Browsing by Author "Lecour, Sandrine"
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- ItemOpen AccessBiomarkers of ventricular remodelling in African hypertensives.(2013) Dike, Ojji; Sliwa, Karen; Lecour, SandrineThere is substantial evidence that the burden of hypertension, hypertension with left ventricular hypertrophy and hypertensive heart failure is very enormous in sub-Saharan Africa. There is therefore the need to look for easier and faster means, compared to electrocardiography and echocardiography of diagnosing and differentiating the different effects of long standing hypertension on cardiac remodelling which ultimately lead to systolic and diastolic dysfunctions as this affects the prognosis, management and treatment modalities of hypertension. We studied 210 subjects who were subdivided into three groups after echocardiography: those without left ventricular hypertrophy (HT) (n=83); those with left ventricular hypertrophy (HTLVH) (n=50) and those with hypertensive heart failure (HHF) (n=77).
- ItemOpen AccessCardioprotective role of signal transducer activator of transcription 3 (STAT-3) against ischaemai reperfusion injuries(2011) King, Jonathan Chan; Lecour, Sandrine; Opie, Lionel HIntroduction: Sphingosine 1 phosphate (S1P) is a major constituent of high density lipoprotein (HDL) cholesterol. Both S1P preconditioning and ischaemic postconditioning reduce myocardial damage following an ischaemia-reperfusion insult but the mechanisms involved remain unclear. Janus kinase/Signal transducer and activator of transcription 3 (JAK/STAT-3) form part of a recently discovered powerful prosurvival path termed as the Survivor Activating Factor Enhancement (SAFE) pathway. The SAFE pathway plays a critical role in ischaemic preconditioning to promote cell survival but whether activation of STAT-3 is required for S1P preconditioning and ischaemic postconditioning induced cardioprotection is unknown. Hypothesis: Activation of the STAT-3 is required for S1P preconditioning and ischaemic postconditioning.
- ItemOpen AccessCharacterisation of cardiac remodeling associated with pregnancy: providing insights to peripartum cardiomyopathy(2021) Kodogo, Vitaris; Sliwa, Karen; Lecour, Sandrine; Azibani, FerielIntroduction: Maternal cardiovascular changes that occur in pregnant women are usually well tolerated by most women experiencing an uncomplicated pregnancy and are reversable postpartum. However, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Understanding of the maternal cardiovascular adaptation during healthy pregnancy is important to identify deviations from regular patterns caused by pathological conditions. The main objective of this study was to explore the functional, structural and molecular cardiovascular changes that are involved in healthy pregnancy with the goal to delineate possible mechanisms involved in the lack of reverse cardiovascular remodeling observed in peripartum cardiomyopathy (PPCM). Methods: Cardiovascular functional, morphological and molecular changes during pregnancy and postpartum were assessed in pregnant wild type mice (C57/BL6) and healthy women. An invitro model of cardiac hypertrophy was then used to explore the involvement of pregnancy hormones in the regulation of cardiac hypertrophy. Finally, we assessed the circulatory level of growth differentiation 15 (GDF-15) in PPCM patients and matched healthy controls. Results: Cardiac structural, functional and morphological changes were observed in mice and all the parameters were resolved postpartum. Strikingly, volume load, cardiac hypertrophy and fibrosis were sustained for a longer period postpartum than previously reported. Proteomics profiling confirmed the prolongation of cardiac hypertrophy in the postpartum and the involvement of the ubiquitin proteasome system (UPS) in the reverse remodeling of cardiac changes that occur during pregnancy. We also identified a set of transcription factors that regulates the protein expression in the postpartum. Left ventricular systolic function was significantly reduced in late pregnancy in humans. Finally, the serum level of GDF-15 was significantly lower in PPCM patients compared to healthy controls Conclusion: We conclude that pregnancy induces cardiac stress which is sustained in the postpartum period. The heart remodels and adapts to meet the demand by both the mother and the fetus. Cardiac changes that occur during pregnancy are strictly regulated and reversed postpartum. However, the postpartum period is a period of intense cardiac stress and activity which requires monitoring for any deviation that may lead to pathological conditions.
