Article: Obesity and Cardiac Microvascular Function496Roux-en-y gastric bypass surgery reverses obesity-induced vascular dysfunction by blunting jnk2-endothelial activation497Involvement of the Fgf21 system in obesity-associated cardiomyopathy498Is low ATM protein responsible for myocardial insulin resistance associated with obesity?[Show abstract] [Hide abstract] ABSTRACT: Introduction Roux-en-Y gastric bypass (RYGB) reduces weight and long-term cardiovascular risk in obese patients. We showed that endothelial-mediated vasorelaxation improves rapidly in diet-induced obese (DIO) rats within 8 days after RYGB and is associated with reduced activation of JNK independently from weight loss. Purpose We investigated whether in vivo inhibition of JNK with two different JNK inhibitors in sham-operated rats mimics the beneficial endothelial effects of RYGB. Methods DIO rats underwent RYGB or sham surgery, and sham-operated ad libitum-fed rats received either vehicle (AL) or the unspecific JNK inhibitor SP600125 40mg/kg/day s.c. (SP) for 8 days post-surgery. In a second experiment, sham-operated rats received either control peptide TAT (TAT) or the highly specific JNK peptide inhibitor D-JNKi-1 20mg/kg/day s.c. (DJNK) for 8 days post-surgery. Thereafter, thoracic aortic rings were isolated and subjected to ex vivo isometric tension recordings. After submaximal contraction with norepinephrine (10-6mol/L), cumulative relaxation responses were performed to GLP-1 (7–36) amide (10-12 to 10-6mol/L) or insulin (10-11 to 10-5mol/L). In TAT and DJNK rats, some aortic rings were isolated as before and pre-incubated ex vivo with 5 uM DJNK for 30 min before vasodilation experiments. Western blot analyses of JNK, the inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on ser307, and downstream cellular insulin signaling including Akt, eNOS-ser1177 activatory phosphorylation and eNOS dimerization were performed on aortic tissue lysates. Results GLP-1- and insulin-induced vasodilation improved in RYGB and tended to improve in SP compared to AL rats. The specific JNK inhibitor DJNK completely mimicked the beneficial effects of RYGB surgery on endothelial function 8 days after surgery. Ex vivo aortic pre-incubation with DJNK improved the vascular relaxation of TAT rats, but did not further ameliorate the already restored vasodilation of rats receiving the in vivo DJNK treatment. Aortic protein phosphorylation of JNK2, but not of JNK1 were specifically decreased. IRS-1 ser307 phosphorylation was decreased, and the axis Akt-eNOS-ser 1177 phosphorylation and dimerization were increased in SP and DJNK rats similarly to RYGB, in comparison with their respective controls. Conclusion Pharmacological JNK inhibition mimics the beneficial effect of RYGB against obesity-induced vascular dysfunction by specifically blunting JNK2-endothelial activation. Our study suggests a novel JNK2-targeted mechanism for the vascular benefits after RYGB.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose There is an ongoing search for new drugs and drug targets to treat diseases like Alzheimer’s disease, cancer and type 2 diabetes (T2D). Both obesity and T2D are characterized by the development of a cardiomyopathy associated with increased hypertension and compensatory left ventricular hypertrophy. Small, specific glycogen synthase kinase-3 (GSK-3) inhibitors were developed to replace lithium chloride for use in psychiatric disorders. In addition, they were advocated as treatment for T2D since GSK-3 inhibition improves blood glucose handling. However, GSK-3 is a regulator of hypertrophic signalling in the heart via phosphorylation of NFATc3 and β-catenin respectively. In view of this, we hypothesized that chronic inhibition of GSK-3 will induce myocardial hypertrophy or exacerbate existing hypertrophy. Methods Rats with obesity-induced prediabetes were treated orally with GSK-3 inhibitor (CHIR118637 (CT20026)), 30 mg/kg/day for the last 8 weeks of a 20-week diet high in sugar content vs a control diet. Biometric and biochemical parameters were measured, echocardiography performed and localization and co-localization of NFATc3 and GATA4 determined in cardiomyocytes. Results Obesity initiated myocardial hypertrophy, evidenced by increased ventricular mass (1.158 ± 0.029 vs 0.983 ± 0.03 g) and enlarged cardiomyocytes (18.86 ± 2.25 vs 14.92 ± 0.50um2) in association with increased end-diastolic diameter (EDD = 8.48 ± 0.11 vs 8.15 ± 0.10 mm). GSK-3 inhibition (i) increased ventricular mass only in controls (1.075 ± 0.022 g) and (ii) EDD in both groups (controls: 8.63 ± 0.07; obese: 8.72 ± 0.15 mm) (iii) localized NFATc3 and GATA4 peri-nuclearly. Conclusion Indications of onset of myocardial hypertrophy in both control and obese rats treated with a GSK-3 inhibitor were found. It remains speculation whether these changes were adaptive or maladaptive.