Publications by authors named "Roisin Kelly-Laubscher"

9 Publications

  • Page 1 of 1

Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart.

Can J Physiol Pharmacol 2021 Sep 24. Epub 2021 Sep 24.

University of Cape Town, Human Biology, 5.14 Anatomy Building, Observatory, Cape Town, South Africa, 7925;

Fingolimod (FTY720) inhibits Ca-permeable, Mg-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca paradox (CP)-induced myocardial damage have not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage, and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca depletion followed by Ca repletion. Hearts of rats pre-treated with MgSO were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg pre-treatment had effect neither on CP-induced infarct size, hemodynamic parameters during CP, nor the level TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca-mediated cardiotoxicity. However, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.
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http://dx.doi.org/10.1139/cjpp-2021-0381DOI Listing
September 2021

Ethanolamine: A Potential Promoiety with Additional Effects in the Brain.

CNS Neurol Disord Drug Targets 2020 Dec 11. Epub 2020 Dec 11.

Department of Pharmacology and Therapeutics, School of Medicine, College of Medicine and Health, University College Cork, Cork,. Ireland.

Ethanolamine is a bioactive molecule found in several cells, including those in the central nervous system (CNS). In the brain, ethanolamine and ethanolamine-related molecules have emerged as prodrug moieties that can promote drug movement across the blood-brain barrier. This improvement in the ability to target drugs to the brain may also mean that in the process ethanolamine concentrations in the brain are increased enough for ethanolamine to exert its own neurological ac-tions. Ethanolamine and its associated products have various positive functions ranging from cell signaling to molecular storage, and alterations in their levels have been linked to neurodegenerative conditions such as Alzheimer's disease. This mini-review focuses on the effects of ethanolamine in the CNS and highlights the possible implications of these effects for drug design.
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http://dx.doi.org/10.2174/1871527319999201211204645DOI Listing
December 2020

The effect of sphingosine-1-phosphate on the endothelial glycocalyx during ischemia-reperfusion injury in the isolated rat heart.

Microcirculation 2020 07 25;27(5):e12612. Epub 2020 Feb 25.

Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Objective: Sphingosine-1-phosphate is a natural metabolite that is cardioprotective, but its effects on endothelial glycocalyx damage during ischemia-reperfusion are unknown. Therefore, we investigated the effect of sphingosine-1-phosphate on the endothelial glycocalyx during ischemia-reperfusion.

Methods: Isolated hearts from Wistar rats were perfused on a Langendorff system with Krebs-Henseleit buffer and pretreated with sphingosine-1-phosphate (10 nmol/L) before ischemia-reperfusion. Infarct size was measured by triphenyl tetrazolium chloride staining (n ≥ 6 per group). Cardiac edema was assessed by calculating total water content (n = 7 per group) and histologically quantifying the interstitial compartment (n ≥ 3 per group). The post-ischemic coronary release of syndecan-1 was quantified using ELISA. Syndecan-1 immunostaining intensity was assessed in perfusion-fixed hearts (n ≥ 3 per group).

Results: Pretreatment with sphingosine-1-phosphate decreased infarct size in isolated hearts subjected to ischemia-reperfusion (P = .01 vs ischemia-reperfusion). However, sphingosine-1-phosphate had no effect on syndecan-1 levels in the coronary effluent or on the intensity of the syndecan-1 immunostaining signal in cardiac tissue. Heart total water content was not significantly different between control and ischemic groups but was significantly decreased in hearts treated with sphingosine-1-phosphate alone.

Conclusion: These results suggest that sphingosine-1-phosphate-induced cardioprotection against ischemia-reperfusion injury is not mediated by the maintenance of syndecan-1 in the endothelial glycocalyx.
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http://dx.doi.org/10.1111/micc.12612DOI Listing
July 2020

First-year medical students' naïve beliefs about respiratory physiology.

