氨基胺通过通过PAR-1和VEGF-R调节内皮细胞骨和NO合成酶来增加血管透性
Julia Böttner1, Tina Fischer-Schaepmann2, Sarah Werner2
1Department of Cardiology, Heart Center Leipzig at Leipzig University, Strümpellstr. 39, 04289, Leipzig, Germany. Julia.Boettner@medizin.uni-leipzig.de.
Scientific reports
|February 13, 2024
概括
胺类型的兴奋剂滥用会导致心血管问题. 这项研究表明,d-胺硫酸盐通过VEGF-R和PAR-1破坏内皮屏障功能,影响eNOS酸化,并可能导致心脏毒性.
科学领域:
- 心血管药理学心血管药理学
- 分子毒理学分子毒理学
- 内皮细胞生物学 内皮细胞生物学
背景情况:
- 胺类兴奋剂 (ATS) 的滥用与严重的心血管不良事件有关,包括心脏突然死亡.
- 虽然涉及catecholamine释放,但直接的血管病理机制,特别是关于内皮功能,仍然不清楚.
- 了解这些机制对于解决与ATS有关的心脏毒性至关重要.
研究的目的:
- 调查d-胺硫酸盐 (DAM) 对血管和内皮功能的急性药物病理影响.
- 确定涉及DAM诱导的血管变化的分子标和信号通路.
- 阐明内皮膜屏障完整性和内皮膜氧化合成酶 (eNOS) 在胺诱导的心脏毒性的作用.
主要方法:
- 对DAM对大鼠动脉环收缩的影响的ex vivo评估.
- 在体外无标签,实时电化学阻抗光谱 (EIS) 来评估内皮屏障功能.
- 药理学阻断特定受体 (VEGF-R, PAR-1) 和信号通路 (ROCK) 以确定分子标.
- 对内皮氧化合成酶 (eNOS) 酸化状态的分析.
主要成果:
- 由血管内皮生长因子受体 (VEGF-R) 和蛋白酶激活受体1 (PAR-1) 介导的DAM诱导显著的血管扩张 (29.3±2.5%的血管度下降).
- EIS表明,DAM破坏了内皮屏障功能 (-75.9±1.1%的初始细胞阻抗),也涉及VEGF-R和PAR-1.
- 罗关联蛋白激酶 (ROCK) 介导的动因细胞骨收缩,导致屏障破坏和在Serine1177和Threonine495.5处的eNOS低酸化.
- 阻止VEGF-R和PAR-1部分恢复了eNOS Threonine495的酸化.
结论:
- 急性d-胺硫酸盐暴露会引发血管扩张,增加血管透性,并导致actin细胞骨收缩.
- 这些效应由VEGF-R,PAR-1和ROCK信号通路介导,导致eNOS低酸化.
- 这些发现提供了对安非他胺诱导的心血管不良影响和心脏毒性背后的分子机制的见解.
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