Doctoral Degrees (Medical Physiology)

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Browsing Doctoral Degrees (Medical Physiology) by Author "Jooste, Tracey"

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    Identification of novel DNA methylation signatures in the development of cardiovascular disease
    (2021) Jooste, Tracey; Johnson, Rabia; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Medical Physiology.
    ENGLISH ABSTRACT: Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, claiming approximately 17.9 million lives annually. The last few decades have seen an exponential increase in the prevalence of major CVD risk factors, such as obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM) in underdeveloped countries, including South Africa. This increase is concomitant to escalating CVD incidence and in part due to increased consumption of diets high in fat and sugar, and sedentary lifestyles. Several mechanisms have been implicated in the pathogenesis of diabetic-induced CVD and recently, increasing evidence suggests that dysregulation of the epigenome may play an important role in the development of T2DM and related cardiac complications. More specifically, aberrant DNA methylation has been extensively investigated and implicated in the development of chronic diseases such as obesity, T2DM and CVD. Nonetheless, it has been suggested that some active dietary compounds may reverse this epigenetic phenomenon which allows for the modification of the transcription of critical genes associated with the progression of CVD. Several plant-polyphenols have been reported to influence gene transcription by altering DNA methylation status. Thus, targeting DNA methylation could provide a promising approach for alternative prevention strategies. This study explored the gene expression networks activated during diet-induced CVD and the ability of a green rooibos extract, Afriplex GRT, to alter this consequence. In addition, the study aimed to evaluate aberrant DNA methylation associated with diet-induced CVD to further elucidate pathophysiology. To this end, cardiomyocytes exposed to high glucose and palmitate (HG + Pal) displayed a diminished antioxidant defence system, mitochondrial dysfunction and increased apoptosis, indicative of cardiac stress. Additionally, the combinatory treatment with HG + Pal induced transcriptional changes associated with inflammation, oxidative stress, altered lipid metabolism and increased contractile dysfunction, ultimately promoting the development of atherosclerosis and hypertrophic cardiomyopathy. Interestingly, post treatment with Afriplex GRT or Aspalathin had no significant effect on the metabolic and molecular derangements induced under HG + Pal stress. Similarly, RNA sequencing conducted on cardiac tissue of Wistar rats that received a high fat, high sugar (HFHS) diet, revealed the downregulation of differentially expressed genes (DEGs) involved in host antioxidant activity and inflammatory response, accompanied with an increase in hypertrophic gene expression possibly affecting cardiac muscle functionality. Supplementation with Afriplex GRT™ yielded no high confidence results for the amelioration of the transcriptomic signatures resulting from HFHS diet feeding. To profile DNA methylation throughout disease progression, cardiac tissue of male Wistar rats maintained on a HFHS diet were subjected to whole genome bisulfite sequencing (WGBS). The latter revealed aberrant DNA methylation of genes linked to the phagosome, platelet activation, toll-like receptor signalling and diabetic cardiomyopathy. Furthermore, hypomethylation within the intergenic and gene body regions of several differentially methylated genes (DMGs) overlapped with DEGs identified in the RNA sequencing analysis. Collectively these results demonstrate the ability of the HFHS diet to act as a pathological stimulus capable of inducing altered gene expression and DNA methylation associated with a heightened proinflammatory and lipid metabolism response that increased the risk of CVD development.