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在小鼠中,DFMG通过抑制TLR4/VEGF通路来降低血管生成,以维持斑块的稳定性

Pingjuan Bai^1,2, Xueping Xiang², Jiawen Kang²

¹Pathology Department, Jiangxi Maternal and Child Health Hospital, Nanchang, Jiangxi Province, China.

|April 18, 2024

概括

7-difluoromethoxy-5,4'-dimethoxygenistein (DFMG) 通过上调调节microRNA-140 (miR-140),从而抑制动脉样硬化斑块血管生成,该微RNA-140 (miR-140) 的向是Toll-like受体4 (TLR4). 这种机制减少了新血管化,并改善了AS中的斑块稳定性.

科学领域:

心血管研究研究心血管研究
分子生物学分子生物学
药理学药理学是指药理学的学科.

背景情况:

动脉样硬化 (AS) 的特征是斑块形成和新血管化.
化合物7-difluoromethoxy-5,4'-dimethoxygenistein (DFMG) 显示出对AS血管生成的抑制作用,但机制尚不清楚.
氧化应激在动脉样硬化病变的初始阶段起着关键作用.

研究的目的:

阐明DFMG在AS斑块中抑制血管生成的机制.
研究微RNA-140 (miR-140) 和托尔类受体4 (TLR4) 在DFMG抗血管原作用中的作用.
在AS模型中评估DFMG对脂质水平,斑块负担和新血管化的影响.

主要方法:

在体外研究中,使用暴露于LPC的人类脉内皮细胞 (HUVEC-12) 模拟氧化应激.
在体内研究中,使用ApoE淘汰赛小鼠食高脂肪饮食以建立AS模型.
管形成试验,胚胎胆 ?? 质膜试验,脂质水平测量和免疫组织化学分析.
双露西法酶记者测定证实了miR-140.0对TLR4的直接向.

主要成果:

在体外和体内,DFMG减少了管状体的形成和新血管化.
在AS小鼠模型中,DFMG降低了血脂水平,动脉样硬化斑块大小和新血管化.
DFMG上调了miR-140的表达和抑制了VEGF的分泌,这种效应被TLR4过度表达抵消了.
发现miR-140直接准TLR4,在AS小鼠中观察到的反向关系.

结论:

通过上调 miR-140.0,DFMG 抑制血管生成并改善动脉样硬化中的斑块稳定性.
DFMG的抗血管效应通过抑制TLR4/NF-κB/VEGF信号通路进行介导,miR-140负面调节.
DFMG通过向参与斑块发育和新血管化的关键分子通路来证明了治疗动脉样硬化的治疗潜力.

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