Adv Physiol Educ 2016 Sep;40(3):342-8

Department of Psychology, Erasmus University, and Institute of Medical Education Research, Rotterdam, The Netherlands;

The present study explored the nature and frequency of physiology naïve beliefs by investigating novices' understanding of the respiratory system. Previous studies have shown considerable misconceptions related to physiology but focused mostly on specific physiological processes of normal respiration. Little is known about novices' broader understanding of breathing in a clinical context. Our study hypothesized that naïve beliefs could hamper participants' ability to understand the interrelatedness of respiratory structures and functions related to breathing during a clinical complication. The study entailed both quantitative and qualitative foci. A two-tier test was designed and administered to 211 first-year medical students. Participants were asked to choose the correct answer out of a set of four options and to substantiate their choices. Questions were purposefully left open to elicit a wide range of responses. Statistical analysis (SPSS) was done to evaluate the frequency of naïve beliefs. Thematic analysis was used to determine themes within the raw data. The majority of participants selected incorrect answers in the multiple-choice question part of the questionnaire. Results from the thematic analysis yielded a considerable range of naïve beliefs about gas exchange, foundational physics, airflow, anatomic structures, and breathing pathways. An awareness of the existence of such naive beliefs in respiratory physiology will allow educators to address them in their teaching and thereby prevent naïve beliefs transforming into misconceptions.
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http://dx.doi.org/10.1152/advan.00193.2015DOI Listing
September 2016

Beneficial Effects of Magnesium Treatment on Heart Rate Variability and Cardiac Ventricular Function in Diabetic Rats.

J Cardiovasc Pharmacol Ther 2017 Mar 8;22(2):169-178. Epub 2016 Jul 8.

1 Department of Human Biology, University of Cape Town, Cape Town, South Africa.

Background: Diabetes mellitus induces life-threatening cardiovascular complications such as cardiac autonomic neuropathy and ventricular dysfunction and is associated with hypomagnesemia. In this study, we investigated the short-term effects of magnesium (Mg) treatment on streptozotocin (STZ)-induced diabetic cardiac complications.

Methods: Adult Wistar rats were treated once with STZ (50 mg/kg, intraperitoneally [ip]) or vehicle (citrate) and then daily for 7 days with MgSO (270 mg/kg, ip) or saline. On the eighth day, in vivo tail-pulse plethysmography was recorded for heart rate variability (HRV) analysis, and ex vivo Langendorff-based left ventricular (LV) pressure-volume parameters were measured using an intraventricular balloon. Measurements of plasma lipid and Mg levels as well as blood glucose and cardiac tissue Mg levels were also performed.

Results: Treatment with Mg prevented diabetes-induced alterations in the standard deviation of the averages of normal-to-normal (NN) intervals (SDANN), root mean square differences of successive NN intervals (RMSSD), heart rate, and low-frequency (LF) power-high-frequency (HF) power ratio. In addition, Mg restored orthostatic stress-induced changes in SDANN, RMSSD, and LF-HF ratio in diabetic rats. In isolated hearts, Mg reversed the diabetes-induced decrease in LV end-diastolic elastance and the right shift of end-diastolic equilibrium volume intercept, without altering LV-developed pressure or end-systolic elastance. However, Mg did not prevent the elevation in blood glucose, total cholesterol, and triglycerides or the decrease in high-density lipoprotein cholesterol in diabetes. Plasma- or cardiac tissue Mg was not different among the treatment groups.

Conclusion: These results suggest that Mg treatment may attenuate diabetes-induced reduction in HRV and improve LV diastolic distensibility, without preventing hyperglycemia and dyslipidemia. Thus, Mg may have a modulatory role in the early stages of diabetic cardiovascular complications.
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http://dx.doi.org/10.1177/1074248416653831DOI Listing
March 2017

Cardioprotective and Anti-arrhythmic Effects of Magnesium Pretreatment Against Ischaemia/Reperfusion Injury in Isoprenaline-Induced Hypertrophic Rat Heart.

Cardiovasc Toxicol 2017 01;17(1):49-57

Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, 7925, South Africa.