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Clinical data advocating an adverse effect of obesity on left ventricular (LV) systolic function independent of comorbidities is controversial. We hypothesized that in obesity with pre-diabetic insulin resistance, circulating fatty acids (FA's) become a valuable fuel source in the maintenance of normal systolic function. Methods: Male Wistar rats were fed a high caloric diet for 32 weeks to induce obesity. Myocardial LV systolic function was assessed using echocardiography and isolated heart preparations. Results: Aortic output was reduced in obese rat hearts over a range of filling pressures (for example: 15 cmH2O, obese: 32.6±1.2 ml/min vs. Control: 46.2±0.9 ml/min, p<0.05) when perfused with glucose alone. Similarly, the slope of the LV end-systolic pressure-volume relationship decreased, and there was a right shift in the LV end-systolic stress-strain relationship as determined in Langendorff perfused, isovolumic rat heart preparations in the presence of isoproterenol (10(-8)M) (LV En, obese: 791±62 g/cm(2) vs. Control: 1186±74 g/cm(2), p<0.01). The addition of insulin to the perfusion buffer improved aortic output while the addition of FA's completely normalized aortic output. LV function was maintained in obese animals in vivo during an inotropic challenge. Conclusions: Elevated circulating FA levels may be important to maintain myocardial systolic function in the initial stages of obesity and insulin resistance.
- [Show abstract] [Hide abstract] ABSTRACT: The ataxia-telangiectasia mutated (ATM) protein kinase is well known to play a significant role in the response to double stranded DNA breaks in the nucleus. Recently, it has become apparent that ATM is also involved in a large number of cytoplasmic processes and responses, some of which may contribute to metabolic and cardiovascular complications when disrupted. Due to its involvement in these processes, therapeutic activation of ATM could potentially be a novel approach for the prevention or treatment of cardiovascular disease. However, relatively little is currently known about the cardiovascular role of ATM. In this review, we highlight studies that have shed some light on the role of ATM in the cardiovascular context, namely in oxidative stress, atherosclerosis and metabolism, insulin resistance and cardiac remodeling.
- [Show abstract] [Hide abstract] ABSTRACT: Melatonin treatment has been shown to prevent the harmful effects of diet-induced obesity and reduce myocardial susceptibility to ischaemia-reperfusion injury (IRI) when administered from the onset of obesity. However, the exact mechanism whereby it exerts its beneficial actions on the heart in obesity and insulin resistance is unknown. In this study we investigated the effects of relatively short-term melatonin treatment on the heart in a rat model of diet-induced obesity. Control (C) and diet-induced obese (D) Wistar rats (fed for 20 weeks (wks)) were divided into 3 groups receiving drinking water with or without melatonin (4mg/kg/day) for the last 6 or 3 wks of experimentation. Isolated hearts were perfused in the working mode, subjected to regional (35min) or global ischaemia (15min) and reperfusion (2h); others were non-perfused (baseline). Myocardial infarct sizes as well as baseline and post-ischaemic activation of PKB/Akt, ERK42/44, GSK-3B and STAT-3 were determined. Blood was collected for study of metabolic parameters. Diet-induced obesity caused significant increases in body weight gain (14.5%), visceral adiposity (70.3%), fasting blood glucose (20%), serum insulin (55.6%) and triglyceride (84.2%) levels with a concomitant increase in post-ischaemic myocardial infarct size (41%) and a reduced cardiac output (12.7%). Melatonin treatment (both 3 and 6 wks) decreased serum insulin levels and the HOMA-index in the D group only (3 wks % reduction: 39%; 47.2%, p<0.05 vs untreated D respectively) with no effect on body weight gain, visceral adiposity, serum triglycerides and glucose levels. It also increased serum adiponectin levels in the D group (113% p<0.05 vs untreated D), reduced myocardial infarct sizes in both groups (3 wks %reduction: C 42.4%; D 61.6%) and activated baseline myocardial STAT-3, PKB/Akt, ERK42/44 and GSK-3< after 10 min reperfusion. Short-term melatonin administration to obese and insulin resistant rats reduced insulin resistance and protected the heart against ex vivo myocardial IRI independently of body weight gain and visceral adiposity. Melatonin-induced cardioprotection was associated with concomitant activation of the RISK and SAFE pathways. Published conference paper
