The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation
<p>Cardiac fibrosis is a histological hallmark of atrial arrhythmogenic structural remodelling characterised by increased deposition and accumulation of fibrillar collagen. Despite recent advances in understanding cardiac fibrogenesis, there is a paucity of effective anti-fibrotic therapies. G...
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| Format: | Thesis |
| Language: | English |
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2020
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| _version_ | 1797106780631728128 |
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| author | Trompf, J |
| author2 | Reilly, S |
| author_facet | Reilly, S Trompf, J |
| author_sort | Trompf, J |
| collection | OXFORD |
| description | <p>Cardiac fibrosis is a histological hallmark of atrial arrhythmogenic structural
remodelling characterised by increased deposition and accumulation of fibrillar
collagen. Despite recent advances in understanding cardiac fibrogenesis, there is a
paucity of effective anti-fibrotic therapies. Given the robust effect that single
microRNAs can have on gene transcript abundance, these small oligonucleotides have been recognised as potential targets for therapeutic manipulation in a wide range of disease states. Our group has recently shown that increased miR31 expression in cardiomyocytes contributes to electrical remodelling begetting atrial fibrillation and our more recent unpublished data show that miR31 is also upregulated in human atrial fibroblasts derived from patients with chronic AF compared to sinus rhythm controls. Given that miR31 has been shown to drive pro-fibrotic phenotype changes in fibroblasts in other disease models, including ischaemic heart disease, we hypothesised that the observed increase in atrial fibroblast miR31 expression in chronic AF was contributing to fibrotic changes seen in this disease state. Consequently, I conducted experiments whereby miR31 abundance was either enriched or depleted in primary human atrial fibroblasts obtained from healthy patient donors to observe whether manipulation of miR31 in vitro would cause pro-fibrotic gene expression- and phenotype-changes. Results did show significant changes in mRNA of key pro-fibrotic signalling genes however inter-donor variability made it difficult to draw robust conclusions on the role of miR31 in fibroblast phenotype. Additional in vitro experiments in human atrial fibroblasts were conducted to investigate whether the transcription factor ETS1 is involved in regulating miR31 expression and results did show increased miR31abundance following ETS1 depletion. Further, the consequence of miR31 up-regulation on
fibrogenesis in vivo was explored in a novel, tamoxifen inducible, global fibroblast-specific miR31 transgenic mouse strain. Results of these mouse experiments demonstrated that increased fibroblast production of miR31 in vivo leads to similar pro-fibrotic gene expression and protein changes observed in human atrial fibroblasts thereby corroborating the separate experimental systems used. Overall, the results of this project are the preliminary evidence that miR31 is involved in the pro-fibrotic response in human atrial fibroblasts, as well as in the intact mouse, and provide the foundation upon which further experiments can be performed and justified. </p> |
| first_indexed | 2024-03-07T07:07:20Z |
| format | Thesis |
| id | oxford-uuid:21e0fdbf-24c2-49d2-83cf-9762ec2f31dc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:07:20Z |
| publishDate | 2020 |
| record_format | dspace |
| spelling | oxford-uuid:21e0fdbf-24c2-49d2-83cf-9762ec2f31dc2022-05-19T11:14:04ZThe role of microRNA-31 in cardiac fibrosis associated with atrial fibrillationThesishttp://purl.org/coar/resource_type/c_db06uuid:21e0fdbf-24c2-49d2-83cf-9762ec2f31dcCardiovascular medicineEnglishHyrax Deposit2020Trompf, JReilly, SLygate, C<p>Cardiac fibrosis is a histological hallmark of atrial arrhythmogenic structural remodelling characterised by increased deposition and accumulation of fibrillar collagen. Despite recent advances in understanding cardiac fibrogenesis, there is a paucity of effective anti-fibrotic therapies. Given the robust effect that single microRNAs can have on gene transcript abundance, these small oligonucleotides have been recognised as potential targets for therapeutic manipulation in a wide range of disease states. Our group has recently shown that increased miR31 expression in cardiomyocytes contributes to electrical remodelling begetting atrial fibrillation and our more recent unpublished data show that miR31 is also upregulated in human atrial fibroblasts derived from patients with chronic AF compared to sinus rhythm controls. Given that miR31 has been shown to drive pro-fibrotic phenotype changes in fibroblasts in other disease models, including ischaemic heart disease, we hypothesised that the observed increase in atrial fibroblast miR31 expression in chronic AF was contributing to fibrotic changes seen in this disease state. Consequently, I conducted experiments whereby miR31 abundance was either enriched or depleted in primary human atrial fibroblasts obtained from healthy patient donors to observe whether manipulation of miR31 in vitro would cause pro-fibrotic gene expression- and phenotype-changes. Results did show significant changes in mRNA of key pro-fibrotic signalling genes however inter-donor variability made it difficult to draw robust conclusions on the role of miR31 in fibroblast phenotype. Additional in vitro experiments in human atrial fibroblasts were conducted to investigate whether the transcription factor ETS1 is involved in regulating miR31 expression and results did show increased miR31abundance following ETS1 depletion. Further, the consequence of miR31 up-regulation on fibrogenesis in vivo was explored in a novel, tamoxifen inducible, global fibroblast-specific miR31 transgenic mouse strain. Results of these mouse experiments demonstrated that increased fibroblast production of miR31 in vivo leads to similar pro-fibrotic gene expression and protein changes observed in human atrial fibroblasts thereby corroborating the separate experimental systems used. Overall, the results of this project are the preliminary evidence that miR31 is involved in the pro-fibrotic response in human atrial fibroblasts, as well as in the intact mouse, and provide the foundation upon which further experiments can be performed and justified. </p> |
| spellingShingle | Cardiovascular medicine Trompf, J The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation |
| title | The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation |
| title_full | The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation |
| title_fullStr | The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation |
| title_full_unstemmed | The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation |
| title_short | The role of microRNA-31 in cardiac fibrosis associated with atrial fibrillation |
| title_sort | role of microrna 31 in cardiac fibrosis associated with atrial fibrillation |
| topic | Cardiovascular medicine |
| work_keys_str_mv | AT trompfj theroleofmicrorna31incardiacfibrosisassociatedwithatrialfibrillation AT trompfj roleofmicrorna31incardiacfibrosisassociatedwithatrialfibrillation |