低剂量联麦氧钒调节高糖诱导内质网应激减轻心肌损伤作用的研究

发布时间：2018-04-19 15:34

本文选题：联麦氧钒 + 糖尿病　；参考：《吉林大学》2016年博士论文

【摘要】：研究背景:糖尿病发病率日益增加,超过半数的糖尿病患者死于心血管并发症。如何在糖尿病情况下保护心血管功能具有重要意义。内质网应激(ERS)作为应激过程细胞凋亡的共同通路,在糖尿病心肌损伤中有起着重要作用。基于对ERS相关分子机制和信号转导途径加以调控,减轻心肌细胞损伤,可能为糖尿病心肌损伤治疗提供新的治疗靶点。目前临床上传统降糖药物不能有效减轻糖尿病心肌损伤的发生,联麦氧钒[bis(maltolato)oxovandium,BMOV]作为一种有机钒络合物,在动物研究中高剂量BMOV具有抑制胰岛细胞ERS作用,但是存在胃肠道不适,限制了进一步临床应用,本研究拟探讨低剂量BMOV是否改善高糖诱导心肌损伤的作用而不引起明显的胃肠道刺激。目的:探讨低剂量BMOV对于STZ建立糖尿病大鼠心肌细胞凋亡的保护作用,检测糖尿病中内质网应激信号通路蛋白及m RNA的表达,进一步在H9C2(2-1)心肌细胞中验证BMOV具有调节内质网应激信号蛋白及m RNA的表达、改善糖尿病大鼠心肌细胞凋亡的作用。方法:Wistar大鼠腹腔注射STZ建立糖尿病动物模型,通过给予不同剂量BMOV干预后检测心肌细胞凋亡。检测低剂量BMOV干预后GRP-78、PERK、XBP-1、CHOP蛋白表达以及各项m RNA水平。进一步在H9C2(2-1)心肌细胞株中模拟高糖环境,验证BMOV干预调节ERS相关蛋白,保护心肌细胞凋亡。结果:研究发现STZ大鼠给予低剂量BMOV后心肌凋亡下降。BMOV干预后心肌细胞凋亡减轻,ERS起始蛋白GRP-78表达下降,ERS通路蛋白PERK表达减弱,下游细胞凋亡蛋白CHOP明显下调,同时细胞促存活相关蛋白XBP-1表达下调,各项蛋白的m RNA均有类似表现。在H9C2(2-1)细胞实验中BMOV同样具有调节ERS反应水平,GRP-78蛋白表达下降,PERK蛋白与凋亡相关CHOP蛋白明显下调,同时细胞促存活相关蛋白XBP-1表达下调。结论:体内体外实验研究提示,BMOV可降低高糖诱导的内质网应激起始蛋白GRP78的高表达,并抑制PERK、CHOP、Caspase12引起的糖尿病心肌细胞的损伤。在细胞层面对于促细胞存活的XBP-1蛋白表达有一定改善作用,在动物实验中并没有发现相应结果。结合大鼠血糖结果,BMOV具有在未影响血糖结果的情况下改善内质网应激诱发凋亡蛋通路引起的细胞凋亡作用,对于ERS引起的细胞促存活蛋白表达无影响。
[Abstract]:Background: the incidence of diabetes is increasing and more than half of diabetics die from cardiovascular complications.How to protect cardiovascular function in diabetes is of great significance.Endoplasmic reticulum stress (ERS), as a common pathway of apoptosis during stress, plays an important role in diabetic myocardial injury.Based on the regulation of ERS related molecular mechanism and signal transduction pathway, myocardial cell injury can be alleviated, which may provide a new therapeutic target for the treatment of diabetic myocardial injury.At present, traditional hypoglycemic drugs can not effectively reduce the occurrence of myocardial injury in diabetic patients. As an organic vanadium complex, bismaltovanadium (BMOV) can inhibit ERS of pancreatic islet cells in animal studies, but there is gastrointestinal discomfort.In order to limit further clinical application, this study aims to investigate whether low dose BMOV can improve myocardial injury induced by high glucose without causing significant gastrointestinal irritation.Aim: to investigate the protective effect of low dose BMOV on myocardial apoptosis in diabetic rats induced by STZ, and to detect the expression of endoplasmic reticulum stress signaling pathway protein and m RNA in diabetic rats.It was further demonstrated that BMOV could regulate the expression of endoplasmic reticulum stress signal protein and m RNA and improve the apoptosis of myocardial cells in diabetic rats.Methods Diabetic animal model was established by intraperitoneal injection of STZ in rats. Cardiomyocyte apoptosis was detected by different doses of BMOV.The expression of XBP-1Hop protein and the levels of m RNA were detected after low dose BMOV intervention.Furthermore, high glucose environment was simulated in H9C2O2-1) cardiomyocytes to verify that BMOV interferes with ERS related proteins and protects cardiomyocytes from apoptosis.Results: it was found that the myocardial apoptosis decreased after STZ rats were given low dose BMOV. After intervention of BMOV, the expression of ERS-initiation protein GRP-78 decreased and the expression of ERS-pathway protein PERK decreased, and the downstream apoptotic protein CHOP was down-regulated.At the same time, the expression of surviving-related protein XBP-1 was down-regulated, and the m RNA of all proteins showed similar expression.In H9C2O2-1) cell experiment, BMOV also regulated the level of ERS response. The expression of GRP-78 protein decreased significantly. PERK protein and apoptosis-related CHOP protein were down-regulated, and the XBP-1 expression of surviving-promoting protein was down-regulated.Conclusion: BMOV can reduce the high expression of ERR stress initiation protein (GRP78) and inhibit the injury of diabetic cardiomyocytes induced by PERKG CHOPN Caspase12 in vivo and in vitro.At the cellular level, the expression of XBP-1 protein which can promote cell survival was improved to some extent, but no corresponding results were found in animal experiments.Combined with the results of blood glucose in rats, BMOV could improve the apoptosis induced by endoplasmic reticulum stress (ER) stress, but had no effect on the expression of surviving-promoting protein induced by ERS.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R587.2;R542.2

【相似文献】