- [Show abstract] [Hide abstract] ABSTRACT: Chronic melatonin treatment has been shown to prevent the harmful effects of diet-induced obesity and reduce myocardial susceptibility to ischaemia-reperfusion injury (IRI). However, the exact mechanism whereby it exerts its beneficial actions on the heart in obesity/insulin resistance remains unknown. Herein, we investigated the effects of relatively short-term melatonin treatment on the heart in a rat model of diet-induced obesity. Control and diet-induced obese Wistar rats (fed a high calorie diet for 20 weeks) were each subdivided into 3 groups receiving drinking water with or without melatonin (4mg/kg/day) for the last 6 or 3 weeks of experimentation. A number of isolated hearts were perfused in the working mode, subjected to regional or global ischaemia-reperfusion; others were non-perfused. Metabolic parameters, myocardial infarct sizes, baseline and post-ischaemic activation of PKB/Akt, ERK42/44, GSK-3β and STAT-3 were determined. Diet-induced obesity caused increases in body weight gain, visceral adiposity, fasting blood glucose, serum insulin and triglyceride levels with a concomitant cardiac hypertrophy, large post-ischaemic myocardial infarct sizes and a reduced cardiac output. Melatonin treatment (3 and 6 weeks) decreased serum insulin levels and the HOMA-index (p<0.05) with no effect on weight gain (after 3 weeks), visceral adiposity, serum triglyceride and glucose levels. It increased serum adiponectin levels, reduced myocardial infarct sizes in both groups and activated baseline myocardial STAT-3 and PKB/Akt, ERK42/44 and GSK-3β during reperfusion. Overall, short-term melatonin administration to obese/insulin resistant rats reduced insulin resistance and protected the heart against ex vivo myocardial IRI independently of body weight change and visceral adiposity.
- [Show abstract] [Hide abstract] ABSTRACT: Background Although obesity is still considered a risk factor in the development of cardiovascular disorders, recent studies suggested that it may also be associated with reduced morbidity and mortality, the so-called “obesity paradox”. Experimental data on the impact of diabetes, obesity and insulin resistance on myocardial ischaemia/reperfusion injury are controversial. Similar conflicting data have been reported regarding the effects of ischaemic preconditioning on ischaemia/reperfusion injury in hearts from such animals. The aim of the present study was to evaluate the susceptibility to myocardial ischaemia/reperfusion damage in two models of diet-induced obesity as well as the effect of ischaemic and pharmacological preconditioning on such hearts. Methods Three groups of rats were fed with: (i) normal rat chow (controls) (ii) a sucrose-supplemented diet (DIO) (iii) a high fat diet (HFD). After 16 weeks, rats were sacrificed and isolated hearts perfused in the working mode and subjected to 35 min regional ischaemia/60 min reperfusion. Endpoints were infarct size and functional recovery. Infarct size was determined, using tetrazolium staining. Activation of PKB/Akt and ERKp44/p42 (RISK pathway) during early reperfusion was determined using Western blot. Statistical evaluation was done using ANOVA and the Bonferroni correction. Results Infarct sizes of non-preconditioned hearts from the two obese groups were significantly smaller than those of the age-matched controls. Ischaemic as well as pharmacological (beta-adrenergic) preconditioning with a beta2-adrenergic receptor agonist, formoterol, caused a significant reduction in infarct size of the controls, but were without effect on infarct size of hearts from the obese groups. However, ischaemic as well as beta-preconditioning caused an improvement in functional performance during reperfusion in all three groups. A clear-cut correlation between the reduction in infarct size and activation of ERKp44/p42 and PKB/Akt was not observed: The reduction in infarct size observed in the non-preconditioned hearts from the obese groups was not associated with activation of the RISK pathway. However, beta-adrenergic preconditioning caused a significant activation of ERKp44/p42, but not PKB/Akt, in all three groups. Conclusions Relatively long-term administration of the two obesity-inducing diets resulted in cardioprotection against ischaemia/reperfusion damage. Further protection by preconditioning was, however, without effect on infarct size, while an improvement in functional recovery was observed.
