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)在维持血管完整性中起着至关重要的作用。VSMC功能障碍导致多种血管疾病。腺苷脱氨酶作用于RNA1(ADAR1),一种RNA编辑酶,显示了RNA编辑和非编辑功能。ADAR1的整体缺失导致胚胎致死,但在SMCs中特异性纯合ADAR1缺失的表型(ADAR1sm-/-)仍有待确定。通过将ADAR1fl/fl小鼠与Myh11-CreERT2小鼠杂交,然后进行他莫昔芬诱导,我们发现ADAR1sm-/-导致成年小鼠在诱导后14天死亡。大体检查显示不同器官广泛出血和有害血管损伤。组织学分析显示,在ADAR1sm-/-主动脉中,弹性蛋白层从VSMC脱离,破坏了动脉结构完整性。此外,ADAR1sm-/-导致严重的VSMC凋亡和线粒体功能障碍。ADAR1sm-/-主动脉段的RNA测序分析表明影响血管健康的基因的深度转录改变,包括原纤维蛋白-1表达的减少。更重要的是,ADAR1sm-/-破坏弹性蛋白和原纤维蛋白-1的相互作用,对动脉结构至关重要的分子事件。我们的结果表明,ADAR1在维持SMC存活和血管稳定性和弹性中起着至关重要的作用。