OpenUCT :: Browsing by Author "Gwanyanya, Asfree"

Browsing by Author "Gwanyanya, Asfree"

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Open Access
A study on the role of oxidative stress and protein kinase signalling in hyperglycaemia induced cardiac remodelling
(2023) Amtha, Nikhil; Gwanyanya, Asfree
Background Almost one-third of all deaths in patients with uncontrolled diabetes mellitus and hyperglycaemia are due to cardiovascular diseases. Chronic exposure of the heart to hyperglycaemia leads to a maladaptation called pathological cardiac remodelling and occurs via oxidative stress due to excess production of reactive oxygen species (ROS). In the heart, ROS modulates cardiac differentiation, cardiomyocyte proliferation, and myocardial tissue growth via ROS-sensitive protein kinases such as the mitogen-activated protein kinase (MAPK). Although there are several different MAPKs, the p38 MAPKs are involved in cardiogenesis and implicated in stimulating myocyte apoptosis, hypertrophy, or even antiapoptotic effects. As such, the role of p38 MAPKs in diabetic cardiac remodelling, especially during cardiac development, remains unclear. This study aims to elucidate the effect of hyperglycaemia on the p38 MAPK signalling pathway in a cardiac developmental model. Methods Pluripotent mouse embryonic stem cells (mESCs) were differentiated in vitro into cardiaclike pulsatile embryoid bodies (EBs) using the hanging drop method. Once pulsatile, EBs were further cultured for 72 hours in either baseline (25mM) or high glucose (50mM) media or with the pro-oxidant hydrogen peroxide (100μM). Changes in EB morphology and beating characteristics were observed using transmitted light microscopy. Immunocytochemistry and fluorescence microscopy imaging was used to detect changes in biomarkers. The nuclear uptake of propidium iodide (PI) was used to evaluate cell viability, whereas the 5-ethynyl-1- deoxyuridine (EdU) assay was used to determine cell proliferation. Western blot was used to analyse protein expression. Results Treatment with hydrogen peroxide stunted EB growth and decreased EB diameter, consistent with the presence of oxidative stress. High glucose increased the number of pyknotic-like nuclei and reduced the number of EdU-positive nuclei. Furthermore, hyperglycaemia elevated the expression of phosphorylated p38 MAPK, without altering total p38 MAPK expression levels. Inhibition of p38 MAPK by SB203580 in high glucose attenuated the increased number of pyknotic-like nuclei in high glucose and enhanced the number of EdUpositive nuclei compared to high glucose alone. High glucose also reduced the expression of the mitochondrial fusion regulatory protein, optic atrophy-1 (OPA1), with the inhibition of p38MAPK in high glucose attenuating this effect. Conclusion Hyperglycaemia induced pyknotic-like phenomenon, suppressed the proliferation, and reduced mitochondrial fusion protein machinery of mESC-derived cardiac-like cells. These effects were likely triggered by a mild form of oxidative stress and involved the activation of p38 MAPK. The findings provide insights into the mechanisms underlying diabetic developmental cardiac remodelling and identify p38MAPKs as a potential therapeutic target.
Open Access
An exploration of the molecular mechanisms underlying the effects of hyperglycaemia on the autorrhythmicity of cardiac-like stem cells
(2023) Menzele, Amanda; Gwanyanya, Asfree
Introduction Diabetes mellitus with uncontrolled hyperglycaemia is a major risk factor for heart rhythm disturbances. Hyperglycaemia during pregnancy is particularly concerning, as offspring of poorly controlled diabetic mothers are at an increased risk of developing life-long serious cardiovascular complications. Although structural abnormalities such as congenital heart defects and hypertrophic cardiomyopathy are by far the most common sequelae in these infants, it is becoming increasingly apparent that a vulnerability towards malignant dysrhythmias is far more prevalent than generally reported in the literature. Unfortunately, the mechanistic link between hyperglycaemia and impaired foetal cardiac electrophysiology is poorly understood. Using a cardiac developmental cellular model, this study aimed to explore the effects of hyperglycaemia on the autorrhythmicity of mouse embryonic stem cell (mESC)-derived cardiac-like cells.
