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阿利沙坦酯对糖尿病大鼠心肌内质网应激和SERCA2a表达的影响
作者:于梦尧1  应长江2  周冬梅2  李伟2 
单位:1. 徐州医科大学 研究生学院, 江苏 徐州 221006;
2. 徐州市第二人民医院 内分泌科, 江苏 徐州 221000
关键词:糖尿病 阿利沙坦酯 内质网应激 葡萄糖调节蛋白78 肌浆网Ca2+-ATP酶 心肌 大鼠 
分类号:R587.1;R33-33
出版年·卷·期(页码):2017·36·第十二期(1709-1713)
摘要:

目的:探讨阿利沙坦酯对糖尿病大鼠内质网应激和肌浆网Ca2+-ATP酶(SERCA2a)表达的影响。方法:健康雄性SD大鼠30只,分为正常组(NC组)、糖尿病组(DM组)、糖尿病+阿利沙坦酯治疗组(AL组),每组10只。采用链脲佐菌素制备糖尿病大鼠模型,造模成功后,AL组给予阿利沙坦30 mg·kg-1,NC组与DM组给予同剂量生理盐水,灌胃给药,1次·d-1,持续12周。12周后,采用心脏彩超检测大鼠心功能;腹主动脉采血,检测血糖、总胆固醇;Western blotting检测心肌组织内质网应激蛋白葡萄糖调节蛋白78(GRP78)和SERCA2a的蛋白水平,Real-time PCR检测GRP78和SERCA2a的mRNA水平;HE染色观察心肌细胞形态。结果:与NC组相比,DM组大鼠左室射血分数及左室短轴缩短率明显下降(P<0.01);血糖和总胆固醇显著升高(P<0.01);左室心肌组织的GRP78蛋白及mRNA表达增加(P<0.01),SERCA2a蛋白及mRNA表达减少(P<0.01);HE染色示心肌细胞形态不一,排列无序,间隙增宽,可见病理损伤。与DM组相比,AL组大鼠左室射血分数及左心室短轴缩短率增加(P<0.05);GRP78蛋白及mRNA表达减少(P<0.01),SERCA2a蛋白及mRNA表达增加(P<0.01);HE染色示心肌细胞病理损伤减轻。结论:阿利沙坦酯可减少糖尿病大鼠的心肌细胞损伤,改善心功能,其机制可能与减轻心肌内质网应激和上调SERCA2a有关。

Objective: To investigate the function and mechanism of Allisartan Isoproxil on endoplasmic reticulum stress (ERS) and sarcoplasmic reticulum Ca2+-ATPase2a (SERCA2a) expression in diabetic rats.Methods: 30 SD rats were randomly divided into the normal control(NC) group, diabetic(DM) group and Allisartan(AL) group. The rats inDM and AL group were injected with streptozotoein (STZ) to establish diabetic models. The rats in AL group received intragastric administration of Allisartan Isoproxil (30 mg·kg-1·d-1). After 12 weeks, cardiac ultrasound was conducted to assess heart function; blood samples from aorta ventral was tested for fasting plasma glucose (FPG) and total cholesterol (TC). After rats sacrificed, the protein and mRNA level of glucose regulated protein78 (GRP78) and SERCA2a in myocardium were detected by Western blotting and quantitative real-time PCR respectively. HE staining was used to observe the pathological changes of myocardium.Results: Compared with NC group,the ejection fraction (EF) and left ventricular fractional shortening (LVFS)were decreased(P<0.05), while FPG and TC were increased(P<0.01) in DM group. The protein and mRNA level of GPR78 were increased(P<0.01), while the protein and mRNA level of SERCA2a were significantly decreased(P<0.01) in DM group. HE staining showed that the myocardial gap was increased and the cardiomyocyte was irregular and disorder arrangement. Compared with DM group, the protein and mRNA levels of GPR78 were decreased(P<0.01),while the protein and mRNA levels of SERCA2a were increased(P<0.01) in AL group. HE staining showed that the myocardial gap was decreased and the cardiomyocyte was regular and order arrangement.Conclusions: Allisartan Isoproxil can protect the cardiac function of diabetic rats, and the mechanism may be concerned with the inhibition of ERS and the up-regulation of SERCA2a expression.

