Doctoral Degrees (Medical Physiology)

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Browsing Doctoral Degrees (Medical Physiology) by Author "Dludla, Phiwayinkosi Vusi"

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    Compounds specific to Aspalathus linearis protects the diabetic heart against oxidative stress: a mechanistic study
    (Stellenbosch : Stellenbosch University, 2016-12) Dludla, Phiwayinkosi Vusi; Johnson, Rabia; Huisamen, Barbara; Essop, M. Faadiel; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Medical Physiology.
    ENGLISH ABSTRACT : In diabetics, hyperglycemia, hyperlipidemia and inflammation potentiates the development of cardiovascular diseases (CVDs). These conditions provoke excessive generation of oxidative stress that has been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). In the diabetic state, excessive generation of free radicals can cause oxidative damage to DNA and alter protein and lipids, leading to the activation of various death-induced signaling pathways. Activation of these death pathways result in structural and functional modifications to the myocardium. Current diabetic drug therapies do not protect the diabetic heart at risk from developing cardiovascular complications. Thus, in search for new therapeutics, we aim to unravel the molecular mechanisms associated with the protective effect of two major bioactive compounds from Aspalathus linearis, phenyl pyruvic acid-2-O-β-D-glucoside (PPAG) and aspalathin against hyperglycemia-induced oxidative stress and apoptosis in H9c2 cardiomyocytes. The study showed that PPAG and aspalathin were able to decrease mitochondrial membrane depolarization and prevent hyperglycemia-induced myocardial apoptosis by increasing the Bcl2/Bax ratio. We revealed that while both compounds were able to reduce hyperglycemia-induced apoptosis, only aspalathin could ameliorate lipid toxicity and oxidative stress-associated with insulin resistance. An important feature of the failing heart is the observed shift in mitochondrial substrate preference that precedes the onset of oxidative damage. The current study revealed that aspalathin improved glucose metabolism by decreasing fatty acid uptake and subsequent β-oxidation. This was achieved through decreasing the expression of adenosine monophosphate-activated protein kinase threonine 172 (pAMPK (Thr172)) and carnitine palmitoyltransferase 1 (Cpt1), while increasing that of acetyl-CoA carboxylase (Acc) and glucose transporter 4 (Glut4). Additionally, it is known that cardiomyocytes have a very low antioxidant capacity and a shift in mitochondrial substrate preference can result in accelerated oxidative damage. In this study, we showed that aspalathin ameliorated oxidative stress by increasing the antioxidant capacity of the cells through activation of the antioxidant response pathway, nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) and its downstream target genes. Moreover, we showed that aspalathin was able to reverse lipid toxicity by increasing the expression of Adiponectin, C1Q and collagen domain containing (Adipoq) and concomitantly decreasing cluster of differentiation 36 (Cd36) and Cpt1 mRNA expression. We further observed that Adipoq negatively regulated sterol regulatory element binding transcription factor 1 (Srebf1), stearoyl-Coenzyme A desaturase 1 (Scd1) and solute carrier family 27 (fatty acid transporter), member 3/5 (Slc27a3/5). This led to reduced lipid accumulation in H9c2 cardiomyocytes, with an associated decrease in total cholesterol, triglycerides and low-density lipoprotein in leptin resistant db/db mice. This was accompanied by decreased mRNA expression of inflammation markers in H9c2 cells, including interleukin 3 and 6 (IL3 and IL6), tumor necrosis factor receptor superfamily, member 1b and 13 (Tnfrsf1b and Tnfsf13), Janus kinase 2 (Jak2) and mitogen-activated protein kinase 3 (Mapk3). Together our results infer that aspalathin can slow down the progression of DCM, and thus protect the myocardium against causal factors associated with the development and progression of CVD.