Open Access
The effects of magnesium treatment on short-term changes in heart rate variability, ventricular function and lipid profile in streptozotocin-induced diabetic rats
(2017) Amoni, Matthew; Gwanyanya, Asfree; Kelly-Laubscher, Roisin
INTRODUCTION: Diabetes mellitus is a major and rapidly growing worldwide health problem, causing mortality largely in developing countries such as South Africa. Diabetes induces life threatening cardiovascular complications including cardiac autonomic neuropathy, ventricular dysfunction and dyslipidaemia, which are dependent on the duration and severity of the diabetes. Most complications are identified at a late, irreversible stage following long-standing diabetes; therefore, early detection and treatment of cardiovascular complications may reverse impairments and improve outcomes. The early treatment of diabetic complications remains ineffective, as the associated underlying features, such as electrolyte disturbances, are poorly understood. A key electrolyte disturbance in diabetes is hypomagnesaemia, which is also an independent cardiovascular risk factor. However, the effects of magnesium (Mg²⁺) supplementation are unclear. Therefore, this study investigated the effects of Mg²⁺ treatment on the early manifestations of streptozotocin (STZ)-induced diabetic cardiac complications. METHODS: Adult male Wistar rats were treated once with STZ (50 mg/kg, i.p.) or vehicle (citrate), and daily for seven days with MgSO4 (270 mg/kg, i.p.) or saline. Blood glucose and body weight were monitored daily. On the eighth day, in vivo tail-pulse plethysmography was recorded for analysis of heart rate variability (HRV), a marker of cardiac autonomic function. Ex vivo, Langendorff-based left ventricular (LV) pressure-volume parameters were measured using an intraventricular balloon. Other hearts were stained with Masson's trichrome and haematoxylin and eosin for histological analysis. Cardiac tissue Mg²⁺ concentration as well as plasma lipid- and Mg²⁺ levels were measured by colorimetric assays. RESULTS: Diabetes reduced heart rate and increased the low-frequency (LF)/high-frequency (HF) power ratio. Mg²⁺ treatment prevented theses diabetes-induced changes in heart rate and in the low-frequency (LF)/high-frequency (HF) power ratio (p < 0.05, n = 9/group). In addition, Mg²⁺ restored orthostatic stress induced changes in heart rate, and LF/HF ratio in diabetic rats (p < 0.05, n = 9/group). In isolated hearts, Mg²⁺ reversed the diabetes-induced decrease in LV end-diastolic elastance (p < 0.05, n = 6/group) and the right shift of end diastolic equilibrium volume intercept from 49 ± 6 μ L to 25 ± 5 μL (p < 0.05, n = 6/group), without altering LV developed pressure or end systolic elastance. Diabetes significantly increased plasma triglyceride, total cholesterol and blood glucose (p < 0.05, n = 7/group), and significantly decreased body weight (p < 0.05, n ≥ 16/group) compared to control, but these changes were not prevented by Mg²⁺ treatment. Neither diabetes nor Mg²⁺ treatment altered plasma- and tissue Mg²⁺ levels. Histologically, diabetes and Mg²⁺ treatment also did not alter cardiomyocyte size or the amount of interstitial collagen in myocardial tissue. CONCLUSION: These results show that Mg²⁺ treatment attenuates diabetes-induced autonomic dysfunction and improves LV diastolic distensibility in short-term diabetes. However, the diabetic metabolic disturbances of hyperglycaemia and dyslipidaemia, the changes in cardiac microstructure or the plasma- and cardiac tissue Mg²⁺ levels were uninfluenced by Mg²⁺ treatment. This suggests that Mg²⁺ exerted its beneficial effects independent of these factors, highlighting the underling mechanisms remain to be clarified. The Mg²⁺ levels not measured in this study by which changes could have been mediated was intracellularly; an aspect that should be further explored in future studies. Furthermore, whether these effects would be translatable to chronic diabetes is an important next question. Thus, the results of this study suggest that Mg²⁺ may have a modulatory role in treating early diabetic cardiovascular complications, but future studies will need to clarify the underlying mechanisms.