The effects of magnesium (Mg) on ischaemic complications of pathological cardiac hypertrophy are unclear. In this study, we investigated effects of Mg pretreatment on ischaemia/reperfusion (I/R) injury in isoprenaline (ISO)-induced hypertrophic hearts. Wistar rats were treated for 7 days with different combinations of ISO (1.25 mg/kg) subcutaneously, MgSO (270 mg/kg) intraperitoneally, or vehicle (saline). On the eighth day, hearts were either subjected to regional I/R during Langendorff perfusion or histologically stained with haematoxylin and eosin and Masson's trichrome. Haemodynamic and electrocardiographic parameters were recorded using the PowerLab data-acquisition system. Infarcts were identified by triphenyltetrazolium chloride staining. Plasma Mg was measured using photometric assays. Mg pretreatment significantly decreased I/R-induced infarct size (p = 0.001) and the overall arrhythmia score (p < 0.001) of I/R-induced ventricular ectopics, ventricular tachycardia, and ventricular fibrillation in hypertrophic hearts, but not non-hypertrophied hearts. Mg also improved post-I/R left ventricular developed pressure in hypertrophic hearts. However, Mg did not reverse the ISO-induced myocyte thickening and interstitial fibrosis or increases in heart weight. Plasma Mg was not different among treatment groups. These results suggest that Mg pretreatment may protect against I/R-induced injury and malignant arrhythmias in hypertrophic hearts, possibly via mechanisms unrelated to long-lasting changes in plasma Mg or prevention of structural changes such as fibrosis.
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http://dx.doi.org/10.1007/s12012-015-9355-6DOI Listing
January 2017

Lack of cardioprotection by single-dose magnesium prophylaxis on isoprenaline-induced myocardial infarction in adult Wistar rats.

Cardiovasc J Afr 2015 Nov-Dec;26(6):242-9. Epub 2015 Jul 14.

Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.

Aim: Magnesium (Mg(2+)) is effective in treating cardiovascular disorders such as arrhythmias and pre-eclampsia, but its role during myocardial infarction (MI) remains uncertain. In this study, we investigated the effects of Mg(2+)pre-treatment on isoprenaline (ISO) -induced MI in vivo.

Methods: Rats divided into four groups were each pre-treated with either MgSO4 (270 mg/kg intraperitoneally) or an equivalent volume of physiological saline, prior to the ISO (67 mg/kg subcutaneously) or saline treatments. One day post-treatment, the electrocardiogram and left ventricular blood pressures were recorded. Infarcts were determined using 2,3,5-triphenyltetrazolium chloride staining, and serum markers of lipid peroxidation were measured with spectrophotometric assays.

Results: Mg(2+) pre-treatment neither altered the ISO-induced infarct size compared with ISO treatment alone (p > 0.05), nor reversed the low-voltage electrocardiogram or the prominent Q waves induced by ISO, despite a trend to decreased Q waves. Similarly, Mg(2+) did not prevent the ISO-induced decrease in peak left ventricular blood pressure or the decrease in minimal rate of pressure change. Mg(2+) did not reverse the ISO-induced gain in heart weight or loss of body weight. Neither ISO nor Mg(2+) altered the concentrations of lipid peroxidation markers 24 hours post MI induction.

Conclusion: Although Mg(2+) had no detrimental effects on electrical or haemodynamic activity in ISO-induced MI, the lack of infarct prevention may detract from its utility in MI therapy.
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http://dx.doi.org/10.5830/CVJA-2015-055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780018PMC
September 2016

Cardiac preconditioning with sphingosine-1-phosphate requires activation of signal transducer and activator of transcription-3.

Cardiovasc J Afr 2014 May-Jun;25(3):118-23

Hatter Institute for Cardiovascular Research in Africa, Chris Barnard Building, Medical School Campus, University of Cape Town, Cape Town, South Africa.

Aim: Sphingosine-1-phosphate (S1P) is a cardioprotective agent. Signal transducer and activator of transcription 3 (STAT-3) is a key mediator of many cardioprotective agents. We aimed to explore whether STAT-3 is a key mediator in S1P-induced preconditioning.

