达格列净降低心力衰竭大鼠心肌内质网应激并缓解左室重构

基础医学与临床 ›› 2021, Vol. 41 ›› Issue (12): 1742-1748.

达格列净降低心力衰竭大鼠心肌内质网应激并缓解左室重构

张志敏¹, 苟丽沙¹, 马丽群², 任可¹, 路军¹, 魏星¹, 李慧杰¹, 周圣华^1*

新疆军区总医院 1.心内科; 2.保健科,新疆乌鲁木齐 830000

收稿日期:2020-09-01 修回日期:2021-01-09 发布日期:2021-12-03
通讯作者: *1070907222@qq.com
基金资助:
新疆维吾尔自治区自然科学基金(2020D01A138)

Dapagliflozin decreases myocardial endoplasmic reticulum stress and relieves left ventricular remodeling in rats with heart failure

ZHANG Zhi-min¹, GUO Li-sha¹, MA Li-qun², REN Ke¹, LU Jun¹, WEI Xing¹, LI Hui-jie¹, ZHOU Sheng-hua^1*

1. Department of Cardiology; 2. Department of Health,General Hospital of Xinjiang Military Region, Urumqi 830000,China

Received:2020-09-01 Revised:2021-01-09 Published:2021-12-03
Contact: *1070907222@qq.com

摘要/Abstract

摘要： 目的观察达格列净对心力衰竭大鼠心肌细胞内质网应激(ERS)的影响,并探讨其与左室重构的关系。方法将大鼠分为对照组、模型组(行主动脉缩窄术, TAC)和达格列净干预组(每日1次灌胃给予达格列净0.5和1.0 mg/kg)。用无创大鼠尾动脉测压仪检测平均动脉压(MAP);称取体质量、全心质量及左心室质量计算大鼠心肌肥厚指数HWI及LVWI;HE染色观察心肌细胞形态学改变;免疫组化及Western blot检测心肌组织中GRP78及CHOP表达水平。超声检测大鼠心功能指标射血分数(EF)及左心室短轴率(FS)。结果 1)与对照组相比,模型组大鼠MAP、HWI、LVWI显著升高(P＜0.01),EF及FS值显著降低(P＜0.01)。与模型组相比,达格列净干预组HWI、LVWI明显降低(P＜0.05),EF及FS值明显升高(P＜0.05)。2)模型组大鼠心肌纤维排除紊乱,形态不规则,组织疏散;达格列净干预组大鼠心肌纤维排列紊乱及组织疏散较模型组好转,细胞形态规则。3)与对照组相比,模型组心肌GRP78、CHOP蛋白表达显著增高(P＜0.01);与模型组相比,达格列净干预组GRP78、CHOP表达明显降低(P＜0.05)。结论达格列净明显抑制心肌细胞ERS,下调GRP78及CHOP表达,保护心肌细胞,有效缓解心室重构及改善心脏功能;ERS可能是达格列净改善心力衰竭的潜在分子机制之一。

关键词: 达格列净, 心力衰竭, 大鼠, 内质网应激, 左室重构

Abstract: Objective To observe the influence of dapagliflozin on ERS of myocardial tissues from rats with heart failure, and explore the its relationship with myocardial remodeling. Methods The rats were divided into the control group, model group (with aortic coarctation, TAC) and Dapagliflozin intervention group (with Dapagliflozin 0.5 and 1.0 mg/kg given by gavage once daily). Non-invasive rat tail artery manometer was used to detect mean arterial pressure. Weigh body weight, whole heart weight and left ventricular weight were recorded to calculate the rat myocardial hypertrophy index HWI and LVWI. Small animal ultrasound was used to detect rat heart function. The morphological changes of cardiomyocytes was microscopied with HE staining. Immuno-histochemistry and Western blot were used to detect GRP78 and CHOP expression in rat myocardial tissue. Results Compared with the control group, MAP, HWI and LVWI in the model group were significantly increased (P＜0.01), EF and FS decreased significantly (P＜0.01). Compared with the model group, HWI and LVWI were reduced (P＜0.05), EF and FS were increased (P＜0.05) in dapagliflozin group. HE staining showed that the myocardial fibers in control group were neatly arranged and morphologically regular; in model group, the myocardial fibers were excluded from the disorder, the morphology was irregular, and the tissue was evacuated; the myocardial fibers in dapagliflozin group were better than that of model group. Compared with control group, the expression of GRP78 and CHOP in the myocardium of model group was significantly increased(P＜0.01);compared with model group, the expression of GRP78 and CHOP in dapagliflozin group was reduced (P＜0.05). Conclusions Dapagliflozin obviously inhibits ERS, down-regulates the expression of GRP78 and CHOP, protects cardiomyocytes, more effectively relieves ventricular remodeling and improves cardiac function. ERS may be one of the molecular biological mechanisms of Dapagliflozin.

Key words: Dapagliflozin, heart failure, rat, endoplasmic reticulum stress, left ventricular remodeling

中图分类号:

张志敏, 苟丽沙, 马丽群, 任可, 路军, 魏星, 李慧杰, 周圣华. 达格列净降低心力衰竭大鼠心肌内质网应激并缓解左室重构[J]. 基础医学与临床, 2021, 41(12): 1742-1748.

ZHANG Zhi-min, GUO Li-sha, MA Li-qun, REN Ke, LU Jun, WEI Xing, LI Hui-jie, ZHOU Sheng-hua. Dapagliflozin decreases myocardial endoplasmic reticulum stress and relieves left ventricular remodeling in rats with heart failure[J]. Basic & Clinical Medicine, 2021, 41(12): 1742-1748.