Open Access
Effects of Mg²⁺ pretreatment and the modulation of Mg²⁺-sensitive cardiac ion channels on Ca²⁺ paradox phenomenon in the heart
(2016) Alatrag, Fatma; Gwanyanya, Asfree; Kelly-Laubscher, Roisin
The aim of this study was to investigate the effects of Mg²⁺ pretreatment and of pharmacological inhibitors of TRPM7 channels on CP-induced cardiac injury in the isolated rat heart.
Open Access
Investigating the integrity of the vasculature and structural relationships of pericytes, astrocytes and the endothelial glycocalyx in an ex vivo hyperglycaemic rat retinal model
(2022) Musa, Glory Chinuru; Van, der Merwe Elizabeth; Gwanyanya, Asfree; Isaacs, Ashwin
Background: Diabetes mellitus-induced retinopathy is the leading cause of adult-onset blindness. The retinopathy is characterised by the degeneration of the retinal microvascular and neural components that form the blood retinal barrier (BRB), and is due to diabetic metabolic derangements such as hyperglycaemia. The cellular components of the BRB include endothelial cells, pericytes and the glial cells (mainly astrocytes), which together maintain the integrity and barrier function of the retinal vasculature. However, there is limited data regarding the interconnecting biochemical pathways that lead to pericyte loss, astrocyte degeneration, and endothelial dysfunction as well as the thinning of the glycocalyx in the retinal vasculature of diabetics. As such, the underlying mechanism of how hyperglycaemia induces retinal damage is not fully understood, particularly at the early stages of the disease. Aim and Objectives: To establish and validate an ex vivo rat retinal model and use a multiimmunolabelled approach on the retina to study the effects of hyperglycaemia on the vasculature and cellular components of the BRB, including effect of time and the retinal preparation type. Methods: Eyes of euthanised Wistar and Sprague-Dawley adult rats (n = 68) were enucleated and the retinae were either dissected out (explant) or kept in situ after removal of the anterior segment, lens and vitreous (eyecup). Retinae were superfused continuously (for 1-, 2- or 3 hours) in a chamber with oxygenated Krebs-Henseleit buffer containing either physiological glucose (5.5 mmol/L; control group) or high glucose (25 mmol/L; hyperglycaemic group). For longer incubation (48 hours), explants were cultured in Dulbecco's Modified Eagle Medium containing the above glucose concentrations. Retinae were multi-immunolabelled to identify pericytes, astrocytes and the glycocalyx protein syndecan-1 with anti-neuron-glial 2 antigen (NG2), anti-glial fibrillary acidic protein (GFAP), and anti-syndecan-1 antibodies respectively. Retinal blood vessels were detected with FITC-conjugated lycopersicon esculentum (Tomato) lectin. Fluorescent signals were detected using confocal microscopy imaging where Z-stack images were randomly sampled from the mid-peripheral retina. Images were analysed using Image J software. Additionally, western blotting was used to determine the abundance of syndecan-1 and heat shock proteins in the rat retina. P value < 0.05 was considered statistically significant. Results: Retinal blood vessels, pericytes and astrocytes showed normal morphology in both explant and eyecup of normoglycaemia retinae, with no difference in fluorescence intensity between explant and eyecup preparations at each time point (1-3 hours). Similarly, there was no change in the vascular-associated syndecan-1 signal intensity over time. However, the syndecan-1 intensity was generally weak and localised mainly to the retinal arteries and their branches, but rarely in capillaries and was unevenly distributed throughout the entire retina in both retinal preparation types. Under hyperglycaemia, at the 3-hour time point of perfusion, the vessel width was reduced in the eyecup group, the neuron glial 2 (NG2) fluorescence intensity on pericytes was diminished with a noticeable reduction in number of pericyte nuclei bulge in the lower vascular bed in the explant and eyecup groups. Although the area coverage and fluorescence signal intensity of astrocytes did not change, retraction of astrocyte processes and signs of cellular disintegration were more evident in the hyperglycaemic eyecup group compared to that in the explant group. Syndecan-1 signal intensity was raised in hyperglycaemia compared to controls in the eyecup group. The preliminary investigation on retinae cultured for 48 hours showed signs of fragmentation and morphological deterioration of the BRB, which included narrowing of blood vessels, loss of pericytes and disintegration of astrocytes, especially in the hyperglycaemic group. Syndecan-1 