Browsing by Author "Woudberg, Nicholas"

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    Open Access
    Exploring the relationship between shifts in high-density lipoprotein (HDL) particle subclass distribution/functionality and cardiac function in doxorubicin (DOX)-induced cardiotoxicity
    (2024) Abrahams, Carmelita Bianca; Lecour, Sandrine; Woudberg, Nicholas
    Introduction: Elucidating the mechanisms involved in cardiotoxicity that develops in cancer patients receiving doxorubicin (DOX) chemotherapy is key to identify potential cardioprotective strategies and early biomarkers in these patients. Both breast cancer and DOX treatment are associated with dyslipidaemia, however changes in high-density lipoprotein (HDL) particle subclass distribution, composition and functionality are unknown. We therefore aimed to investigate whether changes in HDL particle subclass distribution, composition and functionality in breast cancer patients and tumour bearing mice receiving DOX chemotherapy may contribute to cardiac dysfunction. Methods: Blood samples were collected in 34 female breast cancer patients (18-65 years old with no co-morbidities) prior (B) to and after completion (E) of DOX chemotherapy (6 cycles every 3 weeks). Breast cancer was induced in female C57/Bl6 mice (6-8 weeks old) by subcutaneous injection of the E0771 cell line. Once a palpable tumour formed, DOX (5 mg/kg, i.p.) was given weekly for 5 weeks. The following groups were considered: Control (C, n=17), DOX (D, n=17), Tumour (T, n=20) and DOX+Tumour (DT, n=17). Cardiac function was measured with echocardiography, and serum was collected at baseline (B) and at endpoint (E). In serum, HDL subclass distribution was measured using the Lipoprint® system. HDL anti-oxidative functionality was assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9C2 cells and measured using the adenosine-triphosphate (ATP) assay. Results: DOX-induced subclinical cardiotoxicity was observed in 9 breast cancer patients. DOX therapy reduced the intermediate HDL subclasses [52.5±1.0% (B) vs 48.6±0.9% (E), p<0.001], an effect that correlated with cardiac dysfunction in patients (r =+0.29, p<0.05). In the mouse model, DOX induced cardiac alterations by reducing radial strain of the left ventricular anterior wall [D: 49.96±2.3% (B) vs 21.8±2.9% (E), p<0.0001 and DT: 46.7±2.7% (B) vs 31.7±4.4% (E), p<0.01]. In mice, breast cancer reduced the intermediate HDL subclasses (D: 74.8±1.2% vs DT: 67.7±2.4%, p<0.001) and increased the large HDL subclasses (D: 24.0±1.2% vs DT: 30.9±2.3%, p<0.001), while DOX treatment increased the small HDL subclasses (T: 0.3±0.2% vs DT: 0.9±0.5%, p<0.05). DOX treatment in breast cancer mice was associated with reduced PON1 activity (C: 0.4±0.0% vs DT: 0.2±0.0%, p<0.05). Interestingly, a reduction in the intermediate HDL subclass, HDL-4, and PON1 activity were associated with a reduction in radial strain of the left ventricular anterior wall (r=+0.41, p<0.05 and r=+0.44, p<0.05, respectively). Most importantly, HDL particles isolated from breast cancer or DOX treated mice could not protect against DOX-induced cytotoxicity in H9C2 cells compared to HDL particles isolated from control mice (C: 100.0±16.6 ATP% vs D: 49.3±11.9 ATP% or T: 52.44±19.8 ATP%, p<0.05 vs C). Conclusion: In breast cancer patients and in tumour bearing mice, a treatment with DOX was associated with a shift in HDL subclass distribution and functionality that correlated with cardiac alterations. This change in HDL particle dynamic caused it to lose its cardioprotective functionality against DOXinduced cardiotoxicity, thus suggesting that HDL particles may play a key role in the development of cardiotoxicity associated with DOX chemotherapy. Our data therefore highlight HDL particles as a potential therapeutic target to limit DOX-induced cardiotoxicity. Our study also improves upon prior research by including a cancer environment in our mouse model of DOX-induced cardiotoxicity and highlights the contribution of the cancer to the pathophysiological changes observed.
