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利拉鲁肽对糖尿病合并心肌梗死小鼠心功能的影响及其作用机制
Effect of liraglutide on cardiac function of mice with diabetes mellitus and concomitant myocardial infarction and its mechanism

广西医学 页码:270-275

作者机构:刘晓玲,硕士,副主任医师,研究方向为糖尿病。

基金信息:广西自然科学基金(2020GXNSFAA238036)

DOI:10.11675/j.issn.0253⁃4304.2024.02.16

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目的 探讨利拉鲁肽对糖尿病合并心肌梗死小鼠心功能的影响及其作用机制。方法 按随机数字表法将75只KM雄性小鼠分为对照组15只和模型处理组60只。对模型处理组的60只小鼠建立糖尿病小鼠模型,建模成功后再按随机数字表法选取模型处理组的45只小鼠建立糖尿病合并心肌梗死小鼠模型,剩余的15只小鼠作为假手术组,且仅对小鼠开胸而不结扎冠状动脉。将45只糖尿病合并心肌梗死小鼠模型按随机数字表法分为模型组(n=15)、心梗干预组(n=15)、糖干预组(n=15),给予心梗干预组小鼠灌胃硫酸氢氯吡格雷+阿托伐他汀钙片干预,给予糖干预组小鼠腹腔注射利拉鲁肽注射液干预,其余小鼠均不做特殊处理。干预7 d后,使用心电图机观察各组小鼠的心电图,采用HE染色及2,3,5⁃氯化三苯四氮唑染色观察各组小鼠的病理情况及心肌梗死面积,采用Western blot检测各组小鼠心肌组织磷脂酰肌醇3⁃激酶(PI3K)、蛋白激酶B(AKT)、糖原合成酶激酶 3β(GSK⁃3β)的蛋白表达量。结果 (1)对照组、假手术组小鼠心电图无明显异常,模型组小鼠心电图存在明显的 ST 段抬高及变异 T 波,心梗干预组、糖干预组小鼠心电图ST 段抬高及变异T波较模型组明显改善,且心梗干预组的改善效果优于糖干预组。(2)对照组、假手术组小鼠心肌纤维排列整齐紧凑,心肌细胞形态完整;相比于对照组、假手术组,模型组小鼠心肌组织可见梗死区,梗死周边区域心肌细胞形态不完整,排列混乱,有大量炎症细胞浸润和纤维组织增生;相比于模型组,心梗干预组和糖干预组小鼠上述病理改变程度均得到改善,心梗干预组改善程度优于糖干预组。(3)与对照组相比,假手术组小鼠心肌梗死区面积百分比无明显变化(P>0.05);与对照组和假手术组相比,模型组小鼠的心肌梗死区面积百分比明显增加(P<0.05);与模型组相比,心梗干预组与糖干预组小鼠的心肌梗死区面积百分比均减少(P<0.05),且心梗干预组小鼠的心肌梗死区面积百分比小于糖干预组,但差异无统计学意义(P>0.05)。(4)与对照组相比,假手术组小鼠心肌组织的PI3K、AKT和GSK⁃3β蛋白表达量升高,而模型组小鼠心肌组织的AKT蛋白表达量降低,GSK⁃3β蛋白表达量则升高(P<0.05),PI3K蛋白表达量的变化无统计学意义(P>0.05);与模型组相比,糖干预组小鼠心肌组织的PI3K、AKT和GSK⁃3β蛋白表达量升高,而心梗干预组小鼠心肌组织的PI3K、AKT蛋白表达量升高(P<0.05),但GSK⁃3β蛋白表达量变化无统计学意义(P>0.05);与心梗干预组小鼠相比,糖干预组小鼠心肌组织的AKT、GSK⁃3β蛋白表达量升高(P<0.05),而PI3K蛋白表达量的变化无统计学意义(P>0.05)。结论 利拉鲁肽可改善糖尿病合并心肌梗死小鼠模型的心功能损伤、心肌梗死面积及心肌间质纤维化,其可能通过PI3K/AKT信号通路调节GSK⁃3β的表达而发挥作用。