signal intensity was also lower in the hyperglycaemic groups compared to the control groups cultured for 48 hours . Syndecan1 protein abundance in the 3-hour superfused retina using western blotting was significantly higher in the hyperglycaemic group than in control. Heat shock proteins showed higher expression in hyperglycaemic rat retina compared to the normoglycaemic group. Conclusion: This study validated the suitability of the ex vivo rat retinal model to study the components of the BRB. The study revealed that there is no significant difference between the retinal preparations (explants vs eyecup) and that the BRB is still structurally intact up to 3 hours in normoglycaemic conditions. The subtle morphological changes of the BRB (blood vessels, pericytes and astrocytes) induced by hyperglycaemia which were more apparent in the lower vascular layers,suggests that this ex vivo model is suitable to study the early pathogenesis of diabetic retinopathy. Furthermore, this study showed that syndecan-1 levels were affected by hyperglycaemia ex vivo, and that this occurred prior to morphological changes to the other BRB structures, thus supporting the notion that syndecan-1 plays a role in the pathophysiology of DR. Preliminary data suggest that heat shock proteins may play a role in response to hyperglycemia-induced oxidative stress.
Open Access
Investigation of the mechanisms underlying the effects of hyperglycaemia on cardiac structural and electrical remodelling
(2022) Aboalgasm, Hamida; Gwanyanya, Asfree; Ballo, Robea
Background: Diabetes mellitus with uncontrolled hyperglycaemia is a major cause of cardiovascular complications and mortality. The developing foetal heart in-utero is particularly susceptible to hyperglycaemia through pathological remodelling, which results in life-long structural abnormalities such as cardiomyopathy and electrical defects like arrhythmias. However, the underlying mechanisms and potential therapeutic drug targets remain unclear. In this study, a cardiac developmental cellular model was used to study hyperglycaemia-induced remodelling. Methods: Mouse embryonic stem cells (mESCs) were differentiated into pulsatile, cardiac-like cells via embryoid body (EB) formation and cultured under baseline- or high glucose conditions. A Ca2+ -sensitive fluorescent dye Fluo-4 was used to measure calcium transients and a voltage-sensitive dye di-4-ANEPPS was used to record action potentials. Cellular biomarkers were detected using immunocytochemistry, confocal microscopy, and Western blotting as well as terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) and 5-ethynyl-2-deoxyuridine (EdU) assay. Results: Undifferentiated mESCs were positive for pluripotent transcription factors Nanog and Oct3/4, whereas the cardiac differentiated mESCs were positive for cardiac proteins troponin T, α-actinin 2, connexin 43, sarco-endoplasmic reticulum calcium ATPase 2 (SERCA 2) and α- and β-myosin heavy chain. Hyperglycaemia decreased the number of beating EBs, their beating rate, and their amplitude of contraction. It also decreased the calcium transient amplitude and the contractile response to ryanodine receptor stimulation by caffeine but did not alter the SERCA 2 expression. The amplitude and duration of action potentials in beating EBs were not altered by hyperglycaemia. However, structural changes included a decrease in EB size and expression of myofilament proteins, α-actinin and α- and β-myosin heavy chain and a disruption of the striated organization of the myofilaments. Hyperglycaemia increased the proportion of TUNEL-positive cells and the expression of the pro-apoptotic marker cytochrome c and decreased the anti-apoptotic protein Bcell lymphoma 2 but did not alter the mitochondrial staining with Mitotracker. It also increased the oxidative stress marker nitrotyrosine but did not alter the extent of EdU nuclear staining nor the expression of the receptor of advanced glycation end-product. The antioxidant n-acetyl cysteine decreased the fraction of hyperglycaemia-induced TUNEL-positive cells and improved the α-actinin striated pattern. Conclusion: Hyperglycaemia suppressed the cardiac differentiation and contractile activity of mESCs as well as disrupted the cardiac myofilament organisation and expression. These effects of hyperglycaemia were likely mediated by mitochondrial-dependent apoptosis triggered by oxidative stress as well as by the abnormalities in calcium signalling. These results have potential clinical implications in foetal diabetic cardiac disease and add novel insights into the mechanistic factors that represent new therapeutic drug targets in the developing foetal heart.