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    Open Access
    Investigating high-density lipoprotein (HDL) subfractions, composition and functionality in people living with HIV
    (2022) Hudson, Peter; Lecour, Sandrine; Strijdom, Hans; Woudberg, Nicholas
    Background: Although antiretroviral therapy (ART) increases survival in individuals living with human immunodeficiency virus (HIV), this population faces an increased risk for cardiovascular disease (CVD). There is mounting evidence that the distribution, composition, and functionality of high-density lipoprotein (HDL) subfractions are altered in the presence of cardiovascular risk factors. We aimed to explore whether HIV and/or ART modulate HDL subfractions and functionality in a population of people living with HIV (PLWH). Methods: Fifty healthy HIV-negative control patients (HIV free control), 44 HIV-infected patients yet to receive any ART treatment (HIV ART-naïve) and 50 HIV-infected patients receiving ART (ART-treated) were included (South African cohort). HDL functionality was assessed by measuring reverse cholesterol efflux capacity, anti-oxidative activity (paraoxonase-1 (PON-1) activity) and anti-thrombotic activity (platelet-activating factor acetylhydrolase (PAF-AH) activity). HDL subfractions were measured using the Lipoprint® system. Results: HIV ART-naïve patients had lower HDL cholesterol than HIV-negative or ARTtreated patients (1.05 ± 0.46 vs 1.33 ± 0.39 vs 1.31 ± 0.74 mmol/L, respectively, p < 0.05). The percentage of the largest subfraction of HDL (HDL-1) was higher in HIV ART-naïve patients compared to HIV-negative patients (12.46 ± 6.33 vs 9.43 ± 4.41%, p< 0.05). The HIV ARTnaïve patients also displayed a change in HDL composition, with decreased levels of apolipoprotein A-I compared to HIV ART-treated patients and HIV-negative patients (38.5 ± 7.5 vs 43.8 ± 13.4 vs 45.5 ± 8.1 μmol/L, respectively, p < 0.05). Large HDL was inversely correlated with CD4+ count (r = -0.279, p < 0.01) and small HDL was positively correlated with CD4+ count (r = 0.333, p < 0.01). Although HDL functionality was not different between groups, PON-1 activity positively correlated with small HDL (r=0.19, p< 0.05). Conclusion: Our study suggests that HIV infection is associated with a change in HDL composition and a shift in HDL subfraction distribution, favouring a higher percentage of large HDL subfractions, which may contribute to the increased risk of CVD in HIV patients. More in-depth studies should be conducted to better understand the exact role of HIV and/or ART on the modification of HDL.
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    Understanding the relationship between high-density lipoprotein (HDL) subclass distribution and functionality in patients at risk of cardiovascular disease
    (2017) Woudberg, Nicholas; Lecour, Sandrine; Goedecke, Julia H; Frias, Miguel
    Background: Risk factors for cardiovascular disease (CVD) include obesity, ethnicity and hypertension. High-density lipoprotein (HDL) has traditionally served as a marker for CVD risk. Latest studies, however, propose that the composition and subclass distribution and the anti-atherogenic function of HDL are more accurate predictors of CVD risk. We therefore explored whether obesity, ethnicity, exercise and hypertension may modulate HDL composition, subclass and function in three different sample populations of patients affected with these CVD risk factors. Methods: The first study sample population consisted of black and white obese and normal-weight South African women (n=40). In the second sample population, obese black South African women were randomly assigned to exercise (combined aerobic and resistance exercise 4 times/week) or control (sedentary) conditions for 12-weeks (n=32). The third sample population included Nigerian out-patients, divided into healthy controls, hypertensive patients and hypertensive patients with heart failure (HF) (n=80). HDL composition measurements included apolipoproteins A1 and M (ApoA1 and ApoM), paraoxonase (PON1) and platelet activating factor acetylhydrolase (PAF-AH) expression (using Western blotting) and sphingosine-1-phosphate (S1P) content (using mass spectometry). Levels of large, intermediate and small HDL subclasses were measured using the Lipoprint® system. HDL functionality was assessed by measuring PON1 activity, PAF-AH activity, reverse cholesterol efflux capacity, HDL-mediated activation of endothelial nitric oxide synthase (eNOS) and quantification of the expression of vascular cell adhesion molecule in endothelial cells. Results: In all sample populations, HDL-cholesterol concentration was not different between groups. PON1 activity was lower in white compared to black women (0.49±0.09 U/L vs 0.78±0.10 U/L, p<0.05). Obese black women had lower PAF-AH activity compared to obese white women (9.34±1.15 U/L vs 13.89±1.21 U/L, p<0.05). Compared to normal-weight women, obese women had lower large HDL, greater intermediate and small HDL. Compared to the sedentary control condition, exercise training was associated with a decrease in PON1 activity (-8.7±2.4% vs +1.1±3.0%, p<0.05), PAF-AH serum expression (-22.1±8.0% vs +16.9±9.8, p<0.005) and small HDL subclasses (-10.1±5.4% vs +15.7±6.6%, p<0.005). S1P content in HDL was lower in hypertensive and HF patients compared to controls (165 ± 55 vs 201 ± 73 pmol/mg, p < 0.05). HDL subclass distribution was different in hypertensive and HF patients with lower large HDL (48 ± 15 vs 63 ± 7%, p<0.005), higher intermediate (45 ± 7 vs 34 ± 5%, p<0.005) and small HDL (7 ± 9 vs 2 ± 4%, p<0.05). In contrast to HDL from control patients, HDL from all hypertensive patients failed to activate eNOS. Conclusions: In all three sample populations, there were associations between CVD risk factors and measures of HDL quality. HDL subclass distribution differences were associated with obesity and hypertensive heart failure, both in cross-sectional studies and in an exercise intervention study. In African sample populations, consideration of HDL quality rather than total HDL quantity may be a more sensitive marker to assess CVD risk.