3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Fenofibrate prevents isoproterenol-induced left ventricular hypertrophy and pump dysfunction in rats(2011-01-31) Maswanganyi, TlangelaniThe role of metabolic remodelling in heart failure is not fully understood, significant evidence has accumulated to suggest that it may be central to the development of left ventricular (LV) remodelling and LV dysfunction. Heart failure is also characterized by sustained neurohumoral activation. We have previously demonstrated that chronic low dose administration of isoproterenol contributes to cardiac structural and functional changes, however, little is known about metabolic and mitochondrial changes that may accompany the development of isoproterenol-mediated heart failure. In the current study, we hypothesised that metabolic dysregulation and loss of mitochondrial integrity mediates left ventricular hypertrophy (LVH) and left ventricular (LV) systolic dysfunction in the isoproterenol model of heart failure. Furthermore, modulation of expression of key metabolic genes and mitochondrial transcription factors by fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, will preserve left ventricular function. To achieve this, male Sprague-Dawley rats weighing between 250-300g were injected with low dose isoproterenol (0.04 mg.kg-1.day-1) and/or administered with fenofibrate (100 mg.kg-1.day-1) for five weeks. Thereafter, metabolic substrates such as glucose, FFAs and TG concentrations were obtained. Left ventricular hypertrophy (LVH) and cardiac function were assessed using echocardiography. Expressions of metabolic and mitochondrial genes such as PPARα, AMP-activated protein kinase alpha 2 (AMPKα2), PPARγ coactivator-1 (PGC-1α), mitochondrial transcription factor (TFAM) and nuclear respiratory factor-1 (NRF-1) were determined using real-time polymerase chain reaction. Mitochondrial integrity was assessed using transmission electron microscopy. Administration of isoproterenol significantly increased left ventricular mass (LVM) and decreased endocardial fractional shortening (FSend); isoproterenol also induced myofibrillar iv derangement, mitochondrial derangement and cristae disruption. Fenofibrate prevented isoproterenol-induced increase in LVM and improved FSend. Fenofibrate co-administration prevented loss of mitochondrial integrity possibly via TFAM. Furthermore, fenofibrate may have induced metabolic remodelling via upregulation of AMPKα2 and downregulation of cardiac PPARα and PGC-1α. Therefore our data suggests that fenofibrate-mediated cardioprotection against isoproterenol-induced LVH and LV systolic dysfunction was accompanied by metabolic switching and preservation of mitochondrial integrity. While isoproterenol did not induce any changes in metabolic genes, fenofibrate-mediated cardioprotection could have been through changes in metabolic genes.Item Gender differences in the response to short term beta-adrenergic induced cardiomyocyte apoptosis and necrosis in rats(2011-01-26) Mielke, CarmellaBackground: Males have a higher prevalence of cardiovascular diseases compared to premenopausal women. However, postmenopausal women are at equal risk to men. It has therefore been suggested that estrogen is cardioprotective. Although the exact mechanisms of the purported cardioprotective effects of estrogen are unknown, estrogen administration has been reported to suppress beta-adrenergic receptor up-regulation in ovariectomized female rats. As beta-adrenergic activation induces cardiomyocyte apoptosis and necrosis, and hence adverse cardiac remodelling and heart failure, I aimed to determine whether the extent of beta-adrenergic induced apoptosis and necrosis differs between males and females. Methods: 27 male Wistar rats were assigned to one of two groups: ISO M (n=14) receiving a beta-adrenergic receptor agonist, isoproterenol (0.02mg/kg) and CON M (n=13) receiving vehicle (saline, 0.2ml). 29 female Wistar rats were assigned to one of two groups: ISO F (n=15) receiving a beta-adrenergic receptor agonist, isoproterenol (0.02mg/kg) and CON F (n=14) receiving vehicle. Isoproterenol and saline were administered by means of daily subcutaneous injections for 5 days. On the 5th day, cardiac geometry and function were assessed before and after ISO or saline administration using echocardiography. Rats were then terminated under anaesthesia within 30 minutes of ISO (or vehicle) administration and blood samples collected for the determination of serum estrogen concentration (ELISA). Female rats were terminated in proestrus which corresponds to peak estrogen concentrations. Cardiac myocyte apoptosis was assessed histologically using the DeadEndTM Colorimetric TUNEL system (Promega, Madison, WI, USA). The number of apoptotic cardiomyocyte nuclei was expressed as a percentage of the total number of cardiomyocyte nuclei per slide (heamotoxylin and eosin stain). Necrosis and fibrosis (pathological score) were assessed by assigning a pathological score to sections stained for fibrosis (van Gieson). Groups were iii compared using two-way (gender and regimen; and including repeated measures for echocardiography data) ANOVA followed by the Tukey-Kramer post hoc test. Results: As expected estrogen concentrations were higher in female compared to male rats (mean±SEM, pg.ml-1; ISO M: 7.04±1.41; CON M: 7.14±0.53; ISO F: 23.00±3.47; CON F: 19.31±3.66; p<0.01). Five days of ISO or saline