Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome
Thoracic aortic aneurysm (TAA) significantly endangers the lives of individuals with Marfan syndrome (MFS), yet the intricacies of their biomechanical origins remain elusive. Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA, with a particular empha...
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Elsevier
2025-02-01
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| Series: | Journal of Pharmaceutical Analysis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S209517792400217X |
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| author | Ming-Yuan Liu Meili Wang Junjun Liu An-Qiang Sun Chang-Shun He Xin Cong Wei Kong Wei Li |
| author_facet | Ming-Yuan Liu Meili Wang Junjun Liu An-Qiang Sun Chang-Shun He Xin Cong Wei Kong Wei Li |
| author_sort | Ming-Yuan Liu |
| collection | DOAJ |
| description | Thoracic aortic aneurysm (TAA) significantly endangers the lives of individuals with Marfan syndrome (MFS), yet the intricacies of their biomechanical origins remain elusive. Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA, with a particular emphasis on the mechanistic contributions of the mammalian target of rapamycin (mTOR) signaling cascade. We uncovered that activation of the mTOR complex 1 (mTORC1) within smooth muscle cells, instigated by the oscillatory wall shear stress (OSS) that stems from disturbed flow (DF), is a catalyst for TAA progression. This revelation was corroborated through both an MFS mouse model (Fbn1+/C1039G) and clinical MFS specimens. Crucially, our research demonstrates a direct linkage between the activation of the mTORC1 pathway and the intensity in OSS. Therapeutic administration of rapamycin suppresses mTORC1 activity, leading to the attenuation of aberrant SMC behavior, reduced inflammatory infiltration, and restoration of extracellular matrix integrity—collectively decelerating TAA advancement in our mouse model. These insights posit the mTORC1 axis as a strategic target for intervention, offering a novel approach to manage TAAs in MFS and potentially pave insights for current treatment paradigms. |
| format | Article |
| id | doaj-art-6c015a582421494e92114c131821cb0b |
| institution | Kabale University |
| issn | 2095-1779 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmaceutical Analysis |
| spelling | doaj-art-6c015a582421494e92114c131821cb0b2025-02-05T04:31:42ZengElsevierJournal of Pharmaceutical Analysis2095-17792025-02-01152101120Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndromeMing-Yuan Liu0Meili Wang1Junjun Liu2An-Qiang Sun3Chang-Shun He4Xin Cong5Wei Kong6Wei Li7Department of Vascular Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing Center of Vascular Surgery, Beijing, 100050, China; Department of Vascular Surgery, Peking University People's Hospital, Beijing, 100044, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, ChinaDepartment of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, ChinaSchool of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, ChinaDepartment of Vascular Surgery, Peking University People's Hospital, Beijing, 100044, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; The Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China; The Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, ChinaDepartment of Vascular Surgery, Peking University People's Hospital, Beijing, 100044, China; The Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China; Corresponding author. Department of Vascular Surgery, Peking University People's Hospital, 100044, China.Thoracic aortic aneurysm (TAA) significantly endangers the lives of individuals with Marfan syndrome (MFS), yet the intricacies of their biomechanical origins remain elusive. Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA, with a particular emphasis on the mechanistic contributions of the mammalian target of rapamycin (mTOR) signaling cascade. We uncovered that activation of the mTOR complex 1 (mTORC1) within smooth muscle cells, instigated by the oscillatory wall shear stress (OSS) that stems from disturbed flow (DF), is a catalyst for TAA progression. This revelation was corroborated through both an MFS mouse model (Fbn1+/C1039G) and clinical MFS specimens. Crucially, our research demonstrates a direct linkage between the activation of the mTORC1 pathway and the intensity in OSS. Therapeutic administration of rapamycin suppresses mTORC1 activity, leading to the attenuation of aberrant SMC behavior, reduced inflammatory infiltration, and restoration of extracellular matrix integrity—collectively decelerating TAA advancement in our mouse model. These insights posit the mTORC1 axis as a strategic target for intervention, offering a novel approach to manage TAAs in MFS and potentially pave insights for current treatment paradigms.http://www.sciencedirect.com/science/article/pii/S209517792400217XThoracic aortic aneurysm (TAA)mTORC1Marfan syndromeBiomechanicalpathogenesisWall shear stress (WSS) |
| spellingShingle | Ming-Yuan Liu Meili Wang Junjun Liu An-Qiang Sun Chang-Shun He Xin Cong Wei Kong Wei Li Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome Journal of Pharmaceutical Analysis Thoracic aortic aneurysm (TAA) mTORC1 Marfan syndrome Biomechanicalpathogenesis Wall shear stress (WSS) |
| title | Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome |
| title_full | Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome |
| title_fullStr | Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome |
| title_full_unstemmed | Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome |
| title_short | Hemodynamic disturbance and mTORC1 activation: Unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in Marfan syndrome |
| title_sort | hemodynamic disturbance and mtorc1 activation unveiling the biomechanical pathogenesis of thoracic aortic aneurysms in marfan syndrome |
| topic | Thoracic aortic aneurysm (TAA) mTORC1 Marfan syndrome Biomechanicalpathogenesis Wall shear stress (WSS) |
| url | http://www.sciencedirect.com/science/article/pii/S209517792400217X |
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