细胞外葡萄糖和功能失调的胰岛素受体信号独立上调动脉光滑肌肉TMEM16A表达
Somasundaram Raghavan1, Masuma Akter Brishti1, Angelica Bernardelli2
1Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, United States.
American journal of physiology. Cell physiology
|April 6, 2024
概括
糖尿病对动脉中的TMEM16A通道进行上调,导致血管收缩. 牛抑制器复合物通常控制TMEM16A基因表达,但在糖尿病中功能失调,导致血管疾病.
科学领域:
- 血管生物学 血管生物学
- 分子医学是分子医学.
- 离子通道生理学 离子通道生理学
背景情况:
- 糖尿病与血管功能障碍有关,包括增加血管收缩.
- 跨膜蛋白16A (TMEM16A) 激活化通道与调节动脉光滑肌肉度有关.
- 之前的研究表明,糖尿病人动脉中的TMEM16A表达升高.
研究的目的:
- 阐明动脉TMEM16A基因表达的调节机制.
- 调查牛抑制器复合体在TMEM16A调控中的作用.
- 了解高葡萄糖和胰岛素抵抗如何影响血管系统中的TMEM16A表达.
主要方法:
- 在糖尿病和非糖尿病小鼠动脉中分析TMEM16A和牛表达 (体内和体外).
- 电泳运动和超变位测试以确定TMEM16A促进体上的牛结合点.
- 评估高葡萄糖反应中的蛋白激酶D1 (PKD1),Akt2和GSK3β信号通路.
- 使用加压小鼠后肢动脉来评估收缩反应的功能研究.
主要成果:
- 一个Snail介导的抑制器复合体被确定为动脉TMEM16A基因转录的调节者,与特定的E-box位点 (-154 nt) 结合.
- 牛表达减少,而TMEM16A表达在糖尿病动脉上升调节,牛抑制剂复合体结合减少.
- 高葡萄糖诱导了双相收缩反应,并减少了非糖尿病动脉中的-PKD1和TMEM16A表达;葡萄糖激活了PKD1,导致了牛降解.
- 糖尿病动脉中的胰岛素抵抗与基-PKD1的增加和Akt2 / pGSK3β的减少有关,增强TMEM16A表达.
结论:
- 动脉TMEM16A表达是由牛介导的抑制器综合体调节的.
- 这种牛综合体的功能障碍,受到胰岛素依赖和独立途径的影响,有助于在糖尿病中提升TMEM16A的调节和血管收缩.
- 这些发现揭示了糖尿病血管疾病中葡萄糖诱导的离子通道功能障碍的新机制.
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