Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent pathway
Myocyte enhancer factor 2 mediates vascular inflammation via the p38-dependent pathway
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DOI：
10.1161/01.res.0000134631.75684.4a
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发表时间：
2004-07-09
影响因子：
20.1
通讯作者：
Hirata, Y
中科院分区：
文献类型：
--
作者：
Suzuki, E;Satonaka, H;Hirata, Y
虽然已经确定肌细胞增强因子2（MEF 2）在心血管系统以及骨骼肌细胞的发育中起关键作用，但是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。为了研究MEF 2在血管炎症中的作用以及p38在MEF 2激活中的作用，我们用表达MEF 2A显性失活突变体（MEF 2ASA）或丝裂原活化蛋白激酶激酶6（MEK 6AA）的腺病毒构建体感染培养的大鼠血管平滑肌细胞（VSMCs），并检测它们对单核细胞趋化蛋白-1（MCP-1）表达的影响，已知其在血管炎症中起重要作用。我们还研究了MEF 2在体内的作用，使用大鼠模型的股动脉经腔线诱导损伤。用编码MEF 2ASA或MEK 6AA的腺病毒感染血管紧张素II（Ang II）诱导的MCP-1 mRNA表达显著抑制。Ang II诱导的MCP-1启动子活性的增加也被MEF 2ASA或MEK 6AA的过表达显著抑制。Ang Ⅱ刺激MEF 2A的反式激活功能，这种激活被MEK 6AA的过表达抑制。感染AdMEF 2ASA抑制MCP-1的表达在股动脉后，经腔机械损伤。AdMEF 2ASA感染还抑制了钢丝损伤股动脉中的巨噬细胞浸润和新生内膜形成。这些结果表明，MEF 2通过p38依赖性途径的激活通过刺激VSMCs中MCP-1的表达和巨噬细胞浸润介导血管炎症。
Although it has been established that myocyte enhancer factor 2 (MEF2) plays pivotal roles in the development of the cardiovascular system as well as skeletal muscle cells, little is known of its role in vascular inflammatory diseases such as atherosclerosis and restenosis after angioplasty. To investigate the role of MEF2 in vascular inflammation and that of p38 in the activation of MEF2, we infected cultured rat vascular smooth muscle cells (VSMCs) with an adenovirus construct expressing a dominant-negative mutant of MEF2A (MEF2ASA) or mitogen-activated protein kinase kinase 6 (MEK6AA), and examined their effects on the expression of monocyte chemoattractant protein-1 (MCP-1), which is known to play important roles in vascular inflammation. We also examined the role of MEF2 in vivo using a rat model of transluminal wire-induced injury of the femoral artery. Angiotensin II (Ang II)-induced expression of MCP-1 mRNA was significantly inhibited by infection with adenoviruses encoding MEF2ASA (AdMEF2ASA) or MEK6AA. Ang II-induced increase of MCP-1 promoter activity was also significantly suppressed by overexpression of MEF2ASA or MEK6AA. Ang II stimulated the transactivating function of MEF2A and this activation was inhibited by overexpression of MEK6AA. Infection with AdMEF2ASA suppressed MCP-1 expression in the femoral artery after the transluminal mechanical injury. AdMEF2ASA infection also inhibited macrophages infiltration and neointimal formation in the wire-injured femoral arteries. These results suggested that MEF2 activation via the p38-dependent pathway mediates vascular inflammation via stimulation of MCP-1 expression in VSMCs and macrophages infiltration.