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Effects of Acute Early Age Statin Treatment on Rat Vasculature

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Effects of Acute Early Age Statin Treatment on Rat Vasculature University of Southampton Research Repository ePrints Soton Copyright © and Moral Rights for this thesis are retained by the author and/or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder/s. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given e.g. AUTHOR (year of submission) "Full thesis title", University of Southampton, name of the University School or Department, PhD Thesis, pagination http://eprints.soton.ac.uk UNIVERSITY OF SOUTHAMPTON FACULTY OF MEDICINE Human Development and Health Effects of acute early age statin treatment on rat vasculature by Piia Heidi Marjatta Keskiväli-Bond Thesis for the degree of Doctor of Philosophy October 2013 2 UNIVERSITY OF SOUTHAMPTON ABSTRACT FACULTY OF MEDICINE Cardiovascular Physiology Thesis for the degree of Doctor of Philosophy EFFECTS OF ACUTE EARLY AGE STATIN TREATMENT ON RAT VASCULATURE Piia Heidi Marjatta Keskiväli-Bond A poor developmental environment increases the risk of cardiovascular disease in humans; this is modelled by protein restriction (PR) during pregnancy in rats. Chronic statin treatment in the PR model from an early age restores endothelial function while an acute early age angiotensin blockade reduces blood pressure long term. The aim of this study was to investigate if acute early age statin treatment could improve vascular function long term in the PR offspring. Female Wistar rats were fed control (18 % protein) or PR (9% casein) diet throughout pregnancy. Subgroups of the offspring from both maternal groups received atorvastatin (10 mg/kg/day) in their drinking water from three to five weeks of age. Vascular reactivity was assessed at five and sixteen weeks. Components of the vasoreactivity signalling pathways were investigated with real-time PCR and Western blotting. Maternal PR did not alter vascular function in the offspring and the effects of statin treatment were independent of maternal diet. At five weeks of age maximal constriction to phenylephrine was reduced in the statin treated male offspring aortae (p<0.01). Conversely, at sixteen weeks maximal constriction was increased of male (p<0.05) and female (p<0.01) statin treated offspring mesenteric arteries. RhoA and ROCK1 mRNA levels were increased in statin treated offspring mesenteric arteries at sixteen weeks (p<0.05). Statin treatment had no effect on NO-mediated vasorelaxation. This study shows that early age acute statin treatment has both short and long term effects on cardiovascular function and molecular markers in rats. The long term effects appear to have arisen as a consequence of the withdrawal rather than being a direct effect of the statin treatment adding to the emerging evidence of a rebound effect after statin withdrawal. The RhoA pathway is indicated as the mechanisms behind the effects of statin withdrawal in this study. i ii Contents ABSTRACT ...................................................................................................................... i Contents .......................................................................................................................... iii List of tables ................................................................................................................... vii List of figures .................................................................................................................. ix DECLARATION OF AUTHORSHIP ........................................................................ xv Acknowledgements ...................................................................................................... xvii Definitions and Abbreviations .................................................................................... xix Chapter 1 Introduction ............................................................................................. 1 1.1 Cardiovascular function and disease .................................................................. 2 1.1.1 Structure of blood vessels ............................................................................. 2 1.1.2 Control of vascular tone ................................................................................ 3 1.1.3 Cardiovascular disease .................................................................................. 7 1.1.4 Cardiovascular disease risk factors ............................................................. 10 1.1.5 Treatment of cardiovascular disease ........................................................... 12 1.2 Statins ............................................................................................................... 12 1.2.1 Development of statins ................................................................................ 13 1.2.2 Pharmacological properties of statins ......................................................... 15 1.2.3 Susceptibility to primary prevention ........................................................... 16 1.2.4 Pleiotropic properties .................................................................................. 16 1.2.5 Effects of statins over time .......................................................................... 19 1.3 Developmental origins of cardiovascular disease ............................................ 20 1.3.1 Epidemiological studies .............................................................................. 20 1.3.2 Animal models for developmental origins of cardiovascular disease ......... 23 1.3.3 Epigenetics .................................................................................................. 25 1.3.4 Intervention in developmentally induced cardiovascular disease models .. 25 1.4 Rationale and aims ........................................................................................... 27 Chapter 2 Methods .................................................................................................. 29 2.1 Animals............................................................................................................. 30 2.1.1 Pregnancy and lactation .............................................................................. 30 2.1.2 Offspring ..................................................................................................... 30 2.1.3 Post mortem ................................................................................................ 31 2.2 Non-invasive tail-cuff plethysmography .......................................................... 31 2.3 Myography ....................................................................................................... 33 2.3.1 Thoracic aorta.............................................................................................. 33 2.3.2 Mesenteric arteries ...................................................................................... 34 2.3.3 Assessment of vasoreactivity ...................................................................... 34 iii 2.4 mRNA levels in the liver and mesenteric arteries ............................................ 36 2.4.1 Phenol-chloroform RNA extraction ............................................................ 37 2.4.2 Reverse transcription ................................................................................... 37 2.4.3 Quantitative real-time polymerase chain reaction ...................................... 38 2.4.4 Identification of stable housekeeping gene ................................................. 39 2.5 Analysis of protein expression ......................................................................... 40 2.5.1 Protein extraction and subcellular fractination ........................................... 40 2.5.2 Bradford analysis ........................................................................................ 40 2.5.3 Western blotting .......................................................................................... 41 2.5.4 Quantification.............................................................................................. 41 2.6 Statistics............................................................................................................ 42 2.6.1 Maternal data and offspring data before statin treatment ........................... 42 2.6.2 Blood pressure............................................................................................. 42 2.6.3 Weekly and post mortem weights ............................................................... 42 2.6.4 Vascular reactivity ...................................................................................... 43 2.6.5 rtPCR ........................................................................................................... 43 2.6.6 Protein expression ....................................................................................... 43 2.7 Compositions, drugs and chemicals ................................................................. 43 Chapter 3 Pregnancy and cardiovascular function in the adolescent offspring 49 3.1 Introduction ...................................................................................................... 50 3.2 Methods
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