MCP-1参与缬沙坦对阿霉素心脏毒性的预保护作用

目的　探讨阿霉素诱导SD大鼠心肌损伤模型中单核细胞趋化蛋白-1（MCP-1）蛋白表达及其潜在的干预机制。方法　选择8周龄雄性SPF级SD大鼠30只，按照随机数字表法分为3组：对照组（Con组，生理盐水灌胃＋腹腔注射）、阿霉素组（Dox组，1.25 mL/kg阿霉素腹腔注射+2 mL/kg生理盐水灌胃）及缬沙坦+阿霉素组（Val+Dox组，1.25 mL/kg阿霉素腹腔注射+2 mL/kg缬沙坦灌胃）各10只，连续干预6周。10周时超声心动图检测心功能变化，留取大鼠心肌组织，电镜观察心肌超微结构变化，采用蛋白芯片技术检测各组血清MCP-1、调节激活正常T细胞表达和分泌因子（RANTES）及次级淋巴组织趋化因子（6Ckine）蛋白含量，采用Western blot检测各组心肌组织MCP-1蛋白表达。结果　超声结果显示，与Con组相比，Dox组和Val+Dox组左心室射血分数（LVEF）、左心室短轴缩短率（LVFS）明显降低，左心室收缩末期内径（LVESD）、左心室舒张末期内径（LVEDD）明显升高（P＜0.05）。与Dox组相比，Val+Dox组LVEF、LVFS明显升高，LVESD、LVEDD明显降低（P＜0.05）。电镜下可见Con组心肌细胞结构清晰；Dox组心肌结构模糊，心肌溶解，可见自噬小体；Val+Dox组心肌结构模糊不清，线粒体体积增大、大小不等，但结构完整。与Con组相比，Dox组血清MCP-1、RANTES、6Ckine蛋白分别上调1.87倍、1.40倍和1.26倍（P＜0.05）。Western blot结果显示，Dox组与Con组相比，心肌组织MCP-1蛋白表达显著升高（P＜0.05）；Val+Dox组与Dox组相比，心肌组织MCP-1蛋白表达显著降低（P＜0.05）。结论　MCP-1蛋白可能参与阿霉素诱导的心肌损伤，缬沙坦可能通过下调MCP-1蛋白表达减轻心肌损伤。

MCP-1 participates in the protective effect of valsartan on doxorubicininduced myocardial injury#br#

Objective To investigate the expression of monocyte chemoattractant protein 1 (MCP-1) in doxorubicin induced myocardial injury in SD rats and its potential intervention mechanism. Methods　Thirty male Sprague-Dawley (SD) rats aged 8 weeks with special pathogen free (SPF) animal grade were randomly divided into three groups: control group (Con group, n=10, gavage and intraperitoneal injection of saline solution), doxorubicin group (Dox group, n=10, intraperitoneal injection of 1.25 mL/kg doxorubicin + gavage of 2 mL/kg saline solution) and valsartan + doxorubicin group (Val+Dox group, n=10, intraperitoneal injection of 1.25 mL/kg doxorubicin + gavage of 2 mL/kg valsartan). After treatment for six weeks, the changes of cardiac function were detected by echocardiography. Myocardial tissue samples were collected for observing the myocardial ultrastructure under electron microscopy. The protein level of serum MCP-1, regulatory and activation of normal T cell expression and secretion factors (RANTES) and secondary lymphoid organ chemokine (6Ckine) were detected by protein chip technology. The expressions of MCP-1 in myocardial tissue samples were tested by Western blot assay. Results　Echocardiography indicated that compared with Con group, left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were significantly decreased in the other two groups, while the left ventricular end-diastolic dimension (LVESD) and left ventricular end-diastolic dimension (LVEDD) were obviously increased (P＜0.05). On the other hand, in comparison with Dox group, LVEF and LVFS were significantly increased in Val+Dox group, while LVESD and LVEDD were significantly decreased in Val+Dox group (P＜0.05).Under the electron microscope,the ultrastructure of myocardial cells was clear in the Con group, and the myocardial structure was dim, autophagic body was observed in the Dox group. In the Val+Dox group, the myocardial structure was blurred, the size of mitochondria was increased, and intact and swollen mitochondria were found to have different sizes. Compared with the Con group, the protein levels of MCP-1，RANTES and 6Ckine were up-regulated 1.87, 1.40 and 1.26-fold in Dox group (P＜0.05). Western blot assay displayed that the protein expression of MCP-1 was significantly higher in the Dox group than that of Con group (P＜0.05), and the protein expression of MCR-1 was significantly lower in the Dox group than that in the Val+Dox group (P＜0.05). Conclusion MCP-1 may be associated with doxorubicin induced myocardial injury, and valsartan may protect myocardial tissue from doxorubicin induced myocardial injury through down-regulating the expression of MCP-1.