- ItemOpen AccessDelineation of the Cardioprotective Agents found in red wine(2009) Lamont, Kim; Lecour, Sandrine; Opie, Lionel HSecondary leach concentrate (SLC) is an important bleed stream for minor elements from Anglo Platinum's Base Metal Refinery (BMR) which produces copper nickel and cobalt sulphate. It contains mainly sulphur, iron jarosites, unleached base metals and platinum group metals (PGMs), which makes the treatment of SLC necessary. The SLC is currently toll-refined at Umicore's Hoboken smelter and refinery to recover revenue from entrapped valuable metals. This method of treatment results in excessively high costs due to high transport and toll refining expenses as well as penalties. Thus, an in-house method of treatment by Anglo Platinum itself would prove beneficial in that it would eliminate these excessive costs and also provide a method of treatment in the event of residues exporting becoming banned or strongly penalised in future. Therefore, a method for treating SLC in-house is investigated. The first stage of the proposed treatment method involves a pyrometallurgical process where the removal of amphoterics by oxidative fuming, followed by reduction to recover base metals from the slag takes place. The PGMs are reported mainly to the metal alloy phase along with the base metals during this process. The project discussed in this report deals with the treatment of this furnace alloy which is referred to as Cu alloy. The Cu alloy is used to produce anodes to be applied to an electrorefining application for the recovery of Cu as a Cu cathode and PGMs in the form of anode slimes. Spent electrolyte from the BMR copper electrowinning section adjusted to specific pH and Cu concentration is used as electrolyte to which dissolvable metals (such as Ni and Fe) are recovered. The purpose of the process is to recover PGMs to anode slimes with a composition suitable to be blended with the final concentrate that is sent to the Precious Metals Refinery (PMR). The performance of this process on the Cu alloy provided is investigated and the anode slimes produced are characterised in order to propose further methods of purification before blending with PMR feed. The typical energy consumption, cathodic current efficiency, anodic copper dissolution rate and deportment of elements (especially PGMs) are determined. The effects of various operating parameters on the performance are also investigated in order to propose operating conditions. The operating parameters that are investigated are current density, Cu and H2SO4 concentrations in electrolyte and the use of an additive. A preliminary process design based on knowledge and experience gained during the literature review and test work is given. -PAGE 3 OF 181 The major technical factors in electrorefining are the cathode purity, the production rate and the specific energy consumption. These factors are influenced primarily by anode quality, electrolyte conditions and cathode current density. Design considerations and typical design parameters for other industrial Cu electrorefining applications are studied as well as possible further treatment of anode slimes for the concentration of PGMs. A total of eleven experiments were performed with a variety combinations of Cu concentration (30, 40 and 50 g/l), H2SO4 concentration (110, 130, 160 and 190 g/l) and current density (100, 125, 150, 250, 300 A/m2). In each experiment only one parameter was changed while all others were kept constant at the base-case setting of 40 g/l Cu, 160 g/l H2SO4, and 125 A/m2. The testwork showed that electrolytic refining of the Cu alloy, produced by a two stage pyrometallurgical treatment of current SLC, produces a highly concentrated PGM residue at an overall SLC mass reduction of 99.3%, with excellent PGM recovery to the anode slimes material. The different operating parameters that were tested successfully, all showed very good repeatability and greater than 99% PGM recovery from the Cu alloy, which would result in an overall recovery of 98% from SLC. Very little or none of the base metals that were supplied by the anode or the electrolyte feed reported to the anode slimes. The typical operating conditions (cell potential, current efficiency, anodic Cu dissolution and element deportment) that were observed correlated well with literature and the theoretically calculated values. The characteristics of the anode slimes produced stayed relatively similar throughout the different operating parameters and strong confidence can be placed in the production thereof and the recovery of the PGMs. The characteristics of the spent electrolyte and the Cu cathodes were also found to be suitable for integration in the BMR circuit. The anode slimes composition was 20 to 30% PGMs, 20 to 30% base metals, 15 to 20% Ag, As, Te, Se, Pb and 2 to 5% Al, Si, Sb, Bi, Zn and Sn. The blending of these slimes with typical PMR feed will result in a new PMR feed where the Pt grade of the feed to PMR is reduced by 4 to 5.5%, the Cu grade increased by 2 to 4% and the Ni content reduced by +-4%. Other concerns are the increase of As, Te, and Pb by between 0.5 and 1%. -PAGE 4 OF 181 The PGM-rich (<60%) phase in the anode slimes is a mostly amorphous matrix phase containing mostly palladium and other PGMs, arsenic and tellurium [Pd73As6Te21] with small amounts of Cu. Anode slimes produced from electrorefining can either be subjected to an additional process step to remove Ag, Pb and base metals before it is blended with the final concentrate (FICO) as feed for PMR, or it can be sent to the metallics section in PMR which includes a roast and a leach stage. The treatment of the anode slimes depends on the nature of the slimes. A preliminary process design was performed with proposed design parameters of electrolyte concentrations of 40 g/l Cu and 160 g/l H2SO4 at 65 deg C and a current density of 200 A/m2. The process consists out of seven cells in series with 55 anode cathode pairs in parallel per cell. The process has a maximum capacity of 127 t/m of anode material which allows 56 days of downtime per year if the current SLC produced (6600 t/a) is treated. The maximum capacity for Cu production is 1349 t/a and anode slimes 50.3 t/m. The power consumption per kg of anode dissolved will be 0.175 kWh/kg.