Objective To explore the effect of liraglutide on cardiac function of mice with diabetes mellitus and concomitant myocardial infarction and its mechanism. Methods A total of 75 KM male mice were assigned to control group (15 mice) or model treatment group (60 mice) according to the random number table method. The diabetic mice model was established on 60 mice in the model treatment group, after successful modeling, the mice model of diabetes mellitus and concomitant myocardial infarction was established in 45 mice of the model treatment group selected by the random number table method; moreover, the remaining 15 mice were taken as sham operation group, and mice only underwent thoracotomy without coronary artery ligation. A total of 45 mice with diabetes mellitus and concomitant myocardial infarction were assigned to model group (n=15), myocardial infarction intervention group (n=15), or glucose intervention group (n=15) according to the random number table method, therein the myocardial infarction intervention group received intragastric administration of clopidogrel bisulfate+atorvastatin calcium tablets for intervention, the glucose intervention group was intervened by intraperitoneal injection of liraglutide injection, and the remaining mice did not receive any special treatment. After 7 days of intervention, electrocardiogram of mice in various groups was observed by using the electrocardiogram machine. The HE staining and 2, 3, 5-triphenyltetrazolium chloride staining were used to observe pathological status and myocardial infarction size of mice in various groups. The Western blot was used to detect protein expressions of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glycogen synthetase kinase 3β (GSK-3β) in myocardial tissues of mice in various groups. Results (1) There was no obvious abnormality in electrocardiogram of the control group and the sham operation group, and there was obvious ST-segment elevation and variant T wave in electrocardiogram of mice in the model group. ST-segment elevation and variant T wave of electrocardiogram in the myocardial infarction intervention group and the glucose intervention group were significantly improved, and the improvement effect of the myocardial infarction intervention group was superior to that of the glucose intervention group. (2) The myocardial fibers of mice in the control group and the sham operation group were arranged neatly and compactly, and the myocardial cells were intact; furthermore, compared with the control and sham operation groups, myocardial tissues of mice in the model group presented as infarct area, incomplete and disordered-arrangement myocardial cell morphology in the peri-infarct area, and a large number of inflammatory cell infiltration and fibrous tissue proliferation; in addition, compared with the model group, the aforementioned pathological changes were improved in the myocardial infarction intervention group and the glucose intervention group, and the improvement degree in the myocardial infarction intervention group was superior to that in the glucose intervention group. (3) Compared with the control group, there was no significant change in the percentage of size of myocardial infarction area in the sham operation group (P>0.05), and the percentage of size of myocardial infarction area in the model group was significantly increased than that in the control group and the sham operation group (P<0.05). Compared with the model group, the percentage of size of myocardial infarction area was reduced in the myocardial infarction intervention and glucose intervention groups (P<0.05), and the percentage of size of myocardial infarction area was smaller in the myocardial infarction intervention group than in the glucose intervention group, but no statistically significant difference was found (P>0.05). (4) Compared with the control group, the sham operation group exhibited elevated protein expressions of PI3K, AKT, and GSK-3β in myocardial tissues, whereas the model group yielded a decreased AKT protein expression in myocardial tissues, and an elevated GSK-3β protein expression in myocardial tissues (P<0.05), but there was no statistically significant difference in PI3K protein expression (P>0.05). Compared with the model group, the glucose intervention group interpreted elevated protein expressions of PI3K, AKT, and GSK-3β in myocardial tissues, whereas the myocardial infarction intervention group depicted elevated protein expressions of PI3K and AKT in myocardial tissues (P<0.05), but no statistically significant difference in GSK-3β protein expression was found (P>0.05). Compared with the myocardial infarction intervention group, the glucose intervention group implied elevated protein expressions of AKT and GSK-3β in myocardial tissues (P<0.05), whereas there was no statistically significant difference in PI3K protein expression (P>0.05). Conclusion Liraglutide can improve cardiac function injury, myocardial infarction size, and myocardial interstitial fibrosis in mice with diabetes mellitus and concomitant myocardial infarction, which may play a role by regulating expression of GSK-3β through PI3K/AKT signaling pathway.

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