辛伐他丁减少Connexin43表达和兔粥样硬化斑块形成

辛伐他丁减少Connexin43表达和兔粥样硬化斑块形成 作者：李建军，林宏，李柱一，李宏增 【关键词】 动脉粥样硬化 Simvastatin reduces Connexin43 expression and inhibits rabbit atherosclerotic lesion formation 　　【Abstract】 AIM: To demonstrate that simvastatin can influence atherosclerotic plaque formation and stability by decreasing the expression of gap junction protein connexin43 (Cx43) in atherosclerotic lesions. METHODS: The role of Cx43 in atherogenesis was examined by a pharmacological approach. The rabbit model of atherogenesis was established by a highcholesterol diet. The expression of connexin 43 and macrophages in vivo was determined by immunohistochemistry and the expression of connexin 43 in cultured smooth muscle cells was determined with Western blot. The quantity of connexin43 expression was analyzed with computer images. RESULTS: We observed that HMGCoA reductase inhibitors, or "statins", lipidlowering drugs well known for their pleiotropic antiatherogenic effects, reduced Cx43 expression in primary human vascular cells in vitro. Atheroma of rabbits orally treated with simvastatin contained fewer inflammatory cells and exhibited thicker fibrous caps than controls, which was associated with reduced Cx43 expression in lesions of statintreated rabbits. CONCLUSION: These data indicate the critical role of Cx43mediated gap junctional communication in atherosclerotic plaque formation. Reduced Cx43mediated intercellular communication leads to changes in atherogenesis. These findings show that Cx43mediated intercellular communication can be used as a new potential therapeutic target in atherogenesis. 　　【Keywords】 atherosclerosis; simvastatin; Connexin43 　　【摘要】 目的：证明辛伐他丁可以通过减少缝隙连接蛋白43（Connexin43, Cx43）的表达影响粥样斑块的形成及稳定性. 方法：高脂饲料喂养建立粥样硬化模型，治疗组给予辛伐他丁口服，活体内的Cx43和巨嗜细胞检测使用免疫组织化学方法，培养平滑肌细胞的Cx43检测使用免疫印记方法，Cx43的半定量使用计算机图像处理. 结果：药物干预的培养细胞和模型治疗组中Cx43的表达均明显减少，斑块的组成中，炎症细胞减少50％，胶原纤维平滑肌细胞含量增加. 结论： Cx43介导的细胞间通讯在粥样硬化形成中起重要作用，同时辛伐他丁减少Cx43的表达可以增加斑块的稳定性，Cx43成为动脉粥样硬化治疗中一个新的治疗靶点. 　　【关键词】 动脉粥样硬化；辛伐他丁；连接蛋白43 　 　　0引言 　　动脉粥样硬化主要是一种免疫炎症性疾病，它的病理过程是多因素参与的. 包括富含脂质的巨嗜细胞和T淋巴细胞在血管内皮下积聚（脂质条纹）. 由多层的泡沫细胞和增生的平滑肌细胞组成，并伴随有细胞外基质的沉积（粥样斑块）. 在粥样斑块形成过程中的决定性因素是循环中的血液细胞和动脉壁内的细胞之间相互协调的作用［1，2］. 　　缝隙连接是由许多相关的蛋白家族组成的，叫做Connexins（Cxs）［3］. 在人体中大约有20多种的Cxs，Cx43是分布最广泛的. Cxs是机能蛋白，半衰期是1～5 h左右，在生理和病理条件下提供了细胞间相互影响的一种方式［4］. 细胞间通道的代表缝隙连接在多细胞有机体中通过直接的交换离子和小分子物质提供了一种简单的同步反应的方式［5］，缝隙连接在慢性的生理过程如细胞的生长发育中起到重要作用. 已经证明在粥样硬化形成中Cx43的表达增加，Cx43在粥样硬化的发病过程中起着重要作用. 我们用实验证明，辛伐他丁可以通过减少Cx43的表达影响粥样斑块形成.