Open Access
Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current
(Multidisciplinary Digital Publishing Institute, 2021-08-14) Gwanyanya, Asfree; Andriulė, Inga; Istrate, Bogdan M.; Easmin, Farjana; Mubagwa, Kanigula; Mačianskienė, Regina
The cardiac Mg²⁺-sensitive, TRPM6, and TRPM7-like channels remain undefined, especially with the uncertainty regarding TRPM6 expression in cardiomyocytes. Additionally, their contribution to the cardiac action potential (AP) profile is unclear. Immunofluorescence assays showed the expression of the TRPM6 and TRPM7 proteins in isolated pig atrial and ventricular cardiomyocytes, of which the expression was modulated by incubation in extracellular divalent cation-free conditions. In patch clamp studies of cells dialyzed with solutions containing zero intracellular Mg²⁺ concentration ([Mg²⁺]_i) to activate the Mg²⁺-sensitive channels, raising extracellular [Mg²⁺] ([Mg²⁺]_o) from the 0.9-mM baseline to 7.2 mM prolonged the AP duration (APD). In contrast, no such effect was observed in cells dialyzed with physiological [Mg²⁺]_i. Under voltage clamp, in cells dialyzed with zero [Mg²⁺]_i, depolarizing ramps induced an outward-rectifying current, which was suppressed by raising [Mg²⁺]_o and was absent in cells dialyzed with physiological [Mg²⁺]_i. In cells dialyzed with physiological [Mg²⁺]_i, raising [Mg²⁺]_o decreased the L-type Ca²⁺ current and the total delayed-rectifier current but had no effect on the APD. These results suggest a co-expression of the TRPM6 and TRPM7 proteins in cardiomyocytes, which are therefore the molecular candidates for the native cardiac Mg²⁺-sensitive channels, and also suggest that the cardiac Mg²⁺-sensitive current shortens the APD, with potential implications in arrhythmogenesis.
