School of Biomedical Sciences - Theses
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ItemDiabetic cardiomyopathy: sex-specific aspects of functional, structural and molecular remodelling( 2017)Background: Clinical studies have revealed increased cardiovascular risk in diabetic patients, which is substantially elevated in women. Perplexingly, while there has been extensive experimental effort in characterising cardiac dysfunction in the progression of diabetic cardiomyopathy, studies investigating sex differences are limited. A mechanistic understanding of sexual dimorphism in diabetic cardiomyopathy remains to be achieved. Aim: The aim of this Thesis was to examine female susceptibility to cardiac pathology in type 1 diabetes (T1D). In particular, this thesis focussed on examining cardiac responses to diabetes (functional and molecular) under basal conditions, during ischemia and with increased cardiac renin angiotensin system (RAS) signalling. The four experimental questions addressed in this thesis are: 1. Are systemic and cardiac T1D phenotypes different between males and females? [Chapter 3] 2. Is there an accentuated female vulnerability to ischemia reperfusion injury in T1D? [Chapter 4] 3. Are there sex-specific changes in cell death, autophagy and metabolism associated with diabetes? [Chapter 5] 4. Does cardiac RAS upregulation interact with sex-specific cardiac responses in T1D? [Chapter 6] Methods: A wide range of in vivo, ex vivo and molecular strategies were employed to characterise the role of sex differences in a streptozotocin (STZ)-induced T1D mouse model. Echocardiographic assessment was performed to examine T1D-induced functional and structural deficits in vivo. Ex vivo isolated heart perfusion analysis was used to characterise the role of sex differences in ischemia-reperfusion injury and recovery in T1D. The mechanistic basis of T1D-induced cardiac pathology was evaluated with various histological, biochemical and molecular techniques. Molecular findings from T1D models were also compared against changes from type 2 diabetic (T2D) mouse models (lean and obese). Finally, the role of RAS in exacerbating the T1D phenotype was assessed using a cardiac-specific angiotensinogen overexpressing mouse model. Results: The overall findings of this thesis are: 1. Although the extent of hyperglycaemia and increase in glycated haemoglobin (HbA1c) was less marked in female T1D in comparison to male T1D, diastolic dysfunction was evident in female T1D, but not in male T1D mice. 2. In males, diabetic hearts showed greater reperfusion recovery associated with reduced cardiac glycogen levels post-ischemia, suggesting better glycogen utilisation during ischemia, compared to male controls. In contrast, despite an earlier onset of ischemic contracture, the reperfusion recovery and glycogen levels were unchanged in female T1D hearts, compared to female control hearts. 3. GABARAPL1, a gene responsible for lysosomal breakdown of glycogen, was upregulated in T1D male hearts, whereas genes from conventional glycogen breakdown pathways (glycogen phosphorylase and glycogen debranching enzyme) were increased in female T1D. In addition, a pronounced increase in expression of genes from macro-autophagy pathway (protein bulk degradation) and apoptotic cell death pathway genes were observed in female T1D but not male T1D hearts. Interestingly, in lean and obese T2D mice, contrasting cardiac gene expression responses were observed in glycogen metabolic and macro-autophagy pathways. 4. With elevated cardiac AngII, T1D-induced cardiac functional and structural changes were exacerbated in males, but these changes were not apparent in females. Conclusion: Collectively, the novel findings in this thesis have contributed new knowledge to the literature on sex-specific attributes of diabetic cardiomyopathy. This study is the first demonstration that a less pronounced hyperglycaemic response in T1D female mice is associated with more marked functional cardiac pathology. This female vulnerability may be partially attributed to a preferential slower/inefficient processing of glycogen and heightened cell death pathology, evidenced from pronounced autophagic drive in female T1D mice. A sex-specific role for cardiac RAS in exacerbating the T1D phenotype has also been identified. The findings in this thesis support a case for sex-specific progression of diabetic cardiac pathology.