- [Show abstract] [Hide abstract] ABSTRACT: Aims In isolated rat heart perfusion experiments, drug administration occurs via retrograde perfusion. This can be done in the non-recirculating mode (coronary effluent is discarded), or recirculating mode (coronary effluent is collected and reused). It was recently observed in our lab while using sanguinarine, an MKP-1 inhibitor, that there were differences in outcomes depending on the mode of recirculation used. Methods and Results Hearts from control (C); diet-induced obese (DIO) Wistar rats and their age matched controls (AMC) were perfused on the rig. Hearts received buffer (control) , insulin, sanguinarine, insulin + sanguinarine combination or methanol (vehicle) for 15mins pre- and 10mins post-ischemia in either a non- or re-circulating manner. Hearts were subjected to 15mins global ischemia and 30mins reperfusion. Mechanical function was documented pre- and post-ischemia . When not-recirculated , sanguinarine alone and in combination with insulin in C, DIO and AMC groups, caused a significant decrease in functional recovery during reperfusion. However, when the coronary effluent was recirculated, hearts perfused with sanguinarine or sanguinarine + insulin exhibited a significant recovery in function when compared with their non-recirculation counterparts (p < 0.01). No differences were seen with either control, insulin nor vehicle hearts. Conclusion Sanguinarine elicited a vast improvement in perfusion outcomes when recirculated compared to non-recirculation . Since this was seen during perfusion only when sanguinarine was present, it is possible that recirculating reperfusion of the drug caused profound changes in its composition. More investigation is needed into the mechanisms involved. Thus caution should be exercised by researchers when designing a perfusion protocol for drug research.
Chapter: Melatonin and the Metabolic Syndrome[Show abstract] [Hide abstract] ABSTRACT: The ongoing worldwide obesity epidemic is paralleled by an elevated incidence of the metabolic syndrome, a disorder referred to as a clustering of metabolic abnormalities that increase the risk for cardiovascular disease and type 2 diabetes. Considered as a multifunctional molecule, the pineal gland hormone melatonin is also involved in body fat mass and energy metabolism regulation. A large body of evidence supports the beneficial effects of melatonin on the cardiovascular function in normal and pathophysiological conditions. However, melatonin’s role in cardiovascular risk factors such as obesity and other related disorders including the metabolic syndrome needs further investigations, particularly in humans. This chapter will address the effects of melatonin on the metabolic syndrome focusing on obesity and insulin-resistant conditions. Since cardiovascular disease is the primary outcome of the metabolic syndrome, the effects of melatonin on cardiovascular function will be also described focusing on normal and pathological conditions. In view of the current knowledge, we aim to reveal the potential clinical relevance of melatonin or melatonin receptor agonists in the setting of obesity-induced metabolic syndrome.
- [Show abstract] [Hide abstract] ABSTRACT: Since it was identified as the elusive endothelium-derived relaxing factor (EDRF) in the 1980s, nitric oxide (NO) has rapidly gained status as one of the most important signalling molecules in the cardiovascular system. Now, 20 years later, NO is regarded by most to be a ubiquitous mediator of cardioprotection. However, due to various complex underlying cellular mechanisms, the actions of NO often seem to be contradictory. This article sheds light on some of the mechanisms that may influence the variable actions of NO in the heart. Its role in conditions of oxygen deprivation (ischaemia and hypoxia) in particular is relevant to basic scientists and clinicians alike, since the prevalence of ischaemic heart disease is on the rise (in both the developed and the developing worlds) and novel therapeutic options are in constant demand. NO is a promising candidate molecule that could find therapeutic application. For this to be achieved, a sound understanding of this simple molecule and its complex actions is required.
