Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway
Abstract 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 V...
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Wiley
2025-01-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70147 |
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| author | Yifan Du Poyi Hu Xiangchao Ding Dashuai Wang Jingjing Luo Sheng Le Lingyun Ren Manhua Chen Ping Ye Jiahong Xia |
| author_facet | Yifan Du Poyi Hu Xiangchao Ding Dashuai Wang Jingjing Luo Sheng Le Lingyun Ren Manhua Chen Ping Ye Jiahong Xia |
| author_sort | Yifan Du |
| collection | DOAJ |
| description | Abstract 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 |
| format | Article |
| id | doaj-art-8180897161b2422fa15fef89f4f30d97 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Medicine |
| spelling | doaj-art-8180897161b2422fa15fef89f4f30d972025-01-25T04:00:38ZengWileyClinical and Translational Medicine2001-13262025-01-01151n/an/a10.1002/ctm2.70147Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathwayYifan Du0Poyi Hu1Xiangchao Ding2Dashuai Wang3Jingjing Luo4Sheng Le5Lingyun Ren6Manhua Chen7Ping Ye8Jiahong Xia9Department of Cardiovascular Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiovascular Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaDepartment of Thoracic Surgery Renmin Hospital of Wuhan University Wuhan ChinaDepartment of Cardiovascular Surgery The First Affiliated Hospital of Zhengzhou University Henan Province ChinaDepartment of Cardiovascular Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaDepartment of Thoracic Surgery Zhongnan Hospital of Wuhan University Wuhan University Wuhan ChinaDepartment of Anesthesiology Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiology Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiology Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaDepartment of Cardiovascular Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan ChinaAbstract 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 VSMCshttps://doi.org/10.1002/ctm2.70147aortic aneurysm and dissectioncGAS–STING pathwayDNA stabilitymicronuclei formationP21 |
| spellingShingle | Yifan Du Poyi Hu Xiangchao Ding Dashuai Wang Jingjing Luo Sheng Le Lingyun Ren Manhua Chen Ping Ye Jiahong Xia Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway Clinical and Translational Medicine aortic aneurysm and dissection cGAS–STING pathway DNA stability micronuclei formation P21 |
| title | Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway |
| title_full | Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway |
| title_fullStr | Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway |
| title_full_unstemmed | Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway |
| title_short | Deficiency of ATF3 facilitates both angiotensin II‐induced and spontaneously formed aortic aneurysm and dissection development by activating cGAS–STING pathway |
| title_sort | deficiency of atf3 facilitates both angiotensin ii induced and spontaneously formed aortic aneurysm and dissection development by activating cgas sting pathway |
| topic | aortic aneurysm and dissection cGAS–STING pathway DNA stability micronuclei formation P21 |
| url | https://doi.org/10.1002/ctm2.70147 |
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