Browsing by Author "Westcott, Corli"

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    Cardiovascular risk and endothelial function in people living with HIV/AIDS: design of the multi-site, longitudinal EndoAfrica study in the Western Cape Province of South Africa
    (BioMed Central, 2017-01-07) Strijdom, Hans; De Boever, Patrick; Walzl, Gerhard; Essop, M. Faadiel; Nawrot, Tim S.; Webster, Ingrid; Westcott, Corli; Mashele, Nyiko; Everson, Frans; Malherbe, Stephanus T.; Stanley, Kim; Kessler, Harald H.; Stelzl, Evelyn; Goswami, Nandu
    Background: There is growing evidence of an interaction between HIV-infection, anti-retroviral therapy (ART) and cardiovascular diseases (CVD). Epidemiological studies in Europe and North America have been observing a shift towards an increased incidence of coronary heart disease and acute myocardial infarctions in HIV-infected populations compared to the general population even after adjusting for traditional cardiovascular risk factors. Despite South Africa (and sub-Saharan Africa, SSA) being regarded as the epicentre of the global HIV epidemic, very little is known about the prevalence of cardiovascular risk factors and precursors of vascular disease in HIV-infected populations in this region. The knowledge gap is further widened by the paucity of data from prospective studies. We present the rationale, objectives and key methodological features of the EndoAfrica study, which aims to determine whether HIVinfection and ART are associated with altered cardiovascular risk and changes in vascular endothelial structure and function in adults living in the Western Cape Province of South Africa. Methods: In this longitudinal study, comprehensive cardiovascular assessments of HIV-negative and HIV-positive (with and without ART) study participants are performed by clinical and biochemical screening for traditional cardiovascular risk factors and biomarkers of CVD. Vascular and endothelial function is determined by brachial artery flow-mediated dilatation (FMD), carotid-intima-thickness (IMT) measurements and quantitative retinal blood vessel analyses, complemented by vascular endothelial biomarker assays. Finally, we aim to statistically determine whether HIVinfection and/or ART are associated with increased cardiovascular risk and vascular endothelial dysfunction, and determine whether there is progression/regression in these endpoints 18 months after the baseline assessments. Discussion: The EndoAfrica study provides a unique opportunity to recruit a cohort of HIV-infected patients and HIVnegative controls who will be comprehensively and longitudinally assessed for cardiovascular risk and disease profile with vascular endothelial function as a potentially important intermediate cardiovascular phenotype. To our knowledge, it is the first time that such a systematic study has been established in the context of SSA and South Africa.
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    Fenofibrate protects endothelial cells against the harmful effects of TNF-alpha
    (South African Heart Association, 2017) Westcott, Corli; Genis, Amanda; Mthethwa, Mashudu; Graham, Roxanne; Van Vuuren, Derick; Huisamen, Barbara; Strijdom, Hans
    Introduction: Fenofibrate exerts pleiotropic effects on endothelial cells (ECs) by, amongst others, increasing nitric oxide (NO) production. We aimed to investigate fenofi brate’s putative beneficial actions in healthy or TNF-alpha-induced dysfunctional ECs. Methods: Fenofi brate-induced pro-vasodilatory responses were assessed in aortic rings (50 - 125μM; 30min) with and without L-NMMA (100μM). Rat cardiac microvascular ECs were treated with fenofibrate (30 and 50μM; 1h). In the pre-treatment experiments, fenofibrate (50μM) was administered one hour before TNFalpha treatment (20ng/ml; 24h). NO-production (DAF-2/DA or Griess assay), mitochondrial ROS-production (MitoSox™), cell viability (propidium iodide staining), and changes in the expression/phosphorylation of critical endothelial proteins were measured by Western blotting. Results: Fenofibrate increased NO-production ˜2-fold in healthy ECs (p<0.05 vs. vehicle). A ˜23% pro-vasodilatory response was induced in aortic rings, which was reversed by L-NMMA (p<0.05 vs. fenofibrate). Fenofibrate pretreatment ameliorated TNF-alpha-induced endothelial dysfunction by reversing the loss of NO, improving oxidative stress, restoring cell viability and preventing caspase-3 activation. Protective effects were underpinned by ˜47% and ˜49% up-regulation of activated eNOS and AMP-kinase, respectively (p<0.05 vs. TNFalpha). Conclusions: Fenofibrate protects TNF-alpha-induced dysfunctional ECs via up-regulated eNOS-NO, reduced oxidative stress and improved cell viability. These novel findings warrant further investigations to explore the potential use of fenofibrate as an anti-endothelial dysfunction therapeutic agent.
