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恩格列净通过 TAK-1/NF-κB 通路抑制血管内皮细胞向间充质细胞转化从而抑制内膜增生。

Empagliflozin inhibits neointimal hyperplasia through attenuating endothelial-to-mesenchymal transition via TAK-1/NF-κB pathway.

机构信息

Department of Vascular Surgery, Second Xiangya Hospital, Central South University, Number 139, Renmin Road, Changsha, Hunan, 410011, PR China; Vascular Disease Institute, Central South University, Changsha, Hunan, 410011, PR China.

Department of Vascular Surgery, Second Xiangya Hospital, Central South University, Number 139, Renmin Road, Changsha, Hunan, 410011, PR China; State Key Laboratory of Cardiovascular Disease, Center of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 10037, PR China; Vascular Disease Institute, Central South University, Changsha, Hunan, 410011, PR China.

出版信息

Eur J Pharmacol. 2023 Sep 5;954:175826. doi: 10.1016/j.ejphar.2023.175826. Epub 2023 Jun 13.

DOI:10.1016/j.ejphar.2023.175826

PMID:37321472

Abstract

OBJECTIVE

To investigate whether empagliflozin could prevent injury-induced vascular neointimal hyperplasia and to further explore its mechanism.

METHODS

Male C57BL/6J mice were divided into two groups with or without the empagliflozin treatment, and carotid ligation injury was performed to induce neointimal hyperplasia. The injured carotid arteries were collected for Western blotting (WB), histology and immunofluorescence analysis after four weeks. The inflammatory responses were analyzed by qRT-PCR to detect the inflammatory gene mRNA expression. To further explore its mechanism, HUVECs were treated with TGFβ-1 to induce EndMT followed by empagliflozin or vehicle treatment in vitro. A23187 (Calcimycin), an agonist of NF-κB signaling was used in the experiment.

RESULTS

The wall thickness and the neointima area was significantly reduced in the empagliflozin treatment group on day 28 after artery ligation. The Ki-67 positive cells were 28.33 ± 12.66% and 48.83 ± 10.41% in the empagliflozin-treated group and control group, respectively (P < 0.05). The mRNA expression levels of the inflammatory genes and inflammatory cells were decreased in the empagliflozin treatment group, as well as the MMP2 and MMP9. Meanwhile, empagliflozin can significantly reduce the migratory ability of inflammatory-treated HUVECs. The CD31 was increased in the TGFβ1+empagliflozin group, whereas the FSP-1, phosphorylation of TAK-1 (p-TAK-1) and phosphorylation of NF-κB (p- NF-κB) expression level were decreased, compared to the control group without empagliflozin treatment. However, the expression level of FSP-1 and p-NF-κB were reversed after co-treatment with A23187, whereas the p-TAK-1 expression level was without any significant difference.

CONCLUSION

Empagliflozin inhibits the inflammation-induced EndMT via the TAK-1/NF-κB signaling pathway.

摘要

目的

研究恩格列净是否可以预防损伤诱导的血管新生内膜增生，并进一步探讨其机制。

方法

雄性 C57BL/6J 小鼠分为有或没有恩格列净处理的两组，进行颈动脉结扎损伤以诱导新生内膜增生。四周后收集损伤的颈动脉进行 Western blot（WB）、组织学和免疫荧光分析。通过 qRT-PCR 分析炎症反应，以检测炎症基因 mRNA 表达。为了进一步探讨其机制，体外用 TGFβ-1 处理 HUVECs 诱导 EndMT，然后用恩格列净或载体处理。在实验中使用 A23187（钙调蛋白）作为 NF-κB 信号通路的激动剂。

结果

动脉结扎后 28 天，恩格列净治疗组的血管壁厚度和新生内膜面积明显减少。恩格列净治疗组和对照组的 Ki-67 阳性细胞分别为 28.33±12.66%和 48.83±10.41%（P<0.05）。恩格列净治疗组炎症基因和炎症细胞的 mRNA 表达水平降低，MMP2 和 MMP9 也降低。同时，恩格列净可显著降低炎症处理后的 HUVEC 的迁移能力。与未用恩格列净处理的对照组相比，TGFβ1+恩格列净组的 CD31 增加，而 FSP-1、TAK-1 磷酸化（p-TAK-1）和 NF-κB 磷酸化（p-NF-κB）表达水平降低。然而，在用 A23187 共同处理后，FSP-1 和 p-NF-κB 的表达水平逆转，而 p-TAK-1 表达水平没有显著差异。