- [Show abstract] [Hide abstract] ABSTRACT: Glycogen synthase kinase-3 (GSK-3) is a serine-threonine protein kinase, discovered as a regulator of glycogen synthase. GSK-3 may regulate the expression of SERCA-2a potentially affecting myocardial contractility. It is known to phosphorylate and inhibit IRS-1, thus disrupting insulin signalling. This study aimed to determine whether myocardial GSK-3 protein and its substrate proteins are dysregulated in obesity and insulin resistance, and whether chronic GSK-3 inhibition can prevent or reverse this. Weight matched male Wistar rats were rendered obese by hyperphagia using a special diet (DIO) for 16 weeks and compared to chow fed controls. Half of each group was treated with the GSK-3 inhibitor CHIR118637 (30 mg/kg/day) from week 12 to16 of the diet period. Biometric and biochemical parameters were measured and protein expression determined by Western blotting and specific antibodies. Ca(2+)ATPase activity was determined spectrophotometrically. Cardiomyocytes were prepared by collagenase perfusion and insulin stimulated 2-deoxy-glucose uptake determined. DIO rats were significantly heavier than controls, associated with increased intra-peritoneal fat and insulin resistance. GSK-3 inhibition did not affect weight but improved insulin resistance, also on cellular level. It had no effect on GSK-3 expression but elevated its phospho/total ratio and elevated IRS-2 expression. Obesity lowered SERCA-2a expression and activity while GSK-3 inhibition alleviated this. The phospho/total ratio of phospholamban underscored inhibition of SERCA-2a in obesity. In addition, signs of myocardial hypertrophy were observed in treated control rats. GSK-3 inhibition could not reverse all the detrimental effects of obesity but may be harmful in normal rat hearts. It regulates IRS-2, SERCA-2a and phospholamban expression but not IRS-1.
- [Show abstract] [Hide abstract] ABSTRACT: Melatonin (N-acetyl-5-methoxytryptamine) has been shown by several workers to protect the heart against ischaemia/reperfusion damage. Melatonin, both in the picomolar and micromolar range, significantly reduces infarct size and improves functional recovery during reperfusion. This may be due to its free radical scavenging and anti-oxidant effects, while the melatonin receptor and its marked anti-adrenergic actions may also be involved. The latter is mediated by nitric oxide (NO), guanylyl cyclase and protein kinase C (PKC). Melatonin-induced cardioprotection is associated with activation of protein kinase B (PKB), extracellular signal-regulated kinase (ERK1/2) (the Reperfusion Injury Salvage Kinase (RISK) pathway) and signal activator and transducer 3 (STAT-3) (the Survivor Activating Factor Enhancement (SAFE) pathway) during reperfusion and inhibition of the mitochondrial permeability transition pore (MPTP). Very little is known about the effect of melatonin on myocardial substrate metabolism. Melatonin was demonstrated to be involved in the regulation of whole body glucose homeostasis via its effects on pancreatic insulin secretion and may thus indirectly affect myocardial substrate metabolism in a circadian manner.