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    Investigating the cholesterol-independent (pleiotropic) effects of selected hypolipidaemic agents in functional and dysfunctional endothelial cells
    (Stellenbosch : Stellenbosch University, 2015-03) Westcott, Corli; Strijdom, Hans; Huisamen, Barbara; Stellenbosch University. Faculty of Health Sciences. Dept. of Biomedical Sciences. Medical Physiology.
    ENGLISH ABSTRACT: Vascular endothelium forms the first line of defence against harmful stimuli in the circulation. Endothelial dysfunction is a valuable predictor of cardiovascular disease and therapies aimed at improving endothelial function are therefore needed. The anti-dyslipidaemic agents, simvastatin and fenofibrate, are known for their beneficial effects on lipid parameters, however additional pleiotropic effects have been shown for both. These include improved endothelial function due to increased levels of nitric oxide (NO), as well as anti-oxidant and anti-inflammatory actions. NO is produced by the enzyme, nitric oxide synthase (NOS), which exists in the endothelial NOS (eNOS), inducible NOS (iNOS) and neuronal NOS (nNOS) isoforms. Most studies investigating the endothelial effects of simvastatin and fenofibrate are performed on macrovascular-derived endothelial cells, and there is a lack of data on endothelial cells (ECs) from the microcirculation, particularly the cardiac microvessels. This dissertation aimed to investigate and elucidate mechanisms underlying the pleiotropic effects of simvastatin and fenofibrate on ECs and vascular tissue using in vitro, ex vivo and in vivo experimental models. In vitro investigations included flow cytometry-based intracellular measurements of NO, as well as different types of reactive oxygen species (ROS) and cell viability parameters. Signalling pathways involved with these changes were measured by western blot analyses of the expression and phosphorylation of critical proteins involved in vascular function. Results on cardiac microvascular ECs (CMECs) demonstrated that fenofibrate (50 μM) exerted a potent, increasing effect on NO production after short periods (1 and 4 hour treatments), but after 24 hours the effects were less robust. Exhaustive investigations suggested that the NOincreasing effects of fenofibrate in baseline CMECs were NOS-independent, a novel finding as far as we are aware. Fenofibrate’s ability to protect ECs against injury was demonstrated when CMECs incubated with the pro-inflammatory cytokine, TNF-α, were pre-treated with fenofibrate, resulting in increased NO and improved cell viability parameters. Simvastatin (1 μM) increased NO to a lesser extent in baseline CMECs, and resulted in increased apoptosis and necrosis. Following the cell studies, their effects on vascular reactivity was measured by aortic ring isometric tension studies. The effects of acutely administered fenofibrate to pre-contracted aortic rings were investigated, and results showed a modest, but significant NOS-dependent vasodilatory response. Next, an in vivo model of Wistar rats treated with simvastatin (0.5 mg/kg/day) and fenofibrate (100 mg/kg/day) for 6 weeks was established. Data showed that neither drug was able to improve aortic ring contraction and dilation above baseline values. Both drug treatments increased iNOS expression, which is usually associated with harmful actions. However, in our hands, increased iNOS expression was associated with a beneficial anticontractile response in the simvastatin-treated animals. Fenofibrate treatment increased NO bioavailability in the blood of these animals. In conclusion, fenofibrate showed endothelio-protective pleiotropic effects with regards to NO production after short treatment periods in CMECs. These effects were mediated via a NOSindependent mechanism, a novel finding. Fenofibrate pre-treatment was also protective against the harmful effects of TNF-α. Simvastatin did not show pronounced pleiotropic effects in vitro or in vivo on endothelial function.