Satonaka Hiroshi, Suzuki Etsu, Nishimatsu Hiroaki, Oba Shigeyoshi, Takeda Ryo, Goto Atsuo, Omata Masao, Fujita Toshiro, Nagai Ryozo, Hirata Yasunobu
Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Circ Res. 2004 Mar 19;94(5):693-700. doi: 10.1161/01.RES.0000118250.67032.5E. Epub 2004 Jan 22.
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.
尽管钙调神经磷酸酶依赖性通路在心肌肥大发展中的作用已得到深入研究，但对于其在动脉粥样硬化和血管成形术后再狭窄等血管炎性疾病中的作用却知之甚少。为了帮助阐明钙调神经磷酸酶在血管炎症中的作用，我们用一种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（VSMC），并检测其对单核细胞趋化蛋白-1（MCP-1）表达的影响。我们还使用大鼠股动脉腔内钢丝损伤模型在体内检测了钙调神经磷酸酶的作用。钙调神经磷酸酶的强制激活在转录和蛋白水平均显著增加了MCP-1的表达。血管紧张素II（Ang II）也显著刺激MCP-1表达，而这种增加被环孢素A（CyA）显著抑制。钙调神经磷酸酶的组成型激活使MCP-1 mRNA稳定，但未增强MCP-1启动子活性。与这些结果一致，CyA并未抑制Ang II诱导的MCP-1启动子活性增加。Ang II使MCP-1 mRNA稳定，而CyA减弱了Ang II的这种作用。CyA抑制了腔内机械损伤后股动脉中MCP-1的表达。CyA还抑制了钢丝损伤股动脉中的巨噬细胞浸润和内膜增生。这些结果表明，钙调神经磷酸酶通过刺激VSMC中MCP-1的表达和巨噬细胞浸润来介导血管炎症。
