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ADAR1 对于平滑肌稳态和血管完整性是必需的。

ADAR1 Is Essential for Smooth Muscle Homeostasis and Vascular Integrity.

机构信息

Departments of Surgery, University of Missouri School of Medicine, Columbia, MO 65212, USA.

The Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO 65201, USA.

出版信息

Cells. 2024 Jul 26;13(15):1257. doi: 10.3390/cells13151257.

DOI:10.3390/cells13151257
PMID:39120288
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11311430/
Abstract

Vascular smooth muscle cells (VSMCs) play a critical role in maintaining vascular integrity. VSMC dysfunction leads to numerous vascular diseases. Adenosine deaminases acting on RNA 1 (ADAR1), an RNA editing enzyme, has shown both RNA editing and non-editing functions. Global deletion of ADAR1 causes embryonic lethality, but the phenotype of homozygous ADAR1 deletion specifically in SMCs (ADAR1sm-/-) remains to be determined. By crossing ADAR1fl/fl mice with Myh11-CreERT2 mice followed by Tamoxifen induction, we found that ADAR1sm-/- leads to lethality in adult mice 14 days after the induction. Gross examination revealed extensive hemorrhage and detrimental vascular damage in different organs. Histological analyses revealed destruction of artery structural integrity with detachment of elastin laminae from VSMCs in ADAR1sm-/- aortas. Furthermore, ADAR1sm-/- resulted in severe VSMC apoptosis and mitochondrial dysfunction. RNA sequencing analyses of ADAR1sm-/- aorta segments demonstrated profound transcriptional alteration of genes impacting vascular health including a decrease in fibrillin-1 expression. More importantly, ADAR1sm-/- disrupts the elastin and fibrillin-1 interaction, a molecular event essential for artery structure. Our results indicate that ADAR1 plays a critical role in maintaining SMC survival and vascular stability and resilience.

摘要

血管平滑肌细胞 (VSMC) 在维持血管完整性方面起着关键作用。VSMC 功能障碍导致多种血管疾病。作用于 RNA1 的腺苷脱氨酶 (ADAR1) 是一种 RNA 编辑酶，具有 RNA 编辑和非编辑功能。ADAR1 的全局缺失会导致胚胎致死，但 ADAR1 在血管平滑肌细胞 (ADAR1sm-/-) 中的纯合缺失的表型仍有待确定。通过将 ADAR1fl/fl 小鼠与 Myh11-CreERT2 小鼠杂交，然后用他莫昔芬诱导，我们发现 ADAR1sm-/- 在诱导后 14 天导致成年小鼠死亡。大体检查显示不同器官广泛出血和血管损伤。组织学分析显示 ADAR1sm-/- 主动脉中动脉结构完整性的破坏，弹性层从 VSMC 上分离。此外，ADAR1sm-/- 导致 VSMC 凋亡和线粒体功能障碍。ADAR1sm-/- 主动脉节段的 RNA 测序分析表明，对包括纤维连接蛋白 1 表达降低在内的影响血管健康的基因进行了深刻的转录改变。更重要的是，ADAR1sm-/- 破坏了弹性蛋白和纤维连接蛋白 1 的相互作用，这是动脉结构所必需的分子事件。我们的结果表明，ADAR1 在维持平滑肌细胞存活和血管稳定性和弹性方面起着关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/18a966380f14/cells-13-01257-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/3d1f6f07684c/cells-13-01257-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/168312fd05e0/cells-13-01257-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/6b2551886548/cells-13-01257-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/86c62730a317/cells-13-01257-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/ad6b1cee8ae9/cells-13-01257-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/18a966380f14/cells-13-01257-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/3d1f6f07684c/cells-13-01257-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/168312fd05e0/cells-13-01257-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/6b2551886548/cells-13-01257-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/86c62730a317/cells-13-01257-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/ad6b1cee8ae9/cells-13-01257-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0803/11311430/18a966380f14/cells-13-01257-g006.jpg

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