Abstract：
Abdominal aortic aneurysm (AAA) is a life-threatening disease characterized by extensive membrane destruction in the vascular wall that is closely associated with vascular smooth muscle cell (VSMC) phenotypic switching. A thorough understanding of the changes in regulatory factors during VSMC phenotypic switching is essential for managing AAA therapy. In this study, we revealed the impact of NRF2 on the modulation of VSMC phenotype and the development of AAA based on single-cell RNA sequencing analysis. By utilizing a murine model of VSMC-specific knockout of nuclear factor E2-related factor 2 (NRF2), we observed that the absence of NRF2 in VSMCs exacerbated AAA formation in an angiotensin II-induced AAA model. The downregulation of NRF2 promoted VSMC phenotypic switching, leading to an enhanced inflammatory response. Through genome-wide transcriptome analysis and loss- or gain-of-function experiments, we discovered that NRF2 upregulated the expression of VSMC contractile phenotype-specific genes by facilitating microRNA-145 (miR-145) expression. Our data identified NRF2 as a novel regulator involved in maintaining the VSMC contractile phenotype while also influencing AAA formation through an miR-145-dependent regulatory mechanism.
摘要：
腹主动脉瘤（AAA）是一种威胁生命的疾病，其特征是血管壁广泛的膜破坏，与血管平滑肌细胞（VSMC）表型转换密切相关。彻底了解VSMC表型转换过程中调节因子的变化对于管理AAA治疗至关重要。在这项研究中,我们基于单细胞RNA测序分析揭示了NRF2对VSMC表型调节和AAA发展的影响.利用VSMC特异性敲除核因子E2相关因子2（NRF2）的小鼠模型，我们观察到,在血管紧张素II诱导的AAA模型中,VSMC中NRF2缺失会加剧AAA的形成.NRF2的下调促进了VSMC表型转换，导致炎症反应增强。通过全基因组转录组分析和功能缺失或获得实验，我们发现NRF2通过促进microRNA-145(miR-145)表达上调VSMC收缩表型特异性基因的表达.我们的数据确定NRF2是一种新型调节因子，参与维持VSMC收缩表型，同时也通过miR-145依赖性调节机制影响AAA形成。
