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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

While some cognitive decline is part of the normal aging process, certain changes have been linked to physical health or lifestyle-related diseases and may be preventable. Hypertension and type 2 diabetes are two conditions that have been associated with a heightened risk of accelerated cognitive decline. In terms of protective factors, physical activity can positively impact a broad range of cognitive processes including memory, attention, and executive function and may also protect against or delay cognitive decline and dementia. The present study examined the extent to which physical activity moderates the impacts of hypertension and diabetes (and their interactions) on different cognitive functions. Data are from the Memory and Aging Project (MAP), a longitudinal study of older adults (N = 1400, mean age = 79). A series of multilevel models evaluated baseline differences and linear and quadratic change on four cognitive measures: mental status, perceptual speed, and immediate and delayed episodic memory. Higher levels of self-reported physical activity were associated with better perceptual speed at baseline, and significantly less linear decline across all four measures. Physical activity was not significantly associated with curvilinear change. Individuals with diabetes had significantly worse immediate episodic memory performance at baseline, but diabetes was largely unrelated to rate of change and initial performance on the other measures. Hypertension was associated with better initial mental status (linear and quadratic models) and delayed episodic memory (quadratic model). Contrary to expectations, most interactions between physical activity and the two health conditions were non-significant. However, physical activity appeared to moderate the relationship between comorbid diabetes and hypertension on immediate episodic memory, such that individuals with the two conditions who were more physically active experienced a reduced rate of linear and curvilinear decline compared to inactive individuals with diabetes and hypertension. The findings from this study suggest that physical activity may reduce the impact of comorbid conditions on certain cognitive functions, and that immediate episodic memory may be particularly susceptible. / Graduate

The studies presented in this thesis were undertaken to investigate the cellular and molecular mechanisms responsible for sympathetic hyperactivity that is observed in the Spontaneous Hypertensive Rat (SHR) and whether these abnormalities arise even before the onset of hypertension. Moreover, selected molecular candidates related to oxidative state in cardiac autonomic signalling have been explored for their potential therapeutic effects. <b>Chapter One</b> is an overview of (i) the relevance of autonomic dysfunction in cardiovascular disease in both human and animal models, (ii) the physiological basis of cardiac sympathetic neurotransmission, (iii) the neuromodulators of peripheral cardiac sympathetic-vagal balance discussed along with how they may be involved in cardiac adrenergic control of neurotransmission and NO-cGMP signalling. This develops the formulation of the specific aims of the thesis. <b>Chapter Two</b> outlines a detailed rationale for the experimental approach taken to (i) characterise protein expression in the pre-hypertensive animal model with immunohistochemistry and Western blotting, (ii) manipulate selected gene expression to amplify NO-cGMP signalling in vivo and in vitro via viral gene transfer, (iii) investigate calcium handling in cardiac sympathetic stellate neurons with calcium imaging , (iv) measure cardiac noradrenergic neurotransmission from double atria using radioactive-labelled [³H]-noradrenaline. <b>Chapter Three</b> demonstrated abnormal NO-cGMP signalling in pre-hypertensive SHRs. Endogenous nNOS protein residing in both cardiac parasympathetic and sympathetic neurons was significantly lower in the pre-hypertensive SHR compared to aged-matched WKYs. This was associated with lower cGMP levels. An enhanced depolarization evoked [Ca²⁺]i transient was observed in cardiac stellate neurons from pre-hypertensive SHR when compared with the WKY, an effect that was reversed by nNOS or sGC inhibition. <b>Chapter Four</b> investigated the role of nNOS and brain natriuretic peptide (BNP) in cGMP signalling pathways. Gene transfer of nNOS via adenoviral vector in SHR cardiac sympathetic neurons increased cGMP concentration and normalised neuronal calcium handling during depolarization. BNP significantly reduces [3H]- noradrenaline release. Overexpression of PDE2 which facilitates the breakdown of cGMP caused an increase in [³H]- noradrenaline release in response to field stimulation and also prevented the inhibitory action of BNP. <b>Chapter Five</b> examined the role of the nNOS adaptor protein, CAPON in NO-cGMP signalling. Endogenous CAPON protein is present in cardiac sympathetic neurons in the WKY, and is significantly reduced in pre-hypertensive SHR cardiac neurons. Artificial up-regulation of cardiac sympathetic CAPON via targeted gene transfer directly attenuated neuronal Ca²⁺ transients, resulting in decreased noradrenaline release in the SHR. <b>Chapter Six</b> is a concluding discussion summarising the main findings from this thesis, placing them in a physiological context and discussing avenues for further research.

Pulmonary arterial hypertension (PAH) is a disease of the lung vessels that causes severe effects on the right ventricle of the heart; ultimately, most patients with severe PAH die as a result of right heart failure. However, little is known about the causes of right heart failure. Here, we describe a pattern of gene expression that differs between the normal rat left ventricle (LV) and right ventricle (RV). These genes are known to be involved in the development of the heart as well as adaptations to the heart during stress. This gene expression pattern is used as a baseline to describe changes in gene expression the occur in the RV as a result of adaptive hypertrophy, stimulated by chronic hypoxia, or right ventricular failure (RVF), caused by administration of Su5416 and hypoxia. The genes differing between RVF and hypertrophy encode glycolytic enzymes, mitochondrial electron transport chain complexes, cell-growth promoting proteins, and angiogenic capillary maintenance proteins. Additionally, we show that RVF is associated with an increase in the serum cytokine production of IL-1 beta, IL-10, TNF-alpha, and VEGF. Finally, we show that treatment with the beta-adrenergic receptor blocker carvedilol partially changed the gene expression pattern seen with RVF. The most profound effects were on the genes encoding glycolytic enzymes and mitochondrial electron transport chain complexes. Together, these results show that the normal LV and RV have a distinct pattern of expression and that the failing RV is characterized by changes in cell growth, angiogenesis, and energy utilization. Treatment with carvedilol can partially reverse these gene expression changes in the failing RV.