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缺乏miR-409-3p可以通过调节DNAJB9/p38 MAPK信号传递来改善心肌新血管化和功能
Furkan Bestepe1, Colette Fritsche1, Kartik Lakhotiya1
1Molecular Cardiology Research Institute, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA.
Molecular therapy. Nucleic acids
|June 19, 2023
概括
微RNA-409-3p损害了心脏病发作后的血管修复,特别是在糖尿病中. 抑制这种microRNA可以改善心脏功能,并减少小鼠模型中的损伤,从而成为潜在的治疗点.
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.
- 代谢调节 代谢调节 代谢调节
背景情况:
- 血管新生对于心肌梗塞 (MI) 后的组织修复至关重要,但因胰岛素抵抗和糖尿病而受损.
- 微RNAs (miRNAs) 是血管生成的关键调节者,影响血管化至关重要的细胞过程.
- 在MI后血管生成的代谢调节中,miR-409-3p的特定作用仍未得到充分研究.
研究的目的:
- 为了研究心肌梗塞 (MI) 后内皮细胞 (EC) 中miR-409-3p的代谢调节.
- 阐明miR-409-3p在ECs中的功能作用,在血管因子对缺血的反应过程中.
- 在心脏修复的背景下,识别 miR-409-3p 调节的下游目标和信号通路.
主要方法:
- 在人类急性冠状动脉综合征 (ACS) 患者和小鼠MI模型中分析miR-409-3p的表达.
- 在体外研究中,使用用棕酸盐,VEGF和FGF治疗的内皮细胞 (EC) 来评估miR-409-3p调节和功能.
- RNA测序 (RNA-seq) 和Argonaute2免疫沉以确定miR-409-3p标,并验证DNAJB9.
- 在高脂肪,高糖饮食中接受缺血-再输液 (I/R) 损伤的EC特异性miR-409-3p淘汰赛 (miR-409ECKO) 小鼠的生成和生理评估.
主要成果:
- 在ACS患者和心脏病后的小鼠中,miR-409-3p表达升高,ECs中由palmitate诱导,VEGF/FGF抑制.
- 过度表达miR-409-3p抑制了EC增殖和迁移,而它的抑制促进了这些过程.
- DNAJB9被确定为miR-409-3p的直接标,其表达通过p38 MAPK通路进行调节.
- 在miR-409ECKO小鼠中,ECs中miR-409-3p的淘汰显著增强了血管新生标志物 (单抗蛋白B4,CD31) 和I/R损伤后的DNAJB9水平.
- 与对照小鼠相比,心脏功能得到改善,证实了miR-409ECKO小鼠的喷射率 (EF) 增加和心脏病发作大小减少.
结论:
- miR-409-3p在对心肌缺血的血管性反应中起着有害的作用,特别是在代谢压力下.
- 在内皮细胞中准miR-409-3p代表了一种有希望的治疗策略,以促进心脏中风后的心脏修复.
- 这些发现突出了miR-409-3p作为关键的调解者,将代谢功能障碍与心脏病中的血管生成受损联系起来.
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