Ncf1 knockout in smooth muscle cells exacerbates angiotensin II–induced aortic aneurysm and dissection by activating the STING pathway

Apr 19, 2024Cardiovascular research

Removing Ncf1 in smooth muscle cells may worsen angiotensin II-caused aortic bulges and tears by triggering the STING immune pathway

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Abstract

Ncf1 deficiency in smooth muscle cells (SMCs) exacerbated Ang II-induced (AAD).

Ncf1 expression increased in injured SMCs and is linked to DNA replication and repair in AAD aortas.
Bioinformatic analysis identified Ncf1 as a mediator of SMC damage associated with AAD.
Knocking out Ncf1 activated pathways related to cell death and immune response in SMCs.
Ncf1 knockout led to increased ubiquitination and degradation of NRF2, which affects STING mRNA stability.
Pharmacological inhibition of STING activation showed potential to prevent the progression of AAD.

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AIMS: (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 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. Bioinformatic 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 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.

CONCLUSION: 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.

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54%

incidence increase

Incidence of in Ang II-challenged Ncf1 knockout mice.

Survival rate improvement

Survival rate of mice treated with the STING inhibitor C-176 during Ang II infusion.

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Ncf1 knockout in smooth muscle cells exacerbates angiotensin II–induced aortic aneurysm and dissection by activating the STING pathway

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