和巨噬细胞浸润。

项目成果

Sata M, Sugiura S, Yoshizumi M, Ouchi Y, Hirata Y, Nagai R: "Acute and chronic smooth muscle cell apoptosis after mechanical vascular Injury can occur independently of the fas-death pathway."Arterioscler Thromb Vasc Blob. 21. 1733-1737 (2001)

Sata M、Sugiura S、Yoshizumi M、Ouchi Y、Hirata Y、Nagai R：“机械性血管损伤后的急性和慢性平滑肌细胞凋亡可以独立于 fas 死亡途径发生。”动脉硬化血栓血管斑点。

Abe M, Sata M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Matsuo H, Hirata Y, Nagai R: "Adrenomedullin augments collateral development in response to acute ischemia."Biochem Biophys Res Commun. 306. 10-15 (2003)

Abe M、Sata M、Nishimatsu H、Nagata D、Suzuki E、Terauchi Y、Kadowaki T、Matsuo H、Hirata Y、Nagai R：“肾上腺髓质素增强侧枝发育以应对急性缺血。”Biochem Biophys Res Commun。

Abe M, Sofa M, Nishimatsu H, Nagata D, Suzuki E, Terauchi Y, Kadowaki T, Minamino N, Kangawa K, Matsuo H, Hirata Y, Nagai R: "Adrenomedullin augments collateral development in response t o acute ischemia."Biochem Biophys Res Commun. 306. 10-15 (2003)

Abe M、Sofa M、Nishimatsu H、Nagata D、Suzuki E、Terauchi Y、Kadowaki T、Minamino N、Kangawa K、Matsuo H、Hirata Y、Nagai R：“肾上腺髓质素增强侧枝发育以应对急性缺血。”Biochem Biophys

Nishimatsu H, Hirata Y 他: "Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury : studies on transgenic/knockout mice of adrenomedullin gene."Circ Res. 90. 657-663 (2002)

Nishimatsu H、Hirata Y 等人：“内源性肾上腺髓质素在调节血管张力和缺血性肾损伤中的作用：对肾上腺髓质素基因转基因/基因敲除小鼠的研究。”Circ Res. 90. 657-663 (2002)

Nishimatsu H, Hirata Y. et al.: "Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury : studies on transgenic/knockout mice of adrenomedullin gene"Circ.Res.. 90. 657-663 (2002)

Nishimatsu H、Hirata Y.等：“内源性肾上腺髓质素在调节血管张力和缺血性肾损伤中的作用：对肾上腺髓质素基因转基因/敲除小鼠的研究”Circ.Res.. 90. 657-663 (2002)