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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

29卷

期数:

2023年04期

页码:

406-412

栏目:

基础医学

出版日期:

2023-07-10

文章信息/Info

Title:

Exploring the mechanism of protective effect of dapagliflozin or sacubitril/valsartan in rats with acute myocardial infarction

文章编号:

1006-8147（2023）04-0406-07

作者:

陶文岐; 姚朱华

天津医科大学人民医院临床学院，天津300122

Author(s):

TENG Jie; CHEN Ye-gang1TAO Wen-qi

Tianjin Union Medical Center，Tianjin Medical University，Tianjin 300122，China

关键词:

达格列净; 沙库巴曲缬沙坦; 急性心肌梗死; 心力衰竭; 细胞凋亡; 自噬

Keywords:

dapagliflozin; sacubitril/valsartan; acute myocardial infarction; heart failure; autophagy; apoptosis

分类号:

R542.2+2

DOI:

-

文献标志码:

A

摘要:

目的：探索在急性心肌梗死（AMI）早期（12h内）使用达格列净（DAPA）的疗效和安全性是否优于沙库巴曲缬沙坦（Sac/Val）并对两药的获益机制进行研究。方法：通过结扎Sprague-Dawley（SD）大鼠左冠状动脉前降支构建AMI模型，Sham组只穿线不结扎。30只成年雄性SD大鼠使用抽签法抽取5只作为Sham组，剩余25只制作AMI模型，存活15只大鼠按抽签法平分为3组：MI组、DAPA干预组和Sac/Val干预组，每组5只。干预4周后，心脏彩超测量左心室收缩末内径（LVIDs）及左室射血分数（LVEF）。苏木精-伊红（HE）染色、马松染色（Masson）和自噬相关蛋白7（ATG7）免疫组化染色明确心肌结构、纤维化以及ATG7分布情况。Western印迹及qPCR检测半胱氨酸天冬氨酸蛋白酶3（Caspase3）、活化的半胱氨酸天冬氨酸蛋白酶3（C-Caspase3）、死骨片1-泛素结合蛋白P62（SQSTM1/p62）、自噬相关蛋白（Beclin1）和ATG7等表达情况。结果：与MI组相比，DAPA或Sac/Val单独应用可改善心脏功能，降低MI面积（F=11.25，P＜0.05）和纤维化区域（F=29.01，P＜0.05），增加ATG7阳性面积（F=8.95，P＜0.05）；Western印迹结果显示，经过DAPA或Sac/Val治疗后可以降低Caspase3（F=7.92，P＜0.05）、C-Caspase3（F=3.70，P＜0.05）和SQSTM1/p62（F=7.12，P＜0.05）的表达，增加ATG7（F=8.08，P＜0.05）和Beclin1（F=5.80，P＜0.05）的表达；AMI后，导致血压明显降低，此时加用Sac/Val会进一步降低血压，而DAPA对血压影响较小。结论：DAPA或Sac/Val主要通过降低心肌细胞凋亡和激活自噬水平，降低心脏纤维化和心室重构，更好地保留心脏结构和功能；DAPA或Sac/Val对心脏功能均有改善作用，且两药无明显差异。

Abstract:

Objective：To explore whether the efficacy and safety of Dapagliflozin（ DAPA） in the early stage of acute myocardial infarction （ AMI）（ within12 hours）was better than that of sacubitril/valsartan（ Sac/Val），and the mechanism of the benefits of the two drugs. Methods：An AMI model was constructed by ligating the anterior descending branch of the left coronary artery in Sprague-Dawley（ SD） rats，while in the sham mice underwent the same procedure without ligation.Thirty adult male SD rats were used by a lottery method to select 5 rats as the Sham group，with the remaining 25 rats for AMI models. Fifteen surviving rats were divided into three groups according to the lottery method：MI group，DAPA intervention group，and Sac/Val intervention group，with 5 rats in each group. After 4 weeks of intervention，LVIDs and LVEF were calculated via standard transthoracicechocardiography.In order to clarify myocardial structure，fibrosis and ATG7 distribution，the samples were subjected to hematoxylin and eosin（ H&E），Masson and immunohistochemical （ IHC） staining. Western blotting and qPCR were used to observe the expression levels of Caspase3，Cleaved Caspase3（ C-Caspase3）， SQSTM1/p62，beclin 1，ATG7，and other key factors. Results：Compared with the MI group，DAPA or Sac/Val alone significantly improved cardiac function，reduced MI area（ F=11.25，P＜0.05） and fibrosis size（ F=29.01，P＜0.05），and decreased the positive IHC stain of ATG7（ F=8.95，P＜0.05）.The protein level of Caspase3（ F=7.92，P＜0.05），C-Caspase3（ F=3.70，P＜0.05） and SQSTM1/p62（ F=7.12， P＜0.05） were significantly decreased，while the expression of ATG7（ F=8.08，P＜0.05） and Beclin1（ F=5.80，P＜0.05） were increased in group DAPA or Sac/Val compared with the MI group. After AMI，blood pressure decreased significantly，and the addition of Sac/Val further reduced blood pressure，while DAPA had little effect on blood pressure. Conclusion：DAPA or Sac/Val or treatment reduces cardiac fibrosis and ventricular remodeling by reducing cardiomyocyte apoptosis and activating autophagy，thereby better preserving the cardiac structure and function. DAPA or Sac/Val both have an improvement effect on cardiac function，and there is no significant difference between the two drugs.

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备注/Memo

备注/Memo:

基金项目: 天津市卫生健康科研项目（ZC20080）
作者简介: 陶文岐（1991-），男，硕士在读，研究方向：心肌梗死；
通信作者：姚朱华，E-mail：tjyzhpci@163.com。

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更新日期/Last Update: 2023-07-10