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Published on: September 28, 2015
Ncf1 knockout in smooth muscle cells exacerbates angiotensin II-induced aortic aneurysm and dissection by activating
Hao Liu1, Peiwen Yang1, Shu Chen1
1Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
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 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 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.
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.
Insights
Neutrophil cytoplasmic factor 1 (Ncf1) deficiency worsens aortic aneurysm and dissection (AAD) by activating the STING pathway and degrading NRF2. Restoring Ncf1 function may offer a new therapeutic strategy for AAD.
Area of Science:
- Cardiovascular Biology
- Cellular and Molecular Medicine
- Immunology
Background:
- Aortic aneurysm and dissection (AAD) results from smooth muscle cell (SMC) loss and has high mortality.
- Understanding SMC apoptosis mechanisms is key to preventing AAD.
- Neutrophil cytoplasmic factor 1 (Ncf1) is vital for reactive oxygen species and SMC apoptosis.
Purpose of the Study:
- Investigate the role of Ncf1 in angiotensin II (Ang II)-induced AAD.
- Determine how Ncf1 influences SMC apoptosis and the STING pathway in AAD.
Main Methods:
- Utilized Sm22CreNcf1fl mice challenged with Ang II.
- Performed bioinformatic and transcriptomic analyses.
- Examined Ncf1 effects on SMC death and the STING pathway in vitro.
Main Results:
- Ncf1 expression increased in injured SMCs and correlated with DNA repair.
- Ncf1 deficiency exacerbated Ang II-induced AAD and activated STING and cell death pathways.
- Ncf1 knockout promoted NRF2 ubiquitination, inhibiting NRF2's suppression of STING mRNA stability.
Conclusions:
- Ncf1 deficiency in SMCs worsens Ang II-induced AAD via NRF2 ubiquitination and STING pathway activation.
- Ncf1 plays a protective role against AAD.
- Ncf1 represents a potential therapeutic target for AAD.
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