- ItemOpen AccessExercise intervention alters HDL subclass distribution and function in obese women(BioMed Central, 2018-10-10) Woudberg, Nicholas J; Mendham, Amy E; Katz, Arieh A; Goedecke, Julia H; Lecour, SandrineBackground Obesity is associated with a change in high-density lipoprotein (HDL) function and subclass. Exercise training reduces cardiovascular risk in obese patients. We aimed to explore the effect of an exercise training stimulus on HDL functionality and subclass in obese women. Methods Thirty-two obese black South African women were randomly assigned to exercise (combined aerobic and resistance exercise) or control (no exercise) conditions for 12-weeks. Pre- and post-testing included venous blood sampling for analysis of lipid profile and HDL functionality, by measuring cellular cholesterol efflux capacity, reduction in endothelial vascular cell adhesion molecule (VCAM) expression (anti-inflammatory function), paraoxonase (PON) (antioxidative function) and platelet activating factor acetylhydrolase (PAF-AH) activities (anti-thrombotic function). PON-1 and PAF-AH expression were determined in serum and in isolated HDL using Western blotting. Levels of large, intermediate and small HDL subclasses were measured using the Lipoprint® system. Results Exercise training resulted in a decrease in body mass index (− 1.0 ± 0.5% vs + 1.2 ± 0.6%, p = 0.010), PON activity (− 8.7 ± 2.4% vs + 1.1 ± 3.0%, p = 0.021), PAF-AH serum expression (− 22.1 ± 8.0% vs + 16.9 ± 9.8, p = 0.002), and the distribution of small HDL subclasses (− 10.1 ± 5.4% vs + 15.7 ± 6.6%, p = 0.004) compared to controls. Exercise did not alter HDL cellular cholesterol efflux capacity and anti-inflammatory function. Conclusions These results demonstrate the potential for exercise training to modify HDL subclass distribution and HDL function in obese women. Trial registration Clinical trials number: PACTR201711002789113 .
- ItemOpen AccessExploring the cardioprotective effect of synthetic wine in Long Evans rats(2015) Dlamini, Lindizwe; Lecour, Sandrine; Blackurst, Dee[No copyright notice] Background: Moderate and chronic consumption of red wine protects against cardiovascular disease. Wine is a complex matrix containing multiple molecules whose concentrations can vary from one bottle to another. Therefore, the delineation of the putative cardioprotective components in wine such as alcohol, resveratrol and melatonin is very challenging when using commercially available red wine. Aim: We aimed to use synthetic wine, whose composition is well characterized, to explore whether the presence of alcohol, resveratrol and melatonin (as found in commercial wines) contributes to the cardioprotective effect of chronic and moderate consumption of red wine (equivalent to 2 glasses of wine/day) in an animal model. Additionally, we hypothesized that synthetic wine enriched with resveratrol and melatonin confers cardioprotection via improvement of overall antioxidant profile.
- ItemOpen AccessExploring 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, NicholasIntroduction: 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.
- ItemOpen AccessInvestigating high-density lipoprotein (HDL) subfractions, composition and functionality in people living with HIV(2022) Hudson, Peter; Lecour, Sandrine; Strijdom, Hans; Woudberg, NicholasBackground: 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.
