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Mckinney, Clare Adele (2014) the Role of Angiotensin-(1-7) and Angiotensin-(1-9) in Vascular Remodelling

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Mckinney, Clare Adele (2014) the Role of Angiotensin-(1-7) and Angiotensin-(1-9) in Vascular Remodelling McKinney, Clare Adele (2014) The role of Angiotensin-(1-7) and Angiotensin-(1-9) in vascular remodelling. PhD thesis. http://theses.gla.ac.uk/5752/ Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten:Theses http://theses.gla.ac.uk/ [email protected] The Role of Angiotensin-(1-7) and Angiotensin-(1-9) in Vascular Remodelling Clare Adele McKinney BSc (Hons) Submitted in fulfilment of the requirements of the degree of Doctor of Philosophy in the Institute of Cardiovascular and Medical Sciences, University of Glasgow Institute of Cardiovascular and Medical Sciences College of Medical, Veterinary and Life Sciences University of Glasgow November 2014 © C.A McKinney 2014 ii Authors Declaration I declare that this thesis has been written entirely by myself and is a record of work performed by me with the exception of analysis of microRNA and target expression, and microRNA inhibitor studies which were performed in collaboration with Miss Lisa McArthur. The plasmid used to express the angiotensin type 2 receptor in cell lines was generated by Mr Daniel Villela, and experiments using this plasmid were performed in collaboration with Mr Daniel Villela. This thesis has not been submitted previously for a higher degree. This research was carried out principally in the Institute of Cardiovascular and Medical Sciences, University of Glasgow, under the supervision of Dr. Stuart A. Nicklin and Prof. Graeme Milligan. Investigation of nitric oxide release from cell lines and small vessel wire myography experiments were carried out in Prof. Robson A. Santos’ lab within the Department of Physiology at the Federal University of Minas Gerais, Brazil. Clare A. McKinney July 2014 iii Acknowledgements First and foremost I would like to thank Dr Stuart A. Nicklin for all of his support, guidance and advice throughout my PhD; I could not have asked for a better supervisor. I would also like to thank Prof Graeme Milligan for his support during my PhD. I would like to acknowledge the Medical Research Council for their support and funding of this project. I would like to thank Dr Simon Kennedy for teaching me the wire injury surgery and his support throughout my in vivo studies and time at Glasgow University. I would also like to thank Dr George Baillie for all of his advice and introducing me to the xCELLigence (the best machine ever!). Thank you to Prof Robson A. Santos and his group at the Federal University of Minas Gerais for accommodating me in his lab and all of their support during my time in Brazil. A special thanks to Luciana Oliviera for kindly allowing me to stay with her, showing me the sights of Belo Horizonte and putting up with my terrible samba skills! A huge thanks to everyone in the lab, past and present, for all of the help and advice over the years, especially Carolyn, Monica, Nic and Gregor for teaching me everything when I first started, Laura for her continuous help and guidance with all things science/book related, and Robert for everything you could possibly think of related to the vasculature. I have made some fantastic friends during my PhD who I would like to thank for making it such an enjoyable experience. A special thanks to Lesley, Jenny, Hollie, Fiona and Erin-I couldn’t have done it without you guys and it certainly wouldn’t have been as much fun! Finally, I would like to thank my family for their continual support, advice and encouragement over the last few years. Mum, I would not have got this far without you…literally as I would still be waiting on the 88! Last but not least, thanks to Paul; I will be forever grateful to you for everything over the last few years, for your patience during all of my late night writing sessions and for reminding me that there is more to life than science! iv Table of Contents Authors Declaration ........................................................................ ii Acknowledgements ......................................................................... iii Table of Contents .......................................................................... iv List of Figures ............................................................................. viii List of Tables ................................................................................. x List of Publications, Presentations and Awards ........................................ xi List of Abbreviations and Definitions ................................................... xii Summary .................................................................................. xviii Chapter - General Introduction ......................................................... 1 1.1 Cardiovascular disease ........................................................... 2 1.1.1 Cardiovascular remodelling ................................................ 2 1.1.2 Vascular remodelling ........................................................ 3 1.1.3 Endothelial dysfunction ..................................................... 6 1.1.4 Hypertension ................................................................. 8 1.1.5 Atherosclerosis ............................................................... 9 1.1.6 Neointimal formation and vein graft failure ............................ 12 1.1.7 Restenosis .................................................................... 13 1.2 The renin-angiotensin system.................................................. 14 1.3 The classical RAS ................................................................ 16 1.3.1 Angiotensin II ................................................................ 16 1.3.2 The angiotensin type 1 receptor ......................................... 19 1.3.3 The angiotensin type 2 receptor ......................................... 21 1.4 Angiotensin cell signalling ...................................................... 24 1.4.1 G-protein coupled pathways .............................................. 24 1.4.2 Mitogen-activated protein kinases ....................................... 24 1.4.3 Tyrosine kinases ............................................................ 25 1.4.4 Reactive oxygen species ................................................... 27 1.5 The counter-regulatory axis of the RAS ...................................... 27 1.5.1 Angiotensin converting enzyme 2 ........................................ 29 1.5.2 Angiotensin-(1-7) ........................................................... 29 1.5.3 Angiotensin-(1-9) ........................................................... 31 1.5.4 Other angiotensin peptide metabolites ................................. 35 1.6 The renin angiotensin system and vascular remodelling ................... 42 1.6.1 Hypertension-induced remodelling ...................................... 42 1.6.2 Pro-atherogenic effects of angiotensin II ............................... 42 1.6.3 Vein graft failure ........................................................... 44 1.6.4 Restenosis .................................................................... 45 v 1.6.5 The counter-regulatory RAS and vascular remodelling................ 45 1.7 Hypothesis and aims ............................................................ 52 Chapter 2- Materials and Methods ..................................................... 54 2.1 Materials .......................................................................... 55 2.2 Human vascular tissue .......................................................... 55 2.3 Cell and tissue culture .......................................................... 55 2.3.1 Isolation of primary endothelial cells from human saphenous veins 56 2.3.2 Isolation of primary smooth muscle cells from human saphenous veins ................................................................................ 56 2.3.3 Cell passage ................................................................. 57 2.3.4 Cryopreservation ........................................................... 57 2.4 Stimulation of HSVSMC and HSVEC ............................................ 58 2.5 Proliferation assay ............................................................... 58 2.6 Migration assay ................................................................... 59 2.6.1 Real time analysis of HSVSMC migration ................................ 60 2.7 Transfection of HSVSMC ........................................................ 61 2.7.1 Transfection efficiency .................................................... 62 2.7.2 RNA interference in HSVSMC migration ................................. 62 2.8 RNA and miRNA extraction from HSVEC and HSVSMC ...................... 62 2.9 Quantification of RNA ........................................................... 63 2.10 Complementary deoxyribonucleic acid (cDNA) synthesis ............... 64 2.10.1 Gene expression .......................................................... 64 2.10.2 miRNA expression ........................................................ 64 2.11 TaqMan® quantitative real-time polymerase chain reaction (qRT-PCR) . ..................................................................................
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