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Title: The role of mitochondria in increased vulnerability to insults of hearts and cardiomyocytes isolated from mice fed a "Western style" high-fat diet
Author: Littlejohns , Ben
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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Cardiovascular diseases arc the most common cause of death in the world. One key contributory factor in cardiovascular diseases is the consumption of a high-fat diet. A high-fat diet can cause direct and indirect effects on the myocardium. Directly it can alter substrate supply and metabolism and indirectly it can cause obesity and associated comorbidities such as diabetes and hypertrophy. Preliminary work in Bristol has shown that a non-obesogenic high-fat diet renders the heart more vulnerable to ischaemia/reperfusion (IIR) injury compared to normal diet. Triggers of UR injury include calcium overload, oxidative stress and mitochondrial permeability transition pore (mPTP) opening. The aim of this thesis was 10 study cardiac remodelling in a mouse model of non-obesogenic high-fat diet and investigate the mechanism(s) responsible for the increased vulnerability to I1R. Male C57BU6 mice were fed cither a normal diet (13 % calories from fat) or a high-fat diet (45 % calories from fat) for 20 weeks. An array of techniques (e.g. echocardiography, fluorescence, electron microscopy, tissue and cell perfusion, western blotting and proteomics) and different preparations (in vivo and isolated hearts, cardiomyocytes and mitochondria) were used to address the stated aim of this thesis. Mice fed a high-fat diet did not become obese and did not show evidence of diabetes, coronary disease, cardiac hypertrophy or heart failure. The key findings are that in the highfat diet group there were changes in Ca2 + handling contributing to an increase in intracellular Ca2+, changes in the oxidative state during IIR, alterations in mitochondrial morphology and dissociation of hexokinase Il from the mitochondria. When the mPTP was inhibited in isolated perfused hearts subjected to IIR the increased vulnerability to IIR in the high-fat diet was abolished. In conclusion, the results suggest that a non-obesogenic high-fat diet increased the probability of mPTP opening which induced more damage during I/R.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available