利拉鲁肽通过调节血管平滑肌细胞钙化缓解糖尿病动脉粥样硬化。
Liraglutide Alleviates Diabetic Atherosclerosis through Regulating Calcification of Vascular Smooth Muscle Cells.
机构信息
Department of Cadre Ward, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
出版信息
Dis Markers. 2022 Apr 25;2022:5013622. doi: 10.1155/2022/5013622. eCollection 2022.
BACKGROUND
Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia, which can induce the development of atherosclerosis (AS). Calcification of vascular smooth muscle cells (VSMCs) exerts an important role in the process of AS. In this study, the effects of liraglutide (LIRA) on VSMC under high-glucose condition and its mechanism were explored.
METHOD
After VSMC was treated by high glucose with or without LIRA , the alkaline phosphatase (ALP) activity was measured by the detection kit, osteogenic marker protein expression was detected by Western blotting, and calcification was determined by alizarin red staining. Subsequently, the DM rat model was established and the ALP activity, calcification, and osteogenic marker proteins were determined . Immunohistochemical (IHC) staining and hematoxylin-eosin staining were performed on the thoracic aorta of DM rats.
RESULT
The positive rate of SM-actin expression in the DM + AS group was significantly lower than that in control rats, but LIRA administration increased the positive rate in the model. The expression of Cbf-1 and OPN in the DM + AS group was significantly higher than that in the control group, while it was decreased after treatment of LIRA. The ALP activity and calcium content were increased in DM + AS rats, and the treatment of LIRA decreased the phenotypes in the rats, so as to delay the progression of AS in DM rats. Meanwhile, LIRA inhibited the ALP activity, upregulated SM- expression, and downregulated expression of OPN and Cbf-1 in VSMC under high-glucose (HG) conditions. Mechanically, HG-enhanced ALP activity, AKT, and ERK phosphorylation were inhibited by LIRA, PI3K antagonist LY294002, or ERK1/2 antagonist PD98059, in which cotreatment of LIRA with LY294002 and PD98059 could further enhance the effect of LIRA on VSMC, and GLP-1R antagonists reversed the phenotypes in the model. LIRA blocked the osteogenic transformation of VSMC through PI3K and ERK1/2 signaling pathways, which can be reversed by GLP-1R antagonists.
CONCLUSION
LIRA inhibited the abnormalities in VSMC calcification mediated by the GLP-1R, which was related to PI3K/Akt and ERK1/2 MAPK pathways. Therefore, the prospect and significance of LIRA in the treatment of DM complicated with AS were clarified.
背景
糖尿病（DM）是一组以高血糖为特征的代谢性疾病，可诱导动脉粥样硬化（AS）的发生。血管平滑肌细胞（VSMC）的钙化在 AS 过程中起着重要作用。本研究探讨了利拉鲁肽（LIRA）在高糖条件下对 VSMC 的作用及其机制。
方法
用高糖处理 VSMC 或同时用 LIRA 处理，用检测试剂盒检测碱性磷酸酶（ALP）活性，用 Western blot 检测成骨标志物蛋白的表达，用茜素红染色法检测钙化。随后建立 DM 大鼠模型，检测 ALP 活性、钙化和成骨标志物蛋白。对 DM 大鼠的胸主动脉进行免疫组化（IHC）染色和苏木精-伊红（H&E）染色。
结果
DM+AS 组 SM-actin 表达的阳性率明显低于对照组，但给予 LIRA 后阳性率增加。DM+AS 组 Cbf-1 和 OPN 的表达明显高于对照组，而给予 LIRA 后表达降低。DM+AS 大鼠的 ALP 活性和钙含量增加，给予 LIRA 后降低了大鼠的表型，从而延缓 DM 大鼠 AS 的进展。同时，LIRA 抑制高糖（HG）条件下 VSMC 的 ALP 活性，上调 SM-actin 表达，下调 OPN 和 Cbf-1 的表达。机制上，HG 增强的 ALP 活性、AKT 和 ERK 磷酸化被 LIRA、PI3K 拮抗剂 LY294002 或 ERK1/2 拮抗剂 PD98059 抑制，其中 LIRA 与 LY294002 和 PD98059 共同处理可进一步增强 LIRA 对 VSMC 的作用，GLP-1R 拮抗剂逆转模型中的表型。LIRA 通过 PI3K 和 ERK1/2 信号通路阻断 VSMC 的成骨转化，该作用可被 GLP-1R 拮抗剂逆转。
结论
LIRA 抑制了 GLP-1R 介导的 VSMC 钙化异常，这与 PI3K/Akt 和 ERK1/2 MAPK 通路有关。因此，阐明了 LIRA 在治疗 DM 合并 AS 中的前景和意义。
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