卡格列净抑制尼古丁诱导血管硬化的作用及机制*

doi:10.3870/j.issn.1672-0741.25.12.035

摘要/Abstract

摘要： 目的探讨卡格列净对尼古丁诱导血管硬化的影响及其可能的作用机制。方法通过对C57BL/6小鼠皮下植入渗透压微量泵持续输注尼古丁,构建尼古丁诱导血管硬化动物模型,并给予模型动物卡格列净干预,探索卡格列净对模型动物血管硬化的影响。体内实验中,采用超声检测技术测定小鼠主动脉脉搏波传导速度(pulse wave velocity,PWV),以此作为血管硬化程度的评估金标准;通过HE染色、Masson染色及EVG染色观察主动脉组织病理形态与血管重构情况,同时采用蛋白质免疫印迹(Western blot)与免疫荧光染色技术,对基质金属蛋白酶2(MMP2)、MMP9、Ⅰ型胶原(Collagen Ⅰ)、纤维连接蛋白(Fibronectin,FN)等蛋白的表达水平进行检测。体外实验中,以尼古丁处理小鼠主动脉平滑肌细胞(Movas)后给予卡格列净干预,采用Western blot技术检测转化生长因子-β1(transforming growth factor-β1,TGF-β1)信号通路关键蛋白的表达变化。结果与模型对照组小鼠相比,卡格列净能够明显抑制尼古丁诱导的小鼠PWV的升高,同时显著减少胶原纤维的沉积以及弹性纤维的降解。此外,卡格列净显著下调尼古丁诱导的Collagen Ⅰ、FN、MMP2和MMP9蛋白表达水平,同时可显著抑制尼古丁介导的Collagen Ⅰ与MMP2 mRNA水平升高。体外实验发现,尼古丁显著上调了小鼠主动脉平滑肌细胞中TGF-β1和Smad2/Smad3的表达,而卡格列净显著逆转尼古丁诱导的上述分子表达上调效应。结论卡格列净显著抑制尼古丁诱导的小鼠血管硬化,其可能的机制是通过抑制小鼠主动脉平滑肌细胞TGF-β1/Smad信号通路抑制尼古丁诱导的胶原纤维沉积和弹性纤维降解。

关键词: 卡格列净, 尼古丁, 血管硬化, TGF-β1

Abstract: Objective To investigate the effects of canagliflozin on nicotine-induced arterial stiffness,and its possible mechanisms of action.Methods An animal model of nicotine-induced arterial stiffness was established by subcutaneously implanting osmotic microinfusion pumps into C57BL/6 mice to deliver a continuous infusion of nicotine;the model animals were then treated with canagliflozin to explore the effect of canagliflozin on arterial stiffness in these animals.In the in vivo experiments,ultrasound technology was employed to measure the aortic pulse wave velocity(PWV)in mice;aortic histopathology and vascular remodeling were examined using hematoxylin-eosin(HE)staining,Masson's trichrome staining,and Verhoeff's van Gieson(EVG)staining.Additionally,Western blot and immunofluorescence techniques were employed to detect the expression levels of matrix metalloproteinase-2(MMP-2),MMP-9,collagen Ⅰ,and fibronectin.Nicotine-treated murine aortic smooth muscle cells(Movas)were treated with canagliflozin in vitro,and Western blot analysis was used to detect changes in the expression of key proteins in the transforming growth factor-β1(TGF-β1)signaling pathway.Results Compared with mice in the control group,canagliflozin significantly suppressed the nicotine-induced increase in PWV in mice,also significantly reduced collagen fibre deposition and elastic fibre degradation.Furthermore,canagliflozin significantly downregulated the nicotine-induced expression of Collagen Ⅰ,fibronectin,MMP2 and MMP9 at the protein level,whilst also significantly inhibiting the nicotine-mediated increase in CollagenⅠ and MMP2 mRNA levels.In vitro experiments revealed that nicotine significantly up-regulated the expression of TGF-β1 and Smad2/Smad3 in mouse aortic smooth muscle cells,whereas canagliflozin significantly reversed the nicotine-induced up-regulation of these molecules.Conclusion Canagliflozin markedly suppressed nicotine-induced arterial stiffness in mice,potentially through its significant inhibition of nicotine-induced collagen fibre deposition and elastic fiber degradation.This effect may involve canagliflozin-mediated suppression of TGF-β1/Smad signaling pathway in mouse aortic smooth muscle cells.

Key words: canagliflozin, nicotine, arterial stiffness, TGF-β1

中图分类号:

R543.5

董攀, 贺扬, 李一筱, 凃玲, 徐西振. 卡格列净抑制尼古丁诱导血管硬化的作用及机制^*[J]. 华中科技大学学报（医学版）, 2026, 55(4): 475-482.

Dong Pan, He Yang, Li Yixiao, et al. The Inhibitory Effects of Canagliflozin on Nicotine-induced Arterial Stiffness and Its Mechanism[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(4): 475-482.

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卡格列净抑制尼古丁诱导血管硬化的作用及机制^*

The Inhibitory Effects of Canagliflozin on Nicotine-induced Arterial Stiffness and Its Mechanism

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