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非编码RNA调节Krm1和Dkk2的表达,以协同影响大动脉损伤

Gaopeng Xian^1,2,3, Rong Huang⁴, Minhui Xu^1,2,3

¹State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.

Experimental & molecular medicine

|June 30, 2024

概括

动脉疾病 (CAVD) 涉及诸如circHIPK3.3之类的非编码RNA. 这项研究表明,circHIPK3和miR-182-5p通过调节Wnt/β-catenin通路来调节膜化,从而提供潜在的治疗点.

科学领域:

心血管生物学心血管生物学
分子医学是分子医学.
在RNA生物学,RNA生物学.

背景情况:

动脉疾病 (CAVD) 是一个日益严重的全球健康问题,药物治疗有限.
非编码RNA与心血管疾病有关,但它们在CAVD中的具体作用尚不清楚.
了解CAVD背后的分子机制对于开发有效疗法至关重要.

研究的目的:

研究非编码RNAs在CAVD.的病变发生过程中的作用.
为了识别特定的非编码RNA及其参与大动脉结石化的点.
阐明在CAVD中由非编码RNA调节的分子通路.

主要方法:

使用测序数据,对正常与化主动脉中的非编码RNA的差异表达分析.
使用CAVD小鼠模型进行体内研究,以评估circHIPK3.3的影响.
在体外实验中对大动脉间歇细胞进行实验,以检查细胞反应和分子相互作用.
研究circHIPK3的m6A修饰及其与DDX5和METTL3.3的相互作用.
分析克雷门1 (Krm1) mRNA的稳定性及其通过circHIPK3.3的调节.
评估miR-182-5p对Dickkopf2 (Dkk2) 的影响及其对Wnt/β-catenin信号传递的影响.

主要成果:

测序确定了CAVD中circHIPK3和miR-182-5p的差异表达.
在CAVD的小鼠模型中,circHIPK3的过度表达减少了主动脉病变.
发现circHIPK3在体外抑制了大动脉间歇细胞的骨质分化.
circHIPK3被m6A修改,这是DDX5和METTL3介导的过程,增强了Krm1mRNA的稳定性.
Krm1作为Wnt/β-catenin通路的负调节剂,其被circHIPK3抑制促进了化.
表明miR-182-5p可以抑制Dkk2,从而减弱Krm1-介导的Wnt信号抑制.
证实Wnt/β-catenin通路的激活对大动脉结石化有显著的贡献.

结论:

非编码RNAs,特别是circHIPK3和miR-182-5p,是CAVD中的关键上游调节者.
克雷门1-Dickkopf2 (Krm1-Dkk2) 轴在调节大动脉中Wnt/β-catenin信号传递方面发挥着至关重要的作用.
针对已识别的非编码RNA调节网络,为CAVD提供了一个有前途的治疗策略.

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