Methods: Langendorff-perfused hearts from Wistar rats and wild-type or cardiomyocyte-specific STAT-3 knockout mice were pre-treated with S1P (10 nmol/l), with or without the STAT-3 pathway inhibitor AG490, before an ischaemia-reperfusion insult. Triphenyltetrazolium chloride and Evans blue staining were used for the determination of infarct size. Western blot analysis was carried out on the S1P pre-treated hearts for detection of cytosolic, nuclear and mitochondrial phosphorylated and total STAT-3 proteins.

Results: Pre-treatment with S1P decreased the infarct size in isolated rat (5 ± 3% vs control 26 ± 8%, p < 0.01) and wild-type mouse hearts (13 ± 1% vs control 33 ± 3%, p < 0.05). This protective effect was abolished in the rat hearts pre-treated with AG490 (30 ± 10%, p = ns vs control) and in the hearts from STAT-3 knockout mice (35 ± 4% vs control 30 ± 3%, p = ns). Levels of phosphorylated STAT-3 were significantly increased in both the nuclear (p < 0.05 vs control) and mitochondrial (p < 0.05 vs control) fractions in the S1P pre-treated hearts, but remained unchanged in the cytosolic fraction (p = ns vs control).

Conclusion: These novel results demonstrate that pharmacological preconditioning with S1P in the isolated heart is mediated by activation of mitochondrial and nuclear STAT-3, therefore suggesting that S1P may be a novel therapeutic target to modulate mitochondrial and nuclear function in cardiovascular disease in order to protect the heart against ischaemia-reperfusion.
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http://dx.doi.org/10.5830/CVJA-2014-016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120131PMC
July 2015

Oleanolic acid: a novel cardioprotective agent that blunts hyperglycemia-induced contractile dysfunction.

PLoS One 2012 16;7(10):e47322. Epub 2012 Oct 16.

Cardio-Metabolic Research Group, Department of Physiological Sciences, Stellenbosch University, Stellenbosch, South Africa.

Diabetes constitutes a major health challenge. Since cardiovascular complications are common in diabetic patients this will further increase the overall burden of disease. Furthermore, stress-induced hyperglycemia in non-diabetic patients with acute myocardial infarction is associated with higher in-hospital mortality. Previous studies implicate oxidative stress, excessive flux through the hexosamine biosynthetic pathway (HBP) and a dysfunctional ubiquitin-proteasome system (UPS) as potential mediators of this process. Since oleanolic acid (OA; a clove extract) possesses antioxidant properties, we hypothesized that it attenuates acute and chronic hyperglycemia-mediated pathophysiologic molecular events (oxidative stress, apoptosis, HBP, UPS) and thereby improves contractile function in response to ischemia-reperfusion. We employed several experimental systems: 1) H9c2 cardiac myoblasts were exposed to 33 mM glucose for 48 hr vs. controls (5 mM glucose); and subsequently treated with two OA doses (20 and 50 µM) for 6 and 24 hr, respectively; 2) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) for 60 min, followed by 20 min global ischemia and 60 min reperfusion ± OA treatment; 3) In vivo coronary ligations were performed on streptozotocin treated rats ± OA administration during reperfusion; and 4) Effects of long-term OA treatment (2 weeks) on heart function was assessed in streptozotocin-treated rats. Our data demonstrate that OA treatment blunted high glucose-induced oxidative stress and apoptosis in heart cells. OA therapy also resulted in cardioprotection, i.e. for ex vivo and in vivo rat hearts exposed to ischemia-reperfusion under hyperglycemic conditions. In parallel, we found decreased oxidative stress, apoptosis, HBP flux and proteasomal activity following ischemia-reperfusion. Long-term OA treatment also improved heart function in streptozotocin-diabetic rats. These findings are promising since it may eventually result in novel therapeutic interventions to treat acute hyperglycemia (in non-diabetic patients) and diabetic patients with associated cardiovascular complications.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3473042PMC
March 2013
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