ATF3缺乏通过激活cGAS-STING通路促进血管紧张素ii诱导和自发形成的主动脉瘤和夹层的发展。

IF 7.9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Yifan Du, Poyi Hu, Xiangchao Ding, Dashuai Wang, Jingjing Luo, Sheng Le, Lingyun Ren, Manhua Chen, Ping Ye, Jiahong Xia
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引用次数: 0

摘要

背景:散发性主动脉瘤和夹层(AAD)是一种以血管平滑肌细胞(VSMCs)的进行性损失和细胞外基质的破坏为特征的危重疾病。然而,AAD中VSMCs表型转换和丢失的分子机制尚不完全清楚。方法和结果:在这项研究中,我们采用了一种发现驱动的、无偏倚的方法。这种方法鼓励我们探索激活转录因子3 (ATF3)的未知功能,而不仅仅是确认现有的假设,而在实验之前没有对ATF3进行假设。我们通过与两名独立观察员进行盲法形态学评估来确保评估的无偏倚性。我们发现ATF3在人类散发性AAD组织和小鼠AAD模型中表达升高。vsmc特异性ATF3条件敲除(ATF3 cKO)小鼠暴露于Ang II后,胸腹主动脉区明显增大、剥离和破裂。有趣的是,老年Atf3 cKO小鼠表现出自发性主动脉夹层和主动脉壁衰老。机制上,ATF3缺乏通过泛素化导致P21的降解。VSMC DNA修复受损导致细胞质中形成微核,激活干扰素基因cyclicGMP-AMP合成酶刺激因子(cGAS-STING)通路,诱导VSMC表型转换和凋亡。最后,P21功能的药理补充和STING表达的下调均可减轻ATF3缺陷诱导的AAD。结论:我们的研究表明,ATF3通过P21-cGAS-STING通路对VSMCs的基因组DNA稳定性至关重要,表明提高ATF3在VSMCs中的表达有助于预防散发性AAD。重点:ATF3缺乏导致P21通过泛素化降解,从而消除G1期阻滞。VSMCs没有修复受损DNA的时间窗口,导致细胞质中产生微核。胞质微核促进cGAS-STING通路的激活,从而诱导VSMCs的表型转换和凋亡。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Deficiency of ATF3 facilitates both angiotensin II-induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway

Deficiency of ATF3 facilitates both angiotensin II-induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway

Background

Sporadic aortic aneurysm and dissection (AAD) is a critical condition characterised by the progressive loss of vascular smooth muscle cells (VSMCs) and the breakdown of the extracellular matrix. However, the molecular mechanisms responsible for the phenotypic switch and loss of VSMCs in AAD are not fully understood.

Methods and results

In this study, we employed a discovery-driven, unbiased approach. This approach encourages us to explore the unknown functions of activating transcription factor 3 (ATF3) rather than merely confirming existing hypotheses, while no assumptions were made about ATF3 prior to the experiments. We ensured the unbiased nature of our assessment by conducting morphological evaluations with two independent observers in a blinded manner. We identified elevated expression of ATF3 in both human sporadic AAD tissues and mouse AAD models. VSMC-specific ATF3 conditional knockout (Atf3 cKO) mice showed notable enlargement, dissection and rupture in both thoracic and abdominal aortic regions after exposure to Ang II. Interestingly, older Atf3 cKO mice exhibited spontaneous aortic dissections and senescence of the aortic wall. Mechanistically, ATF3 deficiency led to the degradation of P21 through ubiquitination. Impaired DNA repair in VSMCs resulted in micronuclei formation in the cytoplasm, activating the  cyclicGMP-AMP synthase- stimulator of interferon genes (cGAS–STING) pathway and inducing VSMC phenotypic switching and apoptosis. Finally, both pharmacological complementation of P21 function and knockdown of STING expression alleviated ATF3 deficiency-induced AAD.

Conclusions

Our study indicates that ATF3 is essential for genomic DNA stability in VSMCs through the P21–cGAS–STING pathway, suggesting that enhancing ATF3 expression in VSMCs could help prevent sporadic AAD.

Key points

  • ATF3 deficiency led to degradation of P21 through ubiquitination, which abolished the G1 phase arrest.

  • VSMCs had no time window to repair the damaged DNA, leading to generation of micronuclei in cytoplasm.

  • Cytoplasmic micronuclei facilitating the activation of cGAS–STING pathway, thus inducing the phenotypic switch and apoptosis of VSMCs

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来源期刊
CiteScore
15.90
自引率
1.90%
发文量
450
审稿时长
4 weeks
期刊介绍: Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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