Open Access
The role of the arterial glycocalyx in sphingosine-1- phosphate induced cardioprotection in the isolated heart of the Wistar rat
(2018) Araibi, Hala; Kelly-Laubscher, Roisin; Gwanyanya, Asfree; Van der Merwe, Elizabeth Lael
Background: Ischemic heart diseases (IHD) are a leading cause of death among cardiovascular diseases. Unfortunately, the myocardial damage due to ischemia in IHD may be worsened by reperfusion therapy, a phenomenon called ischemic-reperfusion (I/R) injury. Coronary vascular damage is a key feature of I/R injury. Among the coronary vascular structures, the endothelial glycocalyx is a delicate polysaccharide and protein-rich layer that plays an important role in the regulation of vascular permeability, and is easily damaged during I/R. Sphingosine-1-phosphate (S1P) is a membrane phospholipid metabolite that has been shown to protect the heart against I/R. It has also been shown to regulate the synthesis of glycocalyx, but its effects on coronary endothelial glycocalyx damage and possible mechanism during I/R are unknown. Therefore, we hypothesized that S1P-induced cardioprotection is mediated by modulation of the glycocalyx during I/R in the isolated rat heart. Methods: Isolated male Wistar hearts were perfused on a Langendorff system with Krebs-Henseleit buffer via retrograde perfusion at constant temperature and pressure. The hearts were stabilized and pre-treated with S1P (10 nM for 7 minutes) before inducing 20 minutes of global ischemia, followed by 60 minutes reperfusion. Functional parameters were recorded throughout the protocol, including left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), heart rate (HR) and coronary flow (CF). Ventricular infarct size was measured by using triphenyltetrazolium chloride stain. Coronary net filtration rate (NFR) was calculated as a ratio of the amount of transudate to CF. Cardiac edema was assessed by calculating the heart wet/dry weight ratio and histologically quantifying size of the interstitial compartment. The shedding of the glycocalyx was estimated by measuring the release of the glycocalyx component syndecan-1 in the coronary effluent using enzyme-linked immunosorbent assay (ELISA) and determining relative syndecan-1 staining intensity between groups in immuno-stained wax sections of perfusion-fixed hearts. In addition, the histo-morphology of the myocardium was assessed using hematoxylin and eosin staining. Results: The cardiac performance was depressed after I/R, as was reflected by decreased LVDP (P=0.02 vs. control), and an increased LVEDP (P<0.0001 vs. control). I/R also significantly increased infarct size (P=0.04 vs. control). Treatment with S1P before I/R significantly decreased infarct size (P=0.01 vs. I/R), but did not improve the post-ischemic decrease in LVDP or stabilize the LVEDP, and had no effect on CF. I/R significantly increased release of syndecan-1 in the coronary effluent (P=0.0002 vs. control). Immunohistochemically-stained imaging also revealed syndecan-1 staining intensity was significantly decreased or absent in ischemic hearts (P≤0.001 vs. control). Pretreatment with S1P had neither effect on syndecan-1 level in the coronary effluent nor on the intensity of syndecan-1 signal in immuno-stained sections (P=n.s vs. I/R). Histological analysis of cardiac edema revealed an increase in the extracellular area in ischemic hearts compared to the control hearts (P≤0.001 vs. control), and S1P treatment decreased the extracellular area (P≤0.01 I/R+S1P vs. I/R). The NFR, and heart wet/dry ratio were not significantly different post-reperfusion between the groups and S1P had no effect on these parameters. Conclusion: This study showed that pretreatment with S1P protects the heart against I/R injury, as was indicated by the decreased infarct size, and decreased extracellular cardiac edema. S1P had no effect on hemodynamic performance or the shedding of syndecan-1. These results suggest that S1P-induced cardioprotection is not mediated by protection of the glycocalyx via stabilization of syndecan-1. However, it is possible that S1P may stabilize other minor glycocalyx components which were not measured in this study, such as heparan sulphate and hyaluronic acid. This is the first study that evaluated syndecan-1 in the cardiac effluent of the isolated heart of rats with global ischemia, and the study opens up prospects for further investigation of the role of the glycocalyx in other models of I/R injury, such as the more clinically-relevant regional ischemia disease model.
