Aims Aortic aneurysm and dissection (AAD) is caused by the progressive loss of aortic smooth muscle cells (SMCs) and is associated with a high mortality rate. Identifying the mechanisms underlying SMC apoptosis is crucial for preventing AAD. Neutrophil cytoplasmic factor 1 (Ncf1) is essential in reactive oxygen species (ROS) production and SMC apoptosis; Ncf1 absence leads to autoimmune diseases and chronic inflammation. Here, the role of Ncf1 in angiotensin II (Ang II)-induced AAD was investigated. Methods and results Ncf1 expression increased in injured SMCs. Bioinformatics analysis identified Ncf1 as a mediator of AAD-associated SMC damage. Ncf1 expression is positively correlated with DNA replication and repair in SMCs of AAD aortas. AAD incidence increased in Ang II-challenged Sm22CreNcf1fl mice. Transcriptomics showed that Ncf1 knockout activated the stimulator of interferon genes (STING) and cell death pathways. The effects of Ncf1 on SMC death and the STING pathway in vitro were examined. Ncf1 regulated the hydrogen peroxide-mediated activation of the STING pathway and inhibited SMC apoptosis. Mechanistically, Ncf1 knockout promoted the ubiquitination of nuclear factor erythroid 2-related factor 2 (NRF2), thereby inhibiting the negative regulatory effect of NRF2 on the stability of STING mRNA and ultimately promoting STING expression. Additionally, the pharmacological inhibition of STING activation prevented AAD progression. Conclusions Ncf1 deficiency in SMCs exacerbated Ang II-induced AAD by promoting NRF2 ubiquitination and degradation and activating the STING pathway. These data suggest that Ncf1 may be a potential therapeutic target for AAD treatment.

中文翻译：

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SMC 中的 Ncf1 敲除通过激活 STING 通路加剧血管紧张素 II 诱导的主动脉瘤和夹层

目的 主动脉瘤夹层 (AAD) 是由主动脉平滑肌细胞 (SMC) 逐渐丧失引起的，并且与高死亡率相关。确定 SMC 凋亡的机制对于预防 AAD 至关重要。中性粒细胞胞质因子 1 (Ncf1) 在活性氧 (ROS) 产生和 SMC 凋亡中至关重要； Ncf1 缺失会导致自身免疫性疾病和慢性炎症。在此，研究了 Ncf1 在血管紧张素 II (Ang II) 诱导的 AAD 中的作用。方法和结果 Ncf1 表达在受伤的 SMC 中增加。生物信息学分析确定 Ncf1 是 AAD 相关 SMC 损伤的介质。 Ncf1 表达与 AAD 主动脉 SMC 中的 DNA 复制和修复呈正相关。 Ang II 攻击的 Sm22CreNcf1fl 小鼠中 AAD 发生率增加。转录组学表明，Ncf1 敲除激活了干扰素基因刺激剂 (STING) 和细胞死亡途径。体外检查了 Ncf1 对 SMC 死亡和 STING 通路的影响。 Ncf1 调节过氧化氢介导的 STING 通路激活并抑制 SMC 凋亡。从机制上来说，Ncf1敲除促进核因子红细胞2相关因子2（NRF2）的泛素化，从而抑制NRF2对STING mRNA稳定性的负调节作用，最终促进STING表达。此外，STING 激活的药理学抑制可防止 AAD 进展。结论 SMCs 中 Ncf1 缺陷通过促进 NRF2 泛素化和降解以及激活 STING 通路加剧 Ang II 诱导的 AAD。这些数据表明 Ncf1 可能是 AAD 治疗的潜在治疗靶点。