2023 年第 6 期 第 18 卷

达格列净抑制急性心肌梗死后心脏炎症的作用分析

The effect of dapagliflozin on inhibiting cardiac inflammation after acute myocardial infarction

作者：丁宁宇1刘燕2周梅2张俊蒙3陈梦娜3刘洁云4

英文作者：Ding Ningyu1 Liu Yan2 Zhou Mei2 Zhang Junmeng3 Chen Mengna3 Liu Jieyun4

单位：1新乡医学院，新乡453003；2北京市心肺血管疾病研究所首都医科大学附属北京安贞医院，北京100029；3北京华信医院清华大学附属第一医院心内科，北京100016；4河南省开封市中心医院心内科，开封475000

英文单位：1Xinxiang Medical University Xinxiang 453003 China; 2Beijing Institute of Heart Lung and Blood Vessel Diseases Beijing Anzhen Hospital Capital Medical University Beijing 100029 China; 3Department of Cardiology Beijing Huaxin Hospital the First Hospital of Tsinghua University Beijing 100016 China; 4Department of Cardiology Kaifeng Central Hospital Henan Province Kaifeng 475000 China

关键词：钠-葡萄糖共转运蛋白2抑制剂；急性心肌梗死；炎症

英文关键词：Sodium-glucosecotransporter-2inhibitor;Acutemyocardialinfarction;Inflammation

• 摘要：

• 目的  探究达格列净对急性心肌梗死（AMI）后心脏炎症反应的作用。方法  本研究选用无特定病原体级8~9周龄雄性C57BL/6J小鼠，选取17只随机分为假手术对照组（6只）和心肌梗死对照组（11只），以AMI后7 d为实验终点，用于验证模型是否建立成功；另选取28只小鼠随机分为假手术组（6只）、心肌梗死组（12只）和达格列净组（10只），以AMI后3 d为实验终点。所有小鼠予常规饮食，达格列净组小鼠于AMI造模前7 d开始给予掺入达格列净的饮食，直至造模后3 d。心肌梗死对照组、心肌梗死组、达格列净组小鼠采用冠状动脉结扎方法建立AMI模型。假手术对照组、假手术组小鼠冠状动脉不结扎，其余手术操作同AMI模型小鼠。实验终点观察各组小鼠心脏炎性细胞浸润、炎性细胞因子mRNA表达量。将人脐静脉内皮细胞分为观察组（达格列净刺激24 h）和对照组（二甲基亚砜刺激24 h），观察达格列净对黏附分子表达的作用。结果  心肌梗死对照组小鼠左心室射血分数、短轴缩短率均低于假手术对照组，心脏质量/体质量比值大于假手术对照组（均P<0.05）。Masson′s染色显示瘢痕组织形成，证明AMI模型建立成功。心肌梗死组心脏组织中性粒细胞、Mac-3阳性面积占比均高于假手术组，而达格列净组均低于心肌梗死组［（0.079±0.039）%比（0.206±0.132）%、（0.532±0.237）%比（1.757±0.646）%］（均P＜0.05）。心肌梗死组心脏组织中肿瘤坏死因子α、白细胞介素1β及基质金属蛋白酶9 mRNA表达量均高于假手术组，而达格列净组均低于心肌梗死组（均P＜0.05）。观察组细胞间黏附分子1和血管细胞黏附分子1 mRNA表达量均低于对照组（均P＜0.05）。结论  达格列净抑制了心肌梗死后心脏炎症反应，这一作用可能是通过减少内皮细胞黏附分子表达实现的。

• Objective    To investigate the effect of dapagliflozin on cardiac inflammation after acute myocardial infarction (AMI). Methods  Male specific pathogen free C57BL/6J mice of 8-9 weeks old were enrolled in this study. There were 17 mice randomly divided into sham operation control group (6 mice) and myocardial infarction (MI) control group (11 mice), and the end point was 7 d after AMI to verify whether the model was established successfully. Another 28 mice were randomly divided into sham operation group (6 mice), MI group (12 mice) and dapagliflozin group (10 mice), and the end point was 3 d after AMI. All mice were given regular diet, and the mice in dapagliflozin group were given a diet mixed with dapagliflozin 7 d before AMI modeling, until 3 d after AMI modeling. AMI models were established by coronary artery ligation in mice of MI control group, MI group and dapagliflozin group. The coronary arteries of mice in sham operation control group and sham operation group were not ligated, and other surgical procedures were the same as those of AMI model mice. Inflammatory cell infiltration and inflammatory cytokine mRNA expression in heart of mice in each group were observed at the end point. Human umbilical vein endothelial cells were divided into observation group (24 h stimulation with dapagliflozin) and control group (24 h stimulation by dimethyl sulfoxide) to observe the effect of dapagliflozin on expression of adhesion molecule. Results  Left ventricular ejection fraction and short axis shortening rate in MI control group were lower than those in sham operation control group, and the ratio of cardiac mass to body mass was greater than that in sham operation control group (all P<0.05). Masson′s staining showed the formation of scar tissue, which proved that the establishment of AMI model was successful. The proportions of neutrophil and Mac-3 positive area in cardiac tissue in MI group were higher than those in sham operation group, while those in dapagliflozin group were lower than those in MI group［（0.079±0.039）% vs （0.206±0.132）%,（0.532±0.237）% vs （1.757±0.646）%］(all P<0.05). Expression levels of tumor necrosis factor-α, interleukin-1β and matrix metalloproteinase 9 mRNA in cardiac tissues in MI group were higher than those in sham operation group, while those in the dapagliflozin group were lower than those in the MI group (all P<0.05). Expression levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 mRNA in observation group were lower than those in control group (both P<0.05). Conclusion  Dapagliflozin inhibits cardiac inflammation reaction after MI, which may be achieved by reducing the expression of endothelial cell adhesion molecules.