达格列净通过调控TMEM16A改善2型糖尿病小鼠血管内皮衰老的机制研究

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摘要 目的: 从血管内皮衰老角度探讨达格列净（Dapagliflozin,DAP）治疗糖尿病血管并发症的可能作用机制。方法: 实验小鼠随机分为空白对照组、模型组和DAP组。腹腔注射STZ构建糖尿病小鼠模型,每组不同方式给药。观察小鼠的一般状态,检测其生理参数;通过HE（hematoxylin-eosin,HE）染色、Masson染色评估各组小鼠颈总动脉组织病理学结果;通过ELISA检测各组小鼠血清中一氧化氮（NO）、活性氧（ROS）生成情况以及炎症因子的含量;通过Western- blot检测小鼠颈总动脉组织骨桥蛋白（osteopontin,OPN）、细胞骨架蛋白（smooth muscle 22α,SM22α）、跨膜成员16A（transmembrane protein16A,TMEM16A）、磷酸化/信号转导及转录激活蛋白3（phosphorylation/signal transducer and activator of transcription 3,STAT3）、p53和p21蛋白的表达水平。结果: DAP有效改善模型组小鼠精神状态、活动、饮食及排泄情况,与模型组相比血糖值显著降低,DAP组动脉膜厚度明显减轻,显著减少了胶原纤维表达沉积。此外,与模型组相比,DAP组逆转了NO下降、抑制ROS产生,小鼠颈总动脉组织中p21、p53、OPN、TMEM16A、p-SATA3蛋白含量显著降低,以及SM22α蛋白含量明显回调。结论: DAP能够有效改善糖尿病小鼠内皮细胞衰老,缓解糖尿病模型小鼠颈总动脉血管内皮细胞发生促进器官纤维化反应,发挥血管衰老保护作用,其机制可能与其抑制TMEM16A表达、血管ROS生成以及IL-6/IL-6R/STAT3信号通路相关。

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	冯春晖
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	刘静芳

关键词 ：达格列净, 内皮细胞衰老, 2型糖尿病, 跨膜成员16A, 磷酸化/信号转导及转录激活蛋白3, 活性氧

Abstract：Objective To explore the possible mechanism of DAP in the treatment of diabetic vascular complications from the perspective of vascular endothelial senescence. Methods The experimental mice were randomly divided into three groups: blank group, model group and DAP group. To construct diabetic mouse model by intraperitoneal injection of STZ, and each group was administered in a different way. Observe the general state of mice and detect their physiological parameters; The histopathology of the common carotid artery in each group was evaluated by HE staining and Masson staining. The contents of nitric oxide (NO), reactive oxygen species (ROS) and inflammatory factors in the serum of mice were detected by ELISA. Expression levels of the common carotid artery osteopontin, phosphorylation/signal transducer and activator of transcription 3, smooth muscle 22α, transmembrane protein 16A, p53 and p21 protein were detected by Western-blot. Results In DAP group, the mental state, activity, diet and excretion of mice were effectively improved, and the blood glucose value was significantly reduced. The expression of collagen fibers and the thickness of the arterial membrane were decreased significantly. In addition, the DAP group reversed the decrease of NO and inhibited the production of ROS, and the protein contents of p21, p53, OPN, TMEM16A and p-SATA3 in the common carotid artery tissues of mice were significantly reduced, the protein content of SM22α was significantly reversed. Conclusion DAP can effectively improve endothelial cell senescence in diabetic mice, alleviate common carotid artery vascular fibrosis in diabetic mice, and play a protective role in vascular senescence. The mechanism may be related to its inhibition of TMEM16A expression, ROS production and IL-6/IL-6R/STAT3 signaling pathway.

Key words： dapagliflozin endothelial cell senescence type 2 diabetes mellitus transmembrane protein16A signal transducer and activator of transcription 3 reactive oxygen species

收稿日期: 2024-06-15

基金资助:河北省卫健委医学科学研究项目“达格列净通过调控TMEM16A改善二型糖尿病小鼠血管内皮衰老的机制研究”（20242075）

通讯作者: 孙文阳, E-mail: swyang00@126. com

引用本文:

冯春晖, 田洋, 孙文阳, 侯亚娜, 刘静芳. 达格列净通过调控TMEM16A改善2型糖尿病小鼠血管内皮衰老的机制研究[J]. 湖南师范大学学报(医学版), 2024, 21(4): 7-11. FENG Chunhui, TIAN Yang, SUN Wenyang, HOU Yana, LIU Jingfang. Study on the mechanism of dapagliflozin in improving vascular endothelial senescence by regulating TMEM16A mice with type 2 diabetes. HuNan ShiFan DaXue XueBao(YiXueBan), 2024, 21(4): 7-11.

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http://yxb.hunnu.edu.cn/CN/ 或 http://yxb.hunnu.edu.cn/CN/Y2024/V21/I4/7

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