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to investigate the mechanism of beta-adrenergic preconditioning (BPC). The roles of adenosine and its receptor subtypes, the generation of oxygen free radicals (ROS) and activation of the KATP channels as well as the phosphoinositide-3-kinase (PI3K)/PKB/Akt and extracellular signal-regulated kinase (ERK) signal transduction pathways during the triggering and mediation phases were evaluated. Using the isolated working rat heart, BPC was elicited by administration of denopamine (beta1 adrenergic receptor agonist, 10−7 M), isoproterenol (beta1/beta2 adrenergic receptor agonist, 10−7 M) or formoterol (beta2 adrenergic receptor agonist, 10−9 M) for 5 min followed by 5 min washout. Index ischaemia was 35 min regional ischaemia and infarct size determined using the tetrazolium method. The role of adenosine was studied using adenosine deaminase and selective antagonists as well as the PI3K and ERK inhibitors, wortmannin and PD98,059, bracketing the triggering and mediating phases. Involvement of ROS, PKC, the mitochondrial KATP channels, release of endogenous opioids and bradykinin was studied by administration of N-acetyl cysteine (NAC), bisindolylmaleimide, the KATP channel blocker 5-hydroxydecanoate (5-HD), naloxone or HOE140, respectively. Activation of PKB/Akt and ERKp44/p42 during triggering and reperfusion was determined by Western blot. Preconditioning with all three beta-adrenergic receptor agonists caused a reduction in infarct size and an improvement in postischaemic function. BPC preconditioning with isoproterenol, denopamine or formoterol was abolished by the adenosine A3 receptor antagonist MRS1191 during both the triggering and mediation phases. Isoproterenol-induced preconditioning (beta1/beta2 PC) was attenuated by MRS1754, an adenosine A2B receptor antagonist, during the triggering phase and abolished during reperfusion. The mediation phase of beta1/beta2 PC was also abolished by ZM241385, an adenosine A2A antagonist. The free radical scavenger NAC caused a significant attenuation of cardioprotection induced by isoproterenol when administered during both trigger and mediation phases, while being effective during the trigger phase with denopamine and during reperfusion in formoterol preconditioned hearts. The mitochondrial KATP channel blocker, 5-HD, was without effect on beta1/beta2 PC during both triggering and mediation phases. BPC in rat hearts is dependent on activation of the A3 adenosine receptors by endogenously produced adenosine and production of free radicals during the triggering and mediation phases while the A2A and A2B adenosine receptors participate mainly during reperfusion. The mitochondrial KATP channels do not contribute to cardioprotection at any stage. Activation of ERK and PI3K/PKB/Akt during the triggering and reperfusion phases is associated with cardioprotection.
Conference Paper: beta-Adrenergic Preconditioning Is Adenosine Mediated
- [Show abstract] [Hide abstract] ABSTRACT: To investigate the effects of dietary creatine supplementation alone and in combination with exercise on basal cardiac function, susceptibility to ischaemia/reperfusion injury and mitochondrial oxidative function. There has been an increase in the use of creatine supplementation among sports enthusiasts, and by clinicians as a therapeutic agent in muscular and neurological diseases. The effects of creatine have been studied extensively in skeletal muscle, but not in the myocardium. Male Wistar rats were swim-trained for 8 weeks, 5 days per week. Hearts were excised and either freeze-clamped for biochemical analysis or perfused on the isolated heart perfusion system to assess function and ischaemia/reperfusion tolerance. Mechanical function was documented in working heart and retrograde mode. The left coronary artery was ligated and infarct size determined. Mitochondrial oxidative capacity was quantified. Aortic output recovery of hearts from the sedentary controls (CSed) was significantly higher than those from creatine-supplemented sedentary (CrSed), creatine-supplemented exercised (CrEx) as well as control exercised (CEx) groups. Ischaemic contracture of hearts from CrEx was significantly higher than that of CSed. There were no differences in infarct size and mitochondrial oxygen consumption. This study suggests that creatine supplementation has no effects on basal cardiac function but reduces myocardial tolerance to ischaemia in hearts from exercise-trained animals, by increasing the ischaemic contracture and decreasing reperfusion aortic output. Exercise training alone also significantly decreased aortic output recovery. However, the exact mechanisms for these adverse myocardial effects are unknown and need further investigation.
- [Show abstract] [Hide abstract] ABSTRACT: The metabolic syndrome is recognized as a cluster of disturbances associated with obesity, type 2 diabetes and hypertension. Over the past two decades, the number of people with the metabolic syndrome has increased at an alarming rate. This increase is associated with the global epidemic of both obesity and diabetes. Cardiovascular mortality is increased among diabetics and obesity-related insulin-resistant patients, and obesity is currently recognized as independent risk factor for cardiovascular disease. We aimed to establish the effects of a short period of an altered diet on the heart using a rat model of hyperphagia-induced obesity (diet supplemented with sucrose and condensed milk for 8 weeks = DIO) compared to age-matched controls. Isolated, perfused hearts were subjected to global or regional ischaemia/reperfusion. Function on reperfusion was recorded and infarct size determined. A plasma lipid profile was established via HPLC-based methods and proteins involved in metabolic signalling determined either by western blotting or RT-PCR. 8 weeks of diet resulted in whole-body but not myocardial insulin resistance, increased plasma triglyceride and phospholipid levels as well as increased lipid peroxidation. Despite the similar baseline function, hearts from DIO animals showed significantly poorer postischaemic recovery than controls (41.9 % RPP recovery vs 57.9 %, P < 0.05, n = 7-11/group) but surprisingly, smaller infarct size (24.95 ± 1.97 vs 47.26 ± 4.05 % of the area at risk, P < 0.005, n = 8/group). Basal phosphorylation of PKB/Akt was elevated but IRS-1 and SERCA-2 expression severely downregulated. In conclusion, after only 8 weeks of a slight change in diet, the rat heart shows signs of metabolic remodelling. Some of these changes may be protective but others may be detrimental and eventually lead to maladaptation.