参考文献:

[1] FELÍCIO J S,KOURY C C,CARVALHO C T,et al.Present insights on cardiomyopathy in diabetic patients[J].Curr Diabetes Rev,2016,12(4):384-395.
[2] 李洁,刘乃丰.糖尿病心肌病发病机制的研究进展[J].现代医学,2006,34(4):292-295.
[3] LIU Q,WANG S,CAI L.Diabetic cardiomyopathy and its mechanisms:Role of oxidative stress and damage[J].J Diabetes Investig,201,5(6):623-634.
[4] AFRIN M R,ARUMUGAM S,WAHED M I I,et al.Attenuation of endoplasmic reticulum stress-mediated liver damage by mulberry leaf diet in streptozotocin-induced diabetic rats[J].Am J Chin Med,2016,44(1):87-101.
[5] TIAN C,ALOMAR F,MOORE C J,et al.Reactive carbonyl species and their roles in sarcoplasmic reticulum Ca2+ cycling defect in the diabetic heart[J].Heart Fail Rev,2014,19(1):101-112.
[6] MAYA L,VILLARREAL F J.Diagnostic approaches for diabetic cardiomyopathy and myocardial fibrosis[J].J Mol Cell Cardiol,2010,48(3):524-529.
[7] GILCA G E,STEFANESCU G,BADULESCU O,et al.Diabetic cardiomyopathy:current approach and potential diagnostic and therapeutic targets[J].J Diabetes Res,2017,2017:1310256.
[8] TAKADAA,MIKI T,KUNO A,et al.Role of ER stress in ventricular contractile dysfunction in type 2 diabetes[J].Plos One,2012,7(6):e39893-e39893.
[9] ZHU G,LEE A S.Role of the unfolded protein response,GRP78 and GRP94 in organ homeostasis[J].J Cell Physiol,2015,230(7):1413-1420.
[10] LIU M,DUDLEY S C Jr.Role for the unfolded protein response in heart disease and cardiac arrhythmias[J].Int J Mol Sci,2015,17(1):pii:E52.
[11] LAKSHMANAN A P,HARIMA M,SUZUKI K,et al.The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats:a differential role of unfolded protein response (UPR) signaling proteins[J].Int J Biochem Cell Biol,2013,45(2):438-447.
[12] FRATI G,SCHIRONE L,CHIMENTI I,et al.An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy[J].Cardiovasc Res,2017,113(4):378-388.
[13] WU T,DONG Z,GENG J,et al.Valsartan protects against ER stress-induced myocardial apoptosis via CHOP/Puma signaling pathway in streptozotocin-induced diabetic rats[J].Eur J Pharm Sci,2011,42(5):496-502.
[14] SHAREEF M A,ANWER L A,POIZAT C.Cardiac SERCA2A/B:therapeutic targets for heart failure[J].Eur J Pharmacol,2014,724(1):1-8.
[15] WU P,ZHAI Y,LI D.The function and significance of SERA2a in congestive heart failure:an analysis of gene therapy trials[J].Histol Histopathol,2017,32(8):767-777.
[16] AKHTAR M S,PILLAI K K,HASSANM Q,et al.Levosimendan reduces myocardial damage and improves cardiodynamics in streptozotocin induced diabetic cardiomyopathy via SERCA2a/NCX1 pathway[J].Life Sciences,2016,153:55-65.
[17] RAJESH M,BÁTKAI S,KECHRID M,et al.Cannabinoid 1 receptor promotes cardiac dysfunction,oxidative stress,inflammation,and fibrosis in diabetic cardiomyopathy[J].Diabetes,2012,61(3):716-727.

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