- ItemOpen AccessInvestigating the possible cytoprotective effects of melatonin isomer against simulated ischemic injury(2017) Victor, Laikyn; Lecour, Sandrine; Adam, TasneemIntroduction: The presence of melatonin in wine contributes to the cardioprotective effect of regular and moderate consumption of wine against lethal ischemia/reperfusion injury. Recently, the presence of melatonin isomers has been identified in red wine, but whether or not these isomers confer any physiological properties is unknown. Aim: The aim of our study was to establish a cell culture model of simulated ischemia to study and compare the possible cytoprotective effects of dietary melatonin and a melatonin isomer against an ischemic insult and to explore the possible role of melatonin receptors in this effect. Methods: H9C2 cardiac fibroblast cells were subjected to simulated ischemia by exposure to 1mM H₂O₂ following a 30min pre-treatment with 75ng/L (dietary concentration), 1μM (pharmacological concentration, 0.232mg/L) melatonin or/and 75mg/L (dietary concentration) melatonin isomer. To determine the role of melatonin receptors, cells were pre-treated with the melatonin receptor inhibitor, luzindole (10 μM) for 1h prior to H₂O₂ treatment. At the end of the simulated ischemic insult, cell viability was assessed using trypan blue staining. Mitochondrial respiration in permeabilized H9C2 cells was measured using the Oroboros Instrument, at two different time points: at the end of a 30min pre-treatment with either 75ng/L melatonin or 75mg/L melatonin isomer, or the afore mentioned pre-treatments prior to a 15min treatment of 1mM H₂O₂. Results: A simulated ischemic insult with 1mM H₂O₂ reduced cell viability from 92.9±1.5% to 28.4±1.4% (p<0.001 vs control). Pre-treatment with the dietary concentrations of melatonin or the melatonin isomer improved the cell viability to a similar extent as a pre-treatment with the pharmacological concentration of melatonin (74.4±3.1%, 73.9±2.7% and 69.0±1.2%, p<0.001 vs H₂O₂ and p<0.01 vs H₂O₂ respectively). A combined pre-treatment of melatonin and the melatonin isomer did not add further cytoprotective benefit. Addition of luzindole fully abolished the cytoprotective effect of dietary melatonin (29.7±2.4%, p<0.001 vs H₂O₂ + Mel), but only partially abolished the cytoprotective effect of the melatonin isomer (41.4±3.6%). Both dietary concentrations of melatonin and the melatonin isomer did not affect mitochondrial respiration in permeabilized H9C2 cells. Conclusion: Our findings suggest that both dietary melatonin and the melatonin isomer confer cytoprotection against a simulated ischemic insult, an effect which is mediated, at least in part, via the activation of melatonin receptors. Both melatonin and melatonin isomers present the advantage to be potentially safe and inexpensive therapies against ischemic heart disease.
- ItemOpen AccessMelatonin as a novel cardioprotective therapy in pulmonary hypertension(2014) Maarman, Gerald Jerome; Lecour, Sandrine; Sliwa-Hahnle, KarenPulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure which leads to right ventricular hypertrophy and failure. The mechanism involved in the pathophysiology of the disease remains unclear but it is suggested that oxidative stress may trigger cardiovascular dysfunction associated with the disease. To date, there is no efficient therapy against PH and novel therapies are urgently needed. Melatonin is a powerful antioxidant that can confer benefit against ischemia-reperfusion injury and hypertension. We therefore hypothesised that melatonin may confer cardiovascular benefits against PH. Methods: Oxidative stress (plasma lipid peroxidation, antioxidant capacity and antioxidant enzyme activity) was assessed in healthy (n=10), in patients with PH (n=10), in Long Evans rats (n≥6) or in a rat model of PH induced 28 days after the injection of monocrotaline (MCT, 80mg/kg, subcutaneous) (n≥6). Melatonin (75ng/L, nutritional concentration), 4mg/kg or 6mg/kg (therapeutic dose) was given daily in the drinking water of rats, with the treatment started 5 days before the injection of MCT, on the day of the injection or 14 days after the injection of MCT. The development of PH was measured by assessing right ventricular hypertrophy, cardiac fibrosis, oxidative stress and cardiac function (via echocardiography and the isolated heart Langendorff perfusion model). Results: Plasma oxidative stress was increased in both patients and rats with PH compared with their respective controls. A chronic treatment with melatonin (75ng/L, 4mg/kg or 6mg/kg) starting on the day of the injection with MCT in rats with PH reduced right ventricular hypertrophy, cardiac dysfunction and plasma oxidative stress compared with control rats. Furthermore, the beneficial effect of melatonin (6mg/kg) could be observed when given as a preventive (5 days prior to the injection of MCT) or as a curative therapy (14 days after the injection of MCT). Conclusions: Our data demonstrate that chronic treatment of melatonin confers cardioprotection in a rat model of PH. As melatonin is inexpensive, safe (no reported side effects) and already available over the counter in many countries, we propose that melatonin should be considered as a novel preventive/curative therapy to limit cardiac dysfunction in patients with PH.
