Ncf1 knockout in SMCs exacerbates angiotensin II-induced aortic aneurysm and dissection by activating the STING pathway.

Abstract

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. 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. 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.