Glucose Utilization and Glycogen Turnover are Accelerated in Hypertrophied Rat Hearts During Severe Low-flow Ischemia (original) (raw)
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The Correlation of Glycogen Metabolism in Rabbit Myocardial Ischemia
Journal of Veterinary Science & Technology, 2015
Ischemia is responsible for several heart injuries, leading to functional disorders and higher mortality in animals. This process is a condition of blood circulatory arrest, leading to hypoxia and an anaerobic glycolysis. In this case, glycogen is fundamental to maintain energy homeostasis, through glycogen synthase kinase 3 (GSK3) regulations. This enzyme is usually involved in cardio protection, as well as several other biological processes. To study glycogen synthase kinase 3β (GSK3β), analyzing the involvement of this enzyme on cardiac system protection to understand its role in energetic metabolism during ischemia and reperfusion. Using the inflow occlusion (IO) application, the circulatory blood to the heart was blocked in adult New Zealand white rabbits. Parameters such hemogasometry as lactate levels were evaluated during the transoperatory period, using CG4+test strips (i-STAT® System). GSK3β transcription and activity analysis was performed by real time qRT-PCR and western blotting respectively, and glycogen quantification was determined enzymatically.GSK3β transcription increased during ischemia, followed by a decrease in glycogen content, suggesting that the consumption of this substrate during ischemia is mediated by GSK3β. Lactate level is highest in ischemia, and the pH value decreased during the same period. The results suggest the importance of GSK3β in the heart metabolic adaptations after ischemia and reperfusion injuries, sustaining glucose anaerobic metabolism through glycogen reserves modulation. The results show that the transcription of GSK3β correlated with cardiac metabolic adaptations after ischemia and reperfusion injuries, sustaining glucose anaerobic metabolism.
Glucose uptake and glycogen levels are increased in pig heart after repetitive ischemia
American journal of physiology. Heart and circulatory physiology, 2002
Repetitive myocardial ischemia increases glucose uptake, but the effect on glycogen is unclear. Thirteen swine instrumented with a hydraulic occluder on the circumflex (Cx) artery underwent 10-min occlusions twice per day for 4 days. After 24 h postfinal ischemia and in the fasted state, echocardiogram and positron emission tomography imaging for blood flow ([(13)N]-ammonia) and 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) uptake were obtained. Tissue was then collected for ATP, creatine phosphate (CP), glycogen, and glucose transporter-4 content, and hexokinase activity. After reperfusion, regional function and CP-to-ATP ratios in the Cx and remote regions were similar. Despite the absence of stunning, the Cx region demonstrated higher glycogen levels (33 +/- 11 vs. 24 +/- 11 micromol/g; P < 0.05), and this increase correlated well with the increase in FDG uptake (r(2) = 0.78; P < 0.01). Hexokinase activity was also increased relative to remote regions (0.62 +/- 0.29 vs. 0.37 +/- ...
Anais da Academia Brasileira de Ciências, 2017
Ischemia is responsible for many metabolic abnormalities in the heart, causing changes in organ function. One of modifications occurring in the ischemic cell is changing from aerobic to anaerobic metabolism. This change causes the predominance of the use of carbohydrates as an energy substrate instead of lipids. In this case, the glycogen is essential to the maintenance of heart energy intake, being an important reserve to resist the stress caused by hypoxia, using glycolysis and lactic acid fermentation. In order to study the glucose anaerobic pathways utilization and understand the metabolic adaptations, New Zealand white rabbits were subjected to ischemia caused by Inflow occlusion technique. The animals were monitