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Title: Exploring pulmonary hypertension through microRNA-155 manipulation : signalling pathways, remodelling and haemodynamics
Author: McGlinchey, Neil
ISNI:       0000 0004 8498 5635
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2019
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Background and Aims: Improving survival in pulmonary arterial hypertension depends on developing novel therapies which target pulmonary vascular remodelling. MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression, many of which have been shown to influence signalling pathways and cell processes which control pulmonary vascular remodelling. However, miRNAs have complex and often contradictory actions on these mechanisms, and better understanding of these complexities is needed. MicroRNA-155 has been linked to factors which drive pulmonary hypertension (PH) including TGF-/BMP signalling, inflammation, vasoactive mediators and cellular response to hypoxia. Through manipulation of miR-155 levels, this thesis aims to establish if the pathobiology of PH can be better understood by examining links to some of these factors or others such as p38 MAPK signalling, and to evaluate the in vitro and in vivo effects of downregulating miR-155, with regards to pulmonary vascular remodelling. Methods and results: Downregulation of miR-155 either via a knockout (KO) mouse model, or pharmacological antagonism in vitro, was studied in the hypoxic model of PH. In vitro, downregulation of miR-155 prevented the proliferative and migratory response of pulmonary artery fibroblasts (PAFs) to hypoxia. This was seen both in PAFs from the KO mice, and in rat PAFs treated with antimiR-155. Reduced hypoxic phosphorylation of p38 MAPK was also seen in both models. Hypoxic activation of Smad5, a member of the TGF-/BMP family, was greater in KO mouse PAFs than in wild type (WT) controls. In vivo, hypoxic KO mice had a lower right ventricular systolic pressure than WT controls. Right ventricular hypertrophy did not develop in the KO mice exposed to hypoxia, and hypoxia-driven vascular remodelling was prevented in the KO mice. Conclusions: Downregulation of miR-155 conveys a protective effect against PH. Remodelling mechanisms are attenuated in vitro, and this translates to an in vivo effect. p38 MAPK has been shown by others to control the hypoxic proliferation of PAFs, so the reduced hypoxic phosphorylation of p38 MAPK in this study may partly explain these results. Manipulation of miR-155 in PH should be studied further to fully elucidate the mechanisms behind these findings.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
Keywords: Q Science (General) ; R Medicine (General)