Role of apoptosis of vascular endothelial cells In atherosclerosis

尽管钙调磷酸酶依赖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）中的作用尚不清楚。为了阐明钙调磷酸酶在血管炎症中的作用，我们用表达钙调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），并检测其对单核细胞趋化蛋白-1 （MCP-1）表达的影响。我们还利用大鼠股动脉腔内金属丝损伤模型研究了钙调磷酸酶在体内的作用。钙调磷酸酶的强制激活在转录和蛋白水平上显著增加MCP-1的表达，血管紧张素II （Ang II）也显著刺激MCP-1的表达，而这种增加被环孢素A （CyA）显著抑制。钙调磷酸酶的组成性激活稳定了MCP-1 mRNA，但没有增强MCP-1启动子的活性。结果表明，angii诱导的MCP-1启动子活性的升高不受CyA的抑制。Ang II稳定MCP-1 mRNA，而这种作用被CyA减弱。CyA抑制股动脉机械损伤后MCP-1的表达。CyA还能抑制股动脉内巨噬细胞的浸润和新生内膜的形成。这些结果表明，钙调磷酸酶通过刺激VSMCs中MCP-1的表达和巨噬细胞浸润介导血管炎症。

Although 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.