miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice
Background Thoracic aortic aneurysms (TAAs) occur because of abnormal remodeling of aortic extracellular matrix and are accompanied by the emergence of proteolytically active myofibroblasts. The microRNA miR‐133a regulates cellular phenotypes and is reduced in clinical TAA specimens. This study test...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-08-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.019862 |
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| author | Adam W. Akerman Elizabeth N. Collins Andrew R. Peterson Lauren B. Collins Jessica K. Harrison Amari DeVaughn Jaleel M. Townsend Rebecca L. Vanbuskirk Jessica Riopedre‐Maqueira Ailet Reyes Joyce E. Oh Charles M. Raybuck Jeffrey A. Jones John S. Ikonomidis |
| author_facet | Adam W. Akerman Elizabeth N. Collins Andrew R. Peterson Lauren B. Collins Jessica K. Harrison Amari DeVaughn Jaleel M. Townsend Rebecca L. Vanbuskirk Jessica Riopedre‐Maqueira Ailet Reyes Joyce E. Oh Charles M. Raybuck Jeffrey A. Jones John S. Ikonomidis |
| author_sort | Adam W. Akerman |
| collection | DOAJ |
| description | Background Thoracic aortic aneurysms (TAAs) occur because of abnormal remodeling of aortic extracellular matrix and are accompanied by the emergence of proteolytically active myofibroblasts. The microRNA miR‐133a regulates cellular phenotypes and is reduced in clinical TAA specimens. This study tested the hypothesis that miR‐133a modulates aortic fibroblast phenotype, and overexpression by lentivirus attenuates the development of TAA in a murine model. Methods and Results TAA was induced in mice. Copy number of miR‐133a was reduced in TAA tissue and linear regression analysis confirmed an inverse correlation between aortic diameter and miR‐133a. Analyses of phenotypic markers revealed an mRNA expression profile consistent with myofibroblasts in TAA tissue. Fibroblasts were isolated from the thoracic aortae of mice with/without TAA. When compared with controls, miR‐133a was reduced, migration was increased, adhesion was reduced, and the ability to contract a collagen disk was increased. Overexpression/knockdown of miR‐133a controlled these phenotypes. After TAA induction in mice, a single tail‐vein injection of either miR‐133a overexpression or scrambled sequence (control) lentivirus was performed. Overexpression of miR‐133a attenuated TAA development. The pro‐protein convertase furin was confirmed to be a target of miR‐133a by luciferase reporter assay. Furin was elevated in this murine model of TAA and repressed by miR‐133a replacement in vivo resulting in reduced proteolytic activation. Conclusions miR‐133a regulates aortic fibroblast phenotype and over‐expression prevented the development of TAA in a murine model. These findings suggest that stable alterations in aortic fibroblasts are associated with development of TAA and regulation by miR‐133a may lead to a novel therapeutic strategy. |
| first_indexed | 2024-03-13T07:05:48Z |
| format | Article |
| id | doaj.art-bba559186768485f8fb4ea7373e8752a |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-03-13T07:05:48Z |
| publishDate | 2021-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-bba559186768485f8fb4ea7373e8752a2023-06-06T12:10:51ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802021-08-01101610.1161/JAHA.120.019862miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in MiceAdam W. Akerman0Elizabeth N. Collins1Andrew R. Peterson2Lauren B. Collins3Jessica K. Harrison4Amari DeVaughn5Jaleel M. Townsend6Rebecca L. Vanbuskirk7Jessica Riopedre‐Maqueira8Ailet Reyes9Joyce E. Oh10Charles M. Raybuck11Jeffrey A. Jones12John S. Ikonomidis13Division of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCDivision of Cardiothoracic Surgery Department of Surgery Medical University of South Carolina Charleston SCDivision of Cardiothoracic Surgery Department of Surgery University of North Carolina Chapel Hill NCBackground Thoracic aortic aneurysms (TAAs) occur because of abnormal remodeling of aortic extracellular matrix and are accompanied by the emergence of proteolytically active myofibroblasts. The microRNA miR‐133a regulates cellular phenotypes and is reduced in clinical TAA specimens. This study tested the hypothesis that miR‐133a modulates aortic fibroblast phenotype, and overexpression by lentivirus attenuates the development of TAA in a murine model. Methods and Results TAA was induced in mice. Copy number of miR‐133a was reduced in TAA tissue and linear regression analysis confirmed an inverse correlation between aortic diameter and miR‐133a. Analyses of phenotypic markers revealed an mRNA expression profile consistent with myofibroblasts in TAA tissue. Fibroblasts were isolated from the thoracic aortae of mice with/without TAA. When compared with controls, miR‐133a was reduced, migration was increased, adhesion was reduced, and the ability to contract a collagen disk was increased. Overexpression/knockdown of miR‐133a controlled these phenotypes. After TAA induction in mice, a single tail‐vein injection of either miR‐133a overexpression or scrambled sequence (control) lentivirus was performed. Overexpression of miR‐133a attenuated TAA development. The pro‐protein convertase furin was confirmed to be a target of miR‐133a by luciferase reporter assay. Furin was elevated in this murine model of TAA and repressed by miR‐133a replacement in vivo resulting in reduced proteolytic activation. Conclusions miR‐133a regulates aortic fibroblast phenotype and over‐expression prevented the development of TAA in a murine model. These findings suggest that stable alterations in aortic fibroblasts are associated with development of TAA and regulation by miR‐133a may lead to a novel therapeutic strategy.https://www.ahajournals.org/doi/10.1161/JAHA.120.019862fibroblastfurinmiR‐133amyofibroblastthoracic aortic aneurysm |
| spellingShingle | Adam W. Akerman Elizabeth N. Collins Andrew R. Peterson Lauren B. Collins Jessica K. Harrison Amari DeVaughn Jaleel M. Townsend Rebecca L. Vanbuskirk Jessica Riopedre‐Maqueira Ailet Reyes Joyce E. Oh Charles M. Raybuck Jeffrey A. Jones John S. Ikonomidis miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease fibroblast furin miR‐133a myofibroblast thoracic aortic aneurysm |
| title | miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice |
| title_full | miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice |
| title_fullStr | miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice |
| title_full_unstemmed | miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice |
| title_short | miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice |
| title_sort | mir 133a replacement attenuates thoracic aortic aneurysm in mice |
| topic | fibroblast furin miR‐133a myofibroblast thoracic aortic aneurysm |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.019862 |
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