葡萄糖调节蛋白78促进肝硬化大鼠心肌细胞凋亡及其机制

 目的： 探讨葡萄糖调节蛋白78/免疫球蛋白重链结合蛋白(GRP78/BiP)是否促进肝硬化大鼠心肌细胞凋亡及其发生机制。方法： 采用复合致病因素法建立肝硬化大鼠模型，在4周、6周和8周分别取材。实验1：取心脏称重并测量左室壁厚度，计算左室壁厚度与心脏重量比值及心脏指数。实验2： TUNEL法观察心肌细胞凋亡情况；免疫组化方法检测心肌组织中GRP78/BiP蛋白以及凋亡相关蛋白CCAAT增强子结合蛋白同源蛋白/生长停滞及DNA诱导蛋白153（CHOP/GADD153）、半胱氨酸天冬氨酸蛋白酶12（caspase-12）、核转录因子κB p65（NF-κB p65）、B细胞淋巴瘤/白血病蛋白2（Bcl-2）的表达。结果： 随肝硬化病程进展，左室壁厚度与心脏重量比值以及心脏指数逐渐增加，8周组增加显著(P<0.05)；心肌细胞凋亡指数、CHOP/GADD153和caspase-12阳性蛋白表达指数逐渐升高，8周组差异显著(P<0.05)；NF-κB p65和Bcl-2阳性蛋白表达指数呈一致性变化，在4周组较其它组明显增高(P<0.05)； GRP78/BiP蛋白阳性表达指数与心肌细胞凋亡指数、CHOP/GADD153、caspase-12蛋白阳性表达指数呈显著正相关，CHOP/GADD153与NF-κB p65、Bcl-2蛋白阳性表达指数呈显著负相关。结论： GRP78高表达在内质网应激介导的肝硬化心肌病发病中可能发挥重要作用。

GRP78 promotes cardiomyocytes apoptosis and its mechanism in cirrhotic rats

Aim: To explore GRP78 promotes cardiomyocytes apoptosis and its mechanism in cirrhotic rats. Methods: Fifty-one male Wistar rats were divided into liver cirrhosis groups of 4th-week、6th-week、8th-week and a normal control group at random. TUNEL was used to analyze cardiomyocytes apoptosis; The protein expression of GRP78, caspase-12, CHOP, NF-kB p65 and Bcl-2 were detected by immunohistochemistry. Resultes: Cardiomyocytes apoptosis index, positive expression index of GRP78，caspase-12 and CHOP proteins were increased in turn during the development of liver cirrhosis; the positive expression index of NF-κB p65 and Bcl-2 was consistency, and significantly higher in 4th-week than the other groups (p<0.05); increased positive expression index of GRP78 was positively correlated with apoptosis index , caspase-12 and CHOP, and negatively correlated with NF-κB p65 and Bcl-2. Conclusion: Elevated expression of GRP78 may play an important role in endoplasmic reticulum stress-mediated myocardium apoptosis in liver cirrhotic rats .