参考文献

[1]Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes[J]. N Engl J Med,2015, 373:2117-2128.
[2]Kaku K, Lee J, Mattheus M, et al. Empagliflozin and cardiovascular outcomes in asian patients with Type 2 diabetes and established cardiovascular disease-results from EMPA-REG OUTCOME^®[J]. Circ J, 2017, 81:227-234.
[3]中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南2018[J]. 中华心血管病杂志, 2018, 46:760-789.
[4]Minamino T, Komuro I, Kitakaze M. Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease[J]. Circ Res, 2010, 107:1071-1082.
[5]Zhang Z, Zhao L, Zhou Y, et al. Taurine ameliorated homocysteine-induced H9C2 cardiomyocyte apoptosis by modulating endoplasmic reticulum stress[J]. Apoptosis, 2017, 22:647-661.
[6]张志敏, 赵连友, 卢凡,等. 高同型半胱氨酸对高血压大鼠心肌细胞GRP78和CHOP表达及左室肥厚的影响[J]. 中国循证心血管医学杂志, 2014,6:223-226.
[7]张波, 杨文英. 钠-葡萄糖共转运蛋白2抑制剂(SGLT2i)在治疗2型糖尿病中的有效性和安全性[J]. 中华内分泌代谢杂志, 2016, 32:171-176.
[8]Scheen AJ. Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG outcome[J]. Diabetes Res Clin Pract, 2016,121:204-214.
[9]Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis[J]. Lancet Diabetes Endocrinol, 2016, 4:411-419.
[10]Gotoh T, Endo M, Oike Y. Endoplasmic reticulum stress-related inflammation and cardiovascular diseases[J]. Int J Inflam, 2011,2011: 259462. doi: 10.4061/2011/259462.
[11]程友琴, 司晓云, 李小鹰, 等. 硫化氢对大鼠压力负荷性心力衰竭发展过程中氧化应激的影响[J]. 中华老年心脑血管病杂志, 2010, 12:74-77.
[12]Riehle C, Bauersachs J. Key inflammatory mechanisms underlying heart failure[J]. Herz, 2019, 44:96-106.
[13]Okada K, Minamino T, Tsukamoto Y, et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis[J]. Circulation, 2004, 110: 705-712.
[14]鲁轩浩, 赵连友, 张志敏,等. 高血压伴高同型半胱氨酸血症大鼠心肌ATF6和CHOP表达对左室肥厚的影响及依叶片干预效果[J]. 中国循证心血管医学杂志, 2016, 8:729-732.

[1]	殷强, 汪磊, 李童浩. 牛磺熊去氧胆酸减轻重症急性胰腺炎诱导的模型大鼠肝损伤[J]. 基础医学与临床, 2024, 44(9): 1249-1255.
[2]	叶俊武, 郑徐洲, 费林聪, 李漱阳, 杨天府. 重组人乳铁蛋白通过促进成骨细胞增殖加速大鼠骨折愈合[J]. 基础医学与临床, 2024, 44(7): 989-996.
[3]	胡川丽, 贺晓松, 赵江, 李华. 基于机器学习算法的心力衰竭预测模型[J]. 基础医学与临床, 2024, 44(6): 845-852.
[4]	杨洋, 张雅茸, 杨红琴, 王婧, 赵红梅. 磷酸二酯酶5在心力衰竭中作用的研究进展[J]. 基础医学与临床, 2024, 44(5): 724-728.
[5]	柴亚如, 邓玉婷, 戴红艳, 管军. Klotho在心力衰竭中作用的研究进展[J]. 基础医学与临床, 2023, 43(6): 998-1002.
[6]	刘幸幸, 王威威, 袁好鑫. 内质网应激在低氧性肺动脉高压中作用的研究进展[J]. 基础医学与临床, 2023, 43(5): 848-851.
[7]	金涛, 杨青山, 吴树金, 朱晓燕, 史宇悰, 牛建雄, 刘林. 内质网应激在骨关节炎中作用的研究进展[J]. 基础医学与临床, 2023, 43(3): 476-480.
[8]	王琴, 张晓艳, 刘雪婷, 李炳蔚, 李宏伟, 杨义力, 韩建群. 全杜仲胶囊对自发性高血压大鼠肠壁微血流灌注的影响[J]. 基础医学与临床, 2023, 43(3): 386-392.
[9]	司常星, 丁艳艳, 尹凤先. 山姜素减轻博来霉素诱导的小鼠肺纤维化[J]. 基础医学与临床, 2023, 43(12): 1827-1833.
[10]	金国钰, 杨春润, 何静, 张舒荣, 刘欢欢, 李长忠. 转化生长因子β1促进大鼠子宫内膜纤维化[J]. 基础医学与临床, 2023, 43(10): 1557-1561.
[11]	王英臣, 孙立群. 二肽基肽酶Ⅲ在治疗脓毒症中的应用进展[J]. 基础医学与临床, 2023, 43(1): 196-199.
[12]	樊佳赛, 杜艺菲, 许佳颖, 陈思臻, 高永桧, 任景怡. 基于中医证候和机器学习构建慢性心力衰竭中西医结合预后模型[J]. 基础医学与临床, 2022, 42(8): 1169-1175.
[13]	刘峰宇, 韩薇. 心肌细胞钙稳态失调在心力衰竭中作用的研究进展[J]. 基础医学与临床, 2022, 42(3): 502-506.
[14]	李明皓, 范亮亮, 项荣. 内质网应激在丙肝病毒感染发病学中作用的研究进展[J]. 基础医学与临床, 2022, 42(2): 316-320.
[15]	易达松, 袁善斌, 曾俊义, 赵健清, 丁露, 文通, 聂俊刚. 自发性高血压大鼠年龄相关性左心室肥厚的动态变化[J]. 基础医学与临床, 2022, 42(10): 1481-1486.