- [Show abstract] [Hide abstract] ABSTRACT: Since the discovery in the 1980s that nitric oxide (NO) is in fact the elusive endothelium-derived relaxing factor, it has become evident that NO is not only a major cardiovascular signalling molecule, but that changes in its bioavailability are crucial in determining whether atherosclerosis will develop or not. Sustained high levels of harmful circulating stimuli associated with cardiovascular risk factors such as diabetes mellitus elicit responses in endothelial cells that appear sequentially, namely endothelial cell activation and endothelial dysfunction (ED). ED, characterised by reduced NO bioavailability, is now recognised by many as an early, reversible precursor of atherosclerosis. The pathogenesis of ED is multifactorial; however, oxidative stress appears to be the common underlying cellular mechanism in the ensuing loss of vaso-active, inflammatory, haemostatic and redox homeostasis in the body’s vascular system. The role of ED as a pathophysiological link between early endothelial cell changes associated with cardiovascular risk factors and the development of ischaemic heart disease is of importance to basic scientists and clinicians alike.
- [Show abstract] [Hide abstract] ABSTRACT: Melatonin plays an important role in body weight regulation and glucose homeostasis. However its metabolic actions on the heart remain unknown. The present study examined the effects of short-term melatonin (Mel) administration on glucose uptake stimulated with or without insulin (Ins) in isolated adult cardiomyocytes. Hearts were isolated from 3 groups of male rats: normal control (NC), control diet (C), and obese (D) groups (high-calorie diet: 65% carbohydrates, 19% protein and 16% fat). Hearts from the latter two groups were studied after 16 to 20 weeks of feeding and compared with those from normal control rats weighing 200-220 g. Rats were weighed, blood collected and cardiomyocytes were isolated. Cardiomyocytes were incubated with Mel (10 to 100 nM), Luzindole (Luz) (5 uM) or Ins (1 nM) and glucose uptake was initiated by addition of 2-deoxy-D-[3H] glucose (1.8 uM) and incubated for 30 min. The high-calorie diet caused significant increases in body weight (p<0.05), visceral adiposity (p<0.01), HOMA index and cardiac hypertrophy (p<0.05). While cardiomyocytes from both groups (16-19 weeks) had no significant difference in Ins stimulation, after 20- 23 weeks Ins stimulation was reduced in the D group compared to their age matched control group [fold stimulation: 1.75±0.09 (C) versus 1.45±0.1 (D), p<0.05]. In all groups, melatonin alone did not affect the glucose uptake compared to basal levels. In cardiomyocytes isolated from NC rats, the presence of melatonin enhanced Ins stimulated glucose uptake [fold stimulation: 2.48±0.2 (Ins), 3.36±0.4 (Ins+Mel); p<0.05). After 16-19 weeks, melatonin enhanced Ins stimulation as a trend [p<0.052 (C), p<0.06 (D)], however, after 20-23 weeks, this trend disappeared in both groups (p>0.5). Luz with or without Ins, in the presence of Mel, attenuated the glucose uptake. Acute melatonin administration may enhance insulin action in normal but not in insulin resistant isolated adult cardiomyocytes. In addition, short-term melatonin treatment does not stimulate glucose metabolism in the heart, the results suggest that melatonin receptors may play a role in its effect on glucose uptake Key words: Melatonin, cardiomyocytes, glucose uptake. Published abstract http://www.academicjournals.org/journal/SRE/article-full-text-pdf/C66E8FF33765.
Stellenbosch, Western Cape, South Africa
- Division of Medical Physiology
University of Cape TownKaapstad, Western Cape, South Africa
St. Boniface Hospital Research
Winnipeg, Manitoba, Canada
- Institute of Cardiovascular Sciences