PDF(Pubmed)
Abstract：
Phenotypic transformation of vascular smooth muscle cells (VSMCs) plays a crucial role in abdominal aortic aneurysm (AAA) formation. CARMN, a highly conserved, VSMC-enriched long noncoding RNA (lncRNA), is integral in orchestrating various vascular pathologies by modulating the phenotypic dynamics of VSMCs. The influence of CARMN on AAA formation, particularly its mechanisms, remains enigmatic. Our research, employing single-cell and bulk RNA sequencing, has uncovered a significant suppression of CARMN in AAA specimens, which correlates strongly with the contractile function of VSMCs. This reduced expression of CARMN was consistent in both 7- and 14-day porcine pancreatic elastase (PPE)-induced mouse models of AAA and in human clinical cases. Functional analyses disclosed that the diminution of CARMN exacerbated PPE-precipitated AAA formation, whereas its augmentation conferred protection against such formation. Mechanistically, we found CARMN\'s capacity to bind with SRF, thereby amplifying its role in driving the transcription of VSMC marker genes. In addition, our findings indicate an enhancement in CAMRN transcription, facilitated by the binding of NRF2 to its promoter region. Our study indicated that CARMN plays a protective role in preventing AAA formation and restrains the phenotypic transformation of VSMC through its interaction with SRF. Additionally, we observed that the expression of CARMN is augmented by NRF2 binding to its promoter region. These findings suggest the potential of CARMN as a viable therapeutic target in the treatment of AAA.
摘要：
血管平滑肌细胞（VSMC）的表型转化在腹主动脉瘤（AAA）的形成中起着至关重要的作用。CARMN,一个高度保守的，富含VSMC的长链非编码RNA（lncRNA），是通过调节VSMC的表型动力学来协调各种血管病变的组成部分。CARMN对AAA形成的影响，特别是它的机制，仍然是个谜.我们的研究,采用单细胞和批量RNA测序，在AAA标本中发现了CARMN的显著抑制，这与VSMC的收缩功能密切相关。CARMN的这种降低的表达在7天和14天的猪胰弹性蛋白酶（PPE）诱导的AAA小鼠模型和人类临床病例中都是一致的。功能分析显示，CARMN的减少加剧了PPE沉淀的AAA形成，而它的增强赋予了对这种形成的保护。机械上,我们发现CARMN与SRF绑定的能力，从而放大其在驱动VSMC标记基因转录中的作用。此外,我们的发现表明CAMRN转录增强，通过NRF2与其启动子区的结合而促进。我们的研究表明，CARMN在预防AAA形成中起保护作用，并通过与SRF的相互作用抑制VSMC的表型转化。此外,我们观察到NRF2与其启动子区的结合增强了CARMN的表达。这些发现表明CARMN作为治疗AAA的可行治疗靶标的潜力。
