Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice
Disturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of Aff3ir-ORF2, a novel nested gene variant, in disturbed flow-induc...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-05-01
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| Online Access: | https://elifesciences.org/articles/103413 |
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| author | Shuo He Lei Huang Zhuozheng Chen Ze Yuan Yue Zhao Lingfang Zeng Yi Zhu Jinlong He |
| author_facet | Shuo He Lei Huang Zhuozheng Chen Ze Yuan Yue Zhao Lingfang Zeng Yi Zhu Jinlong He |
| author_sort | Shuo He |
| collection | DOAJ |
| description | Disturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of Aff3ir-ORF2, a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces Aff3ir-ORF2 expression in athero-prone regions. Using three distinct mouse models with manipulated Aff3ir-ORF2 expression, we demonstrate that Aff3ir-ORF2 exerts potent anti-inflammatory and anti-atherosclerotic effects in Apoe-/- mice. RNA sequencing revealed that interferon regulatory factor 5 (Irf5), a key regulator of inflammatory processes, mediates inflammatory responses associated with Aff3ir-ORF2 deficiency. Aff3ir-ORF2 interacts with Irf5, promoting its retention in the cytoplasm, thereby inhibiting the Irf5-dependent inflammatory pathways. Notably, Irf5 knockdown in Aff3ir-ORF2 deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific Aff3ir-ORF2 supplementation using the CRISPR/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for Aff3ir-ORF2 in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of Irf5, highlighting its potential as a valuable therapeutic approach for treating atherosclerosis. |
| format | Article |
| id | doaj-art-b071ceff09d3477dbe027168a674d832 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
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| spelling | doaj-art-b071ceff09d3477dbe027168a674d8322025-08-20T02:28:11ZengeLife Sciences Publications LtdeLife2050-084X2025-05-011310.7554/eLife.103413Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in miceShuo He0https://orcid.org/0009-0004-5912-9930Lei Huang1https://orcid.org/0000-0002-3911-0915Zhuozheng Chen2Ze Yuan3Yue Zhao4https://orcid.org/0000-0002-6818-2352Lingfang Zeng5https://orcid.org/0000-0002-0390-4561Yi Zhu6Jinlong He7https://orcid.org/0000-0001-7349-8135Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; NHC Key Laboratory of Hormones and Development; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, ChinaDepartment of Heart Center, The Third Central Hospital of Tianjin; Tianjin Universiy Central Hospital; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases; Artificial Cell Engineering Technology Research Center; Tianjin Institute of Hepatobiliary Disease; Nankai University Affinity the Third Central Hospital, Tianjin, ChinaProvince and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; NHC Key Laboratory of Hormones and Development; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, ChinaProvince and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; NHC Key Laboratory of Hormones and Development; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, ChinaDepartment of Heart Center, The Third Central Hospital of Tianjin; Tianjin Universiy Central Hospital; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases; Artificial Cell Engineering Technology Research Center; Tianjin Institute of Hepatobiliary Disease; Nankai University Affinity the Third Central Hospital, Tianjin, China; School of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Sciences and Medicine, King's College London, London, United KingdomSchool of Cardiovascular and Metabolic Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, Faculty of Life Sciences and Medicine, King's College London, London, United KingdomProvince and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; NHC Key Laboratory of Hormones and Development; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, ChinaProvince and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics; NHC Key Laboratory of Hormones and Development; Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, ChinaDisturbed shear stress-induced endothelial atherogenic responses are pivotal in the initiation and progression of atherosclerosis, contributing to the uneven distribution of atherosclerotic lesions. This study investigates the role of Aff3ir-ORF2, a novel nested gene variant, in disturbed flow-induced endothelial cell activation and atherosclerosis. We demonstrate that disturbed shear stress significantly reduces Aff3ir-ORF2 expression in athero-prone regions. Using three distinct mouse models with manipulated Aff3ir-ORF2 expression, we demonstrate that Aff3ir-ORF2 exerts potent anti-inflammatory and anti-atherosclerotic effects in Apoe-/- mice. RNA sequencing revealed that interferon regulatory factor 5 (Irf5), a key regulator of inflammatory processes, mediates inflammatory responses associated with Aff3ir-ORF2 deficiency. Aff3ir-ORF2 interacts with Irf5, promoting its retention in the cytoplasm, thereby inhibiting the Irf5-dependent inflammatory pathways. Notably, Irf5 knockdown in Aff3ir-ORF2 deficient mice almost completely rescues the aggravated atherosclerotic phenotype. Moreover, endothelial-specific Aff3ir-ORF2 supplementation using the CRISPR/Cas9 system significantly ameliorated endothelial activation and atherosclerosis. These findings elucidate a novel role for Aff3ir-ORF2 in mitigating endothelial inflammation and atherosclerosis by acting as an inhibitor of Irf5, highlighting its potential as a valuable therapeutic approach for treating atherosclerosis.https://elifesciences.org/articles/103413shear stressendothelial cell activationatherosclerosisnested geneIRF5human |
| spellingShingle | Shuo He Lei Huang Zhuozheng Chen Ze Yuan Yue Zhao Lingfang Zeng Yi Zhu Jinlong He Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice eLife shear stress endothelial cell activation atherosclerosis nested gene IRF5 human |
| title | Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice |
| title_full | Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice |
| title_fullStr | Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice |
| title_full_unstemmed | Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice |
| title_short | Disruption of the novel nested gene Aff3ir mediates disturbed flow-induced atherosclerosis in mice |
| title_sort | disruption of the novel nested gene aff3ir mediates disturbed flow induced atherosclerosis in mice |
| topic | shear stress endothelial cell activation atherosclerosis nested gene IRF5 human |
| url | https://elifesciences.org/articles/103413 |
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