administration had no effect on cardiac function or geometry in either the male or the female rats. Inotropic effects (increased heart rate and cardiac function) were observed in response to acute ISO administration in both male and female rats. The female rats had slower heart rates (p<0.05) and showed a greater heart rate response to acute ISO administration than the male rats (p<0.05). But the acute ISO induced increments in cardiac function were similar between genders. Five days of ISO administration induced cardiomyocyte apoptosis in male rats but not in female rats (mean±SEM, % ; ISO M: 0.086±0.013; CON M: 0.030±0.004; ISO F: 0.053±0.004; CON F: 0.041±0.007; p<0.05). Furthermore, 5 days of ISO administration induced cardiomyocyte necrosis in male rats but not in female rats (mean±SEM, pathological score; ISO M: 1.21±0.21, CON M: 0.46±0.14, ISO F: 0.50±0.11, CON F: 0.68±0.12, p<0.01). Conclusion: Male rats are more susceptible than female rats to beta-adrenergic induced cardiomyocyte apoptosis and necrosis. The protective effects of estrogen against the adverse effects of beta-adrenergic activation on the heart, may explain the lower risk of cardiovascular disease in premenopausal women compare to men; however, the possible role of progesterone cannot be ignored.Item Systolic chamber function in rats with exercise-induced compared to pathological cardiac dilation(2009-04-17T12:12:51Z) Anamourlis, Prodromos ChristopherABSTRACT In pathological left ventricular hypertrophy (LVH) with a normal intrinsic myocardial function, eccentric chamber remodelling (cardiac dilatation) can produce a right shift in systolic pressure-volume (P-V) relations (systolic chamber dysfunction). Whether comparable degrees of cardiac dilatation in physiological (exercise-induced eccentric left ventricular remodelling) and pathological LVH produce similar effects on chamber function has not been determined. Hence, the aim of my thesis was to determine the impact of cardiac dilatation on systolic chamber function in chronically exercised rats with comparable increases in cardiac diastolic volumes as those produced by two rat models of pathological dilatation. Methods: Two models of cardiac dilatation were used, namely: (1) a model of pathological cardiac hypertrophy and dilatation (induced by chronic β-adrenoreceptor agonist administration to either Sprague-Dawley or spontaneously hypertensive rats), and (2) a model of physiological cardiac hypertrophy and dilatation (induced in Sprague-Dawley rats by 4-5 months of voluntary running activity on exercise wheels). 33 Sprague-Dawley rats were placed on spontaneous running wheels for 4-5 months (Exer group) and 24 Sprague-Dawley sedentary control rats (Con group) were placed individually in normal rat cages. To induced pathological dilatation, the β-agonist, isoproterenol (ISO) was administered daily to Sprague-Dawley rats for 7 months (SD-ISO, n=10) and to spontaneously hypertensive rats (SHR) for 4-5 months (SHR+ISO, n=22). Saline was administered daily to controls (SD, n=10; SHR, n=21) and to normotensive Wistar Kyoto rats (WKY, n=17). In isolated, perfused heart preparations, left ventricular (LV) dilatation was determined from the diastolic pressure-volume (P-V) relation and the volume intercept of the diastolic P-V relation (LV V0). Systolic chamber function was assessed by comparing LV developed pressures at specific filling volumes. Intrinsic systolic myocardial function was determined from the slope of the LV systolic developed stress-strain relation (myocardial systolic elastance). Results: ISO adminstered to SD and to SHR rats produced cardiac dilatation [LV V0 (ml): SD 0.20±0.01, SD-ISO 0.27±0.02, p<0.005; SHR 0.21±0.01, SHR-ISO 0.30±0.01, p<0.001], systolic chamber dysfunction (decrease in left ventricular developed pressures at incremental filling volumes) but normal intrinsic systolic myocardial function. Habitual exercise resulted in a right shifted LV diastolic P-V relation and an increased LV V0 (Exer 0.22±0.01, Con 0.18±0.01, p<0.005). In exercised rats (Exer-dilated, n=10) with equivalent dilatation as SD-ISO and SHR-ISO (LV V0 within 95% CI of SD-ISO and SHR-ISO), despite comparable LV diastolic P-V relations and LV V0 values (0.28±0.01); both systolic chamber function and intrinsic systolic myocardial function were normal. Conclusions: These data provide evidence to indicate that as compared to pathological dilatation, a similar extent of exercise-induced dilatation does not produce the same adverse effects on systolic chamber function.Item A comparative study of the effects of lipopolysaccharide and poly 1 : C in rats(2008-10-23T07:17:20Z) Fajandar, ShaheenThe acute phase response induced by bacterial pyrogens, but not by viral pyrogens, has been thoroughly investigated. Polyinosinic:polycytidylic acid (poly I:C) is a synthetic viral pyrogen that is used to simulate viral infection. This dissertation describes how I determined an effective peripheral route and dose of administration of poly I:C to rats. Thereafter I investigated whether poly I:C induced sickness behaviour, and whether repeated administration of poly I:C resulted in the development of tolerance. Intraperitoneal administration of at least 1000μg/kg poly I:C induced fevers in rats, but not sickness behaviour. Unlike repeated administration of LPS, repeated administration of poly I:C in rats did not result in the development of tolerance.