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Title: The effects of high fat diet feeding on cardiac function in the C57BL6/J mouse
Author: Isackson, Henrik C. A.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Abstract:
It has been established that placing the C57BL6/J mouse on a high fat diet induces obesity and impaired glucose homeostasis, and produces a model that is pathophysiologically relevant to the human condition of the metabolic syndrome. The cardiovascular changes in this model have been relatively poorly explored. I have focussed my work on understanding the effects of this diet on cardiac function using in vivo cardiac functional assessment in combination with in vitro analysis of intact single cardiomyocyte dynamics and Ca2+ handling, as well as demembranated left ventricle trabeculae for the study of myofilament function. High fat diet caused increased left ventricular end diastolic pressure after 30 weeks as assessed by in vivo pressure catheterisation. This change was associated with, increased passive tension in demembranated trabeculae at 30 w, increased collagen 3 expression on mRNA level and increased total tissue collagen from high fat diet after 40 weeks. Reversion to normal diet for 10 weeks had no discernible effect on whole organ function compared with animals continually fed with the high fat diet, despite body fat content and glucose homeostasis becoming normalised. Isolated cardiomyocytes exhibited increased relaxation rate after 40 weeks which was partly reversed by a return to normal diet. The increased cardiomyocyte relaxation rate occurred without changes to the intracellular Ca2+ transient, thus suggesting it may be caused by altered myofilament Ca2+ sensitivity. There was no established decreased myofilament Ca2+ sensitivity seen in demembranated trabeculae at week 40, even though trends were seen towards increased phosphorylation of serines 23/24 of cardiac troponin I, a modification known to induce Ca2+ desensitisation. It is concluded that high fat diet feeding in the C57BL6/J mouse is a mild but valid model for studying the effects on cardiac function of obesity and impaired glucose handling. It results in impaired diastolic function at the whole organ level after 30 weeks feeding. This effect is likely principally caused by extracellular deposition of collagen (which reduces compliance) rather than by changes at the cardiomyocyte level. This whole organ diastolic alteration appears to become established, not responding to dietary fat reduction. The increased relaxation rate of cardiomyocytes more likely originates from changes at the myofilament level as opposed to Ca2+ handling although this could not be statistically verified in this study. As high fat diet feeding was found to increase myocardial NADPH oxidase activity, myofilament function was also assessed in a mouse model ofNADPH oxidase 2 over-expression. NADPH oxidase 2 over-expression was found to cause myofilament sensitisation to Ca2+ and increased actomyosin cross bridge cycling rate at maximum Ca2+ activation. This was associated with an increased total phosphorylation of cardiac troponin I independent of phosphorylation of serines 23/24. This finding may represent a new signalling pathway linking NADPH oxidase 2 activity to contractile activation via the myofilament but appears opposite to myofilament changes induced by high fat diet feeding.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.665160  DOI: Not available
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