Open Access
The effects of magnesium administration on cardiac ventricular function, heart rate variability, and myocardial morphological changes in a chronic diabetes disease model in rats
(2018) Aboalgasm, Hamida; Gwanyanya, Asfree
Introduction: Diabetes mellitus (DM) is a leading cause of morbidity and mortality all over the world, and the main cause of the mortality is cardiovascular complications. Such diabetic cardiovascular complications include coronary heart disease, cardiac autonomic neuropathy and ventricular dysfunction. Furthermore, DM is associated with electrolyte disturbances such as those involving potassium, calcium and magnesium (Mg2+). Among these electrolyte disturbances hypomagnesemia is common in diabetes and is associated with increased cardiovascular risk. Recent evidence has shown that Mg2+ supplementation can prevent cardiac autonomic dysfunction and improve ventricular compliance in acute DM. However, the underlying mechanisms of Mg2+ action and Mg2+ effects in chronic DM are unknown. Therefore, the present study explored the effects of Mg2+ administration and its possible mechanisms of action in chronic streptozotocin (STZ) induced diabetic rats. Methods: Adult male Wistar rats were injected intraperitoneally (i.p) once with either STZ (50 mg/Kg body weight) or the STZ vehicle (citrate buffer). The rats were then injected i.p once daily with either magnesium sulphate (MgSO4; 270 mg/Kg body weight) or the MgSO4 vehicle (normal saline) for 28 consecutive days. Blood glucose and body weight were measured throughout the period of the study. On day 28 of the experiments, in-vivo heart rate variability (HRV) parameters were measured to assess cardiac autonomic function using tail pulse plethysmography. Orthostatic stress was induced by tilting the animals from flat position to 70° head-up position. Ex-vivo hemodynamic and electrocardiograph (ECG) measurements were performed on a Langendorff perfusion system. Histological studies of ventricular tissue were performed using haematoxylin-eosin and Masson’s trichrome staining. Western blot analyses of the cardiac autonomic presynaptic marker (synaptophysin) and of the mitochondrial marker of oxidative stress (ATP5A) were performed on right atrial tissue. Plasma Mg2+ concentration was measured using automated photometric assays. Results: STZ treatment significantly increased the blood glucose level and decreased the body weight, and these STZ effects were not prevented by Mg2+ treatment. Diabetes decreased the root mean square differences of successive normal-to-normal intervals (RMSSD) and increased the low frequency (LF) /high frequency (HF) power ratio, which are both indicative of abnormal HRV. These diabetes effects on HRV parameters were significantly prevented by Mg2+ treatments (P < 0.05, STZ+Mg vs. STZ). DM also reduced both the heart rate and orthostatic stress-induced tachycardia, and these effects were reversed by Mg2+ treatment (P < 0.05, STZ+Mg vs. STZ). DM also decreased the left ventricular (LV) developed pressure and the maximal rate of LV pressure increase (+dP/dt), and these diabetic effects were prevented by Mg2+ treatment (P < 0.05, STZ+Mg vs. STZ). DM also decreased the maximal rate of LV pressure decline (-dP/dt) and the rate pressure product, but these parameters were not improved by Mg2+ treatment. DM and Mg2+ treatment did not affect the ECG waveforms and the coronary flow rate in all groups. Histologically, there were no differences in ventricular cardiomyocyte width or in the extent of interstitial fibrosis in all groups. Western blot analysis qualitatively showed a decrease in the expression of synaptophysin in DM that was prevented by Mg2+ treatment. Neither DM nor Mg2+ treatment altered ATP5A expression. The plasma Mg2+ concentration was not altered by DM or Mg2+ treatment. Conclusion: This study showed that Mg2+ treatment prevented cardiac autonomic dysfunction and improved hemodynamic function impairment in chronic DM. Based on the expression of synaptophysin, the mechanism through which Mg2+ improved cardiac autonomic function could involve the prevention of synaptic degradation in diabetes. The effects of Mg2+ on hemodynamic impairment in diabetes seemed to be unrelated to the Mg2+ effects on the cardiac histological structure or on the changes in coronary perfusion. Moreover, the overall effects of Mg2+ in diabetes were independent of its effects on the blood glucose level or the alteration of plasma Mg2+ level. Thus, Mg2+ treatment may have long-lasting therapeutic effects on ventricular dysfunction and cardiac autonomic impairment in chronic diabetes, but further studies are needed to explore the precise underlying mechanisms.

Browsing by Author "Gwanyanya, Asfree"

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