- ItemOpen AccessThe role of melatonin in peripartum cardiomyopathy(2013) Nicholson, Lauren; Lecour, Sandrine; Sliwa, KarenPeripartum cardiomyopathy (PPCM) is a heart disease of unknown aetiology emerging in previously healthy women towards the end of pregnancy or first postpartum months. Previous studies have suggested that oxidative stress contributes to the pathogenesis of PPCM. Melatonin is a powerful endogenous antioxidant that can limit the damaging effect of oxidative stress. Melatonin levels are known to be altered in sleep disruption, depression and other cardiac diseases. The aim of this study was to determine if melatonin levels are disrupted in women with PPCM compared to healthy patients. We hypothesised that sleep disruption and depression may contribute to a disruption in their melatonin levels.
- ItemOpen AccessThe role of melatonin in red wine-induced cardioprotection(2012) Lamont, Kim; Lecour, Sandrine; Opie, Lionel HSeveral epidemiological studies have suggested that the regular moderate consumption of red wine confers cardioprotection. However, the exact components in red wine that confer this effect are unclear. Previous studies performed in our laboratory suggest that neither the well-known polyphenol resveratrol nor alcohol (12%) present in red wine contribute to the cardioprotective effect of red wine when administered chronically, on their own. Therefore, other compounds present in red wine may contribute to its beneficial effects. The aim of the study was to explore whether melatonin, recently discovered in red wine, may play a vital role in red wine-induced cardioprotection. Furthermore, we propose that the protective effect may be mediated via the activation of the survivor-acting factor enhancement (SAFE) pathway that involves two integral components, tumour necrosis factor ± and signal transducer and activator of transcription 3 (STAT3). The drinking water of either male Wistar rats, TNF KO or STAT3 KO mice and their wild-type littermates were supplemented with a French Cabernet Sauvignon (12% alcohol by volume) or melatonin (75ng/â ) to a final concentration corresponding to the concentration found in two glasses of wine per day. After 14 days of treatment hearts were subjected to an ex vivo or an in vivo ischemia reperfusion insult or to a permanent ligation of the left descending coronary artery as a model of ischemic heart failure. Functional parameters and infarct size were assessed. The chronic moderate consumption of red wine for 14 days reduced infarct size from 60±2.3% to 23.3±1.8% after ischemia reperfusion injury, p<0.001. The pretreatment with melatonin protected to a similar extent as red wine given on its own (infarct size of 20.1±1.7%, p<0.001). Interestingly, the cardioprotective effect of red wine was partially abolished with prazosin, a melatonin receptor 3 inhibitor (40±0.9%, p<0.001 vs. wine). Furthermore, the cardioprotective effects of regular moderate consumption of red wine or melatonin were abolished in STAT3 KO and TNF KO mice. In a model of ischemic heart failure melatonin improved ejection fraction and fractional shortening compared to plain drinking water control in wild-type mice (p<0.001). The protective effect of melatonin was not abolished in TNK KO and STAT3 KO mice p<0.001 vs. control), therefore suggesting that the long-term treatment with melatonin in ischemic heart failure protects independently of the SAFE pathway. Our novel findings suggest that the moderate regular consumption of red wine (equivalent to 2-3 glasses per day) confers cardioprotection, in part due to its melatonin content. The protective effect against ischemia I/R injury of both melatonin and red wine is mediated via the activation of melatonin receptor 3 and the activation of the SAFE pathway while the protective effect of melatonin against ischemic heart failure is independent of the SAFE pathway. Melatonin is a safe, cheap and easily accessible drug that may be considered as an innovative therapeutic agent in the treatment against acute myocardial infarction and ischemic heart failure.
- ItemOpen AccessRole of nuclear factors kappa-B in TNFα-induced cytoprotection(2006) Somers, Sarin J; Lecour, Sandrine; Opie, Lionel HIncludes bibliographical references (leaves 67-81).
- ItemOpen AccessThe role of signal transducer and activator of transcription-3 (STAT-3) in ischaemic and pharmacological postconditioning(2011) Somers, Sarin J; Lecour, SandrineIncludes abstract. Includes bibliographical references (leaves 131-147).
- ItemOpen AccessRole of the SAFE pathway and the mitochondria in HDL cholesterol (and its constituent sphingosine-1-phosphate) induced cardioprotection(2011) Hacking, Damian; Lecour, SandrineHigh density lipoprotein cholesterol (HDL) and its component sphingosine-1-phosphate (S1P) protect against myocardial infarction. Recently, the SAFE (survivor activating factor enhancement) pathway, involving tumour necrosis factor (TNF) and the transcription factor signal transducer and activator of transcription 3 (STAT-3), has been identified as a key signalling pathway in cardioprotection, although the end effector remains unclear.
- ItemOpen AccessThe role of Toll-like receptor 4 (TLR-4) in wine-induced cardioprotection(2012) Albertyn, Zulfah; Lecour, Sandrine; Opie, Lionel HModerate and chronic consumption of red wine confers cardioprotection. Melatonin, present in wine, may contribute to this cardioprotective effect. Melatonin confers cardioprotection via the activation of tumor necrosis factoralpha (TNF-α) and the signal transducer and activator of transcription-3(STAT-3), via mechanisms that still remain to be delineated. We therefore hypothesise that South African red and white wines confer a cardioprotective effect in relation to their melatonin content. Furthermore, we propose that the cardioprotective effect of melatonin (at a concentration found in red wine) is dependent on the activation of Toll-like receptor 4 (TLR-4) to activate TNF-α/STAT-3.
- ItemOpen AccessRole of Tumour Necrosis Factor Alpha (TNFa) in ischaemic and pharmacological postconditioning(2010) Lacerda, Lydia; Lecour, SandrineIschaemic postconditioning (IPostC) is a powerful protective mechanism that activates prosurvival intrinsic signalling cascades to limit reperfusion injury but the exact signalling pathway involved in this cardioprotective effect still remains unclear.
- ItemOpen AccessSignalling pathways involved in TNFα-induced cytoprotection : role of reactive oxygen species(2005) Lacerda, Lydia; Lecour, Sandrine; Opie, Lionel HTumour necrosis factor alpha (TNFa) is a pleiotropic cytokine which has both beneficial and deleterious effects. It has previously been shown in our laboratory that TNFa can mimic ischemic preconditioning (IPC). However, the signalling pathways involved in this protection remain incompletely understood. One potential protective pathway involves the generation of reactive oxygen species (ROS), which are known to be activated by TNFa. It was therefore hypothesized that TNFa-induced cytoprotection requires the generation of ROS. In addition, it was postulated that this ROS generation originates in the mitochondria.
- ItemOpen AccessTargeting heart rate as a novel therapeutic approach in acute heart failure(2018) Imamdin, Aqeela; Lecour, Sandrine; Azibani, Feriel; Sliwa, Karen; McCarthy, JoyBackground and hypothesis: Standard pharmacological treatment for heart failure improves cardiac remodelling and survival in the setting of chronic heart failure, but is suboptimal in cases of acute heart failure (AHF). Peripartum cardiomyopathy (PPCM), de-novo hypotension (often due to haemorrhagic shock), and Takotsubo cardiomyopathy (TC) are conditions which have acute onset of heart failure, and often present with high mortality rates. In patients treated for these pathologies, a variation in the heart rate is observed and could potentially be used as a target to improve the treatment of AHF. We therefore questioned whether the use of a sinoatrial node inhibitor (ivabradine) to modulate heart rate may improve outcomes in AHF. Objectives and methods: Our objectives were 3-fold: (1) to explore the effect of a standard treatment strategy on heart rate in a South African cohort of PPCM patients after 6 and 12 months follow-up. (2) To explore the effect of ivabradine, a sinoatrial node inhibitor in an established signal transducer and activator of transcription 3 (STAT3) knockout mouse model of PPCM (with 3 consecutive pregnancies). Mice were fed ivabradine for 30 days (10mg/kg/day in drinking water), following the 3rd weaning. Trans-thoracic echocardiograms (TTE) were done at the end of the 3rd weaning, and after 30 days of treatment with ivabradine. Hearts were harvested after the second TTE for histology staining and messenger ribonucleic acid (mRNA) quantitation of transcripts involved in heart failure. (3) To explore the role of the sinoatrial node inhibitor in an ex-vivo model of de-novo AHF due to hypotension, and a newly developed ex-vivo model of TC. In the AHF model, hearts were stabilised before administering Ivabradine (3μM) in a buffer containing high free fatty-acids at a low pressure (to mimic hypotension/ haemorrhage shock conditions). A pressure- sensing balloon in the left ventricle measured heart rate, diastolic and systolic pressure, left ventricular developed pressure, rate pressure products and functional recovery. In the TC model, hearts were stabilised, then given a buffer with high free fatty-acid content and 10 times a physiological dose of adrenaline to mimic the adrenergic response seen in TC. Thereafter, hearts were restored to stabilisation pressure and substrate for recovery. Results: (1) Clinical outcomes indicated that patients on maximum standard therapy improved symptomatically and on the New York Heart Association scale. However, heart rates of PPCM patients remained elevated after 6 months of treatment. (2) In PPCM mice, a treatment with ivabradine was associated with reduced fibrotic infiltration in cardiac tissue and with a decrease in levels of atrial natriuretic peptide and Fibronectin mRNAs. (3) Both hypotensive AHF and TC models showed a tendency toward better cardiac function with ivabradine at the end of the acute phases. This advantage was lost after withdrawal of ivabradine during recovery. Conclusion: In South African women with PPCM treated with standard therapy, heart rate remains elevated, therefore suggesting that these women may benefit from the use of ivabradine as an additional therapy, particularly in patients who may be intolerant to β-blockers. The long-term use of ivabradine in the setting of cardiac dysfunction appears to have beneficial effects on remodelling, as treatment with ivabradine in our mouse PPCM model showed reduced cardiac fibrosis. The ex-vivo models of hypotensive AHF and TC both showed benefit in reducing heart rate during the acute phases, and hold the potential of being an intervention therapy to improve the outcome in patients who are brought to hospital while still in the acute phase.
- ItemOpen AccessTesting metabolic and pharmacological agents for recovery following de novo acute heart failure in an isolated rat heart model(2014) Deshpande, Gaurang; Opie, Lionel H; Lecour, SandrineAcute heart failure is a potentially lethal clinical emergency without any effective therapy. Using an isolated rat heart model, we established and validated a model of de novo acute heart failure to study novel putative cardio protective therapies against acute heart failure, including glucose, insulin and the molecular agent sphingosine-1-phosphate(component of high density lipoprotein) for recovery. In isolated rat hearts, the protocol consisted of three phases: stabilization at normotensive perfusion pressure, hypotensive acute heart failure and recovery by restoring normotension. Low glucose (2.5mM) and high albumin-bound free fatty acids (1.3mM) (±adrenaline 10-M) were added in theperfusate. Molecular and metabolic agents were administered either alone or in combination in the acute heart failure or recovery phases. Effects of glucose, insulin and sphingosine-1-phosphatewere observed on heart function, cell death and mitochondrial respiration. In the absence of adrenaline, combination of glucose andsphingosine-1-phosphateduring acute heart failure improved functional recovery by increasing the heart rate. In the presence of adrenaline, glucose and sphingosine-1-phosphate administered separately were cardioprotective in the recovery phase by improving heart rate. The combination of glucose+insulin and glucose+sphingosine-1-phosphate in the recovery phase also increased heart rate. Glucos9+sphingosine-1-phosphate+insulin increased heart rate and left ventricular developed pressure.Sphingosine-1-phosphate reduced expression of cytochrome C, but metabolic agents had no effect.AG490 (inhibitor of signal transducer and activator of transcription 3) attenuated the cardio protective effect of sphingosine-1-phosphatewithincreased expression of the phosphorylated inactive form of this transcription factor protein. Conclusion: We have established and validated an ex-vivo model of de novoacute heart failure. The combination of metabolic and molecular treatments improved heart function by increasingsinus node activity_ Sphingosine-1-phosphate not only improved heart rate, but also reduced cell death, an effect mediated via activation of signal transducer and activator of transcription 3. Our data provide novel principles and approaches for the treatment of acute heart failure.