Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation
Calcineurin promotes the expression of monocyte chemoattractant protein-1 in vascular myocytes and mediates vascular inflammation
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DOI：
10.1161/01.res.0000118250.67032.5e
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发表时间：
2004-03-19
影响因子：
20.1
通讯作者：
Hirata, Y
中科院分区：
文献类型：
--
作者：
Satonaka, H;Suzuki, E;Hirata, Y
虽然钙调神经磷酸酶依赖性途径在心肌肥大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。钙调磷酸酶的强制激活显着增加MCP- 1的表达在转录和蛋白质水平。血管紧张素II（Ang II）也显着刺激MCP- 1的表达，这种增加显着抑制环孢菌素A（CyA）。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。与结果一致，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还抑制了钢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。
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.