摘要
目的:探讨葡萄糖调节蛋白78(GRP78)在肝硬化大鼠肠源性内毒素血症引发心脏病变中的作用。方法:51只Wistar雄性大鼠随机分为肝硬化模型4周组、6周组、8周组和同期正常对照组。于第8周检测大鼠心功能;检测各组心肌组织匀浆中肿瘤坏死因子α(TNF-α)和丙二醛(MDA)水平;甲苯胺蓝染色和van Giesan染色分别观察心肌细胞数量的变化和计算心肌胶原容积分数(CVF);免疫组化法检测心肌组织GRP78和缺氧诱导因子1α(HIF-1α)蛋白表达情况。结果:随肝硬化病程进展:(1)肝硬化8周组大鼠左室舒张末期压(LVEDP)及左室内压最大上升和下降速率(±LV dp/dtmax)均较对照组降低(P<0.05);(2)心肌组织中TNF-α、MDA、CVF、GRP78蛋白和HIF-1α蛋白水平均逐渐升高并显著高于正常对照组(P<0.05);(3)甲苯胺蓝染色显示模型各组心肌细胞数量逐渐减少并显著低于正常对照组(P<0.05);(4)血浆中内毒素水平分别与丙氨酸氨基转移酶(ALT)、同型半胱氨酸(Hcy)、TNF-α、GRP78和MDA呈显著正相关(P<0.05);(5)GRP78蛋白分别与HIF-1α、Hcy、MDA、ALT和CVF呈显著正相关(P<0.05)。结论:肝硬化大鼠伴发的肠源性内毒素血症通过直接或间接作用引起内质网应激和GRP78表达增加,后者可能是引起心肌重构、导致心脏功能变化的关键分子。
AIM： To explore the role of glucose-regulated protein 78（GRP78） in the alteration of myocardium induced by intestinal endotoxemia in cirrhotic rats. METHODS： Fifty-one male Wistar rats were randomly divided into liver cirrhosis groups of 4-week,6-week and 8-week,and normal control groups at corresponding time points.The cardiac functions of the 8-week rats were measured.Tumor necrosis factor α（TNF-α） and malondialdehyde（MDA） in myocardial tissues were detected.The number of myocardial cells and the collagen volume fraction（CVF） were determined with toluidine blue and van Giesan staining,respectively.The expression of GRP78 and hypoxia-inducible facotr 1α（HIF-1α） was analyzed by the method of immnunohistochemistry. RESULTS： Compared with normal control group at corresponding time point,left ventricular end-diastolic pressure（LVEDP） and ±LV dp/dtmax in 8-week group were significantly decreased（P0.05）.The levels of TNF-α,MDA and CVF,the protein expression of GRP78 and HIF-1α in the myocardial tissues were significantly increased in every model group（P0.05）,and the number of myocardial cells was gradually decreased（P0.05）.Elevated levels of endotoxin in plasma were positively correlated with the levels of alanine aminotransferase（ALT）,homocysteine（Hcy） and TNF-α in plasma,the levels of TNF-α,MDA and CVF,and protein levels of GRP78 and HIF-1α in the myocardial tissues（P0.05）.Elevated protein expression of GRP78 in the myocardial tissues was positively correlated with the levels of ALT,Hcy in plasma and MDA,CVF,HIF-1α protein in the myocardial tissues（P0.05）. CONCLUSION： Intestinal endotoxemia induced by liver cirrhosis may directly or indirectly lead to endoplasmic reticulum stress and overexpression of GRP78.GRP78 may be a key molecule in the pathogenesis of myocardial remodeling and functional alteration induced by liver cirrhosis.
出处
《中国病理生理杂志》
CAS
CSCD
北大核心
2012年第4期577-582,共6页
Chinese Journal of Pathophysiology
基金
国家自然科学基金资助项目(No.81070339)
山西省国际科技合作计划资助项目(No.2010081068)
山西省回国留学人员科研基金资助项目(No.2008-88)
山西医科大学细胞生理学省部共建教育部重点实验室主任基金资助项目(No.2010-09)
关键词
肝硬化
肠源性内毒素血症
糖调节蛋白78
心肌重构
Liver cirrhosis
Intestinal endotoxemia
Glucose-regulated protein 78
Myocardial remodeling
