Mitochondrial energy transfer in animal models of left and right ventricular hypertrophy: Investigating mitochondrial oxidative phosphorylation and calcium handling in the heart and their contribution to contractile dysfunction in cardiac hypertrophy

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dc.contributor.advisor Ward, M en
dc.contributor.advisor Hickey, A en
dc.contributor.advisor Crossman, D en
dc.contributor.author Power, Amelia en
dc.date.accessioned 2017-12-17T21:20:38Z en
dc.date.issued 2017 en
dc.identifier.uri http://hdl.handle.net/2292/36758 en
dc.description.abstract Chronically high blood pressure in the systemic or pulmonary circulatory system elevates the work required by the heart to maintain cardiac output. In response the heart undergoes compensatory hypertrophy, which is initially beneficial but then progresses to decompensated heart failure. Increased work performed by the heart also requires elevated energy supply in the form of adenosine triphosphate (ATP). Within cardiomyocytes, ATP is mainly provided by mitochondrial oxidative phosphorylation (OXPHOS). Mitochondria make up ~ 35 % of the cardiomyocyte volume and are evenly spaced between the ATP consuming contractile proteins (myofibrils). The aim of this thesis was to investigate mitochondrial dysfunction, adenylate transfer and altered sub-cellular structure in the hypertrophic heart as possible contributors to unsustainable pathological hypertrophy. Rat models of systemic hypertension (spontaneously hypertensive rats, SHRs) and pulmonary hypertension (60 mg kg-1 monocrotaline injection), in which left and right ventricular hypertrophy develop respectively, were compared to their age-matched normotensive controls (Wistars). High-resolution respirometry combined with fluorometry is a new technique that provides concurrent measurement of mitochondrial respiration with ATP dynamics, reactive oxygen species (ROS) production or mitochondrial membrane potential. This was utilized to measure mitochondrial function from cardiac homogenates and permeabilised fibres, where the in situ mitochondrial architecture remains intact. Sub-cellular structure was examined by confocal imaging of fixed ventricle tissue labelled for mitochondria, myofibrils and the extracellular matrix. Contractile function and intracellular Ca2+ transients in response to energetically demanding stimuli were also assessed in cardiac trabeculae from the rats with pulmonary hypertension. In aged (20 months old) SHRs, hearts showed a 35 % depression of mitochondrial function in comparison to controls, yet produced at least double the amount of ROS within the left ventricle. Impaired transfer of ADP between the myofibrils and the mitochondria in permeabilised fibres suppressed respiration and elevated ROS production more in the SHR fibres relative to controls. Confocal imaging identified a 34 % increase in the mean distance from the centres of myofibrils to the nearest mitochondrion in the SHR hearts, which increased transverse metabolite diffusion distances. In comparison to systemic hypertension, pulmonary hypertension causes right ventricular (RV) hypertrophy which rapidly develops to heart failure. Pulmonary hypertension is associated with greater morbidity and earlier mortality relative to systemic hypertension. Despite this, right heart failure is poorly studied in comparison to the left. Rats were studied four weeks post-monocrotaline (MCT) injection when RV hypertrophy was evident but there were no overt signs of heart failure. RV trabeculae from MCT rat hearts had a negative force-frequency response compared to controls. β-adrenergic stimulation altered the time course, but not the amplitude, of Ca2+ transients or twitch force in MCT trabeculae. Maximum Ca2+-activated stress in permeabilised trabeculae reliant on mitochondrial ATP production was unaltered, suggesting MCT RV trabeculae were adequately supplied with ATP. There was also no difference in the mitochondrial respiration, net ATP production or membrane potential in RV homogenates from MCT and control hearts. From these studies it was concluded that impaired Ca2+ handling is present in RV hypertrophy before detectable mitochondrial energetic deficits occur. While there was no difference in mitochondrial function between the MCT rats with RV hypertrophy and controls, there was a significant correlation between decreased ATP production and the progression to heart failure. Therefore, MCT rats in heart failure were studied to determine if mitochondrial function deteriorated further, and whether adenylate diffusion barriers within RV cardiomyocytes existed. In addition, the rats were treated with a β-adrenergic receptor blocker, metoprolol, which is routinely and effectively used to treat left sided heart failure. RV mitochondrial respiration was lower in the right heart failure animals compared to controls, however, there were no further diffusion limitations to respiration, or significantly increased ROS production. Metoprolol treatment did not improve mitochondrial function but potentially contributed to the pathogenesis by increasing mitochondrial ROS production. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.relation.isreferencedby UoA99265055913502091 en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/nz/ en
dc.title Mitochondrial energy transfer in animal models of left and right ventricular hypertrophy: Investigating mitochondrial oxidative phosphorylation and calcium handling in the heart and their contribution to contractile dysfunction in cardiac hypertrophy en
dc.type Thesis en
thesis.degree.discipline Biomedical Sciences en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The author en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.elements-id 719356 en
pubs.record-created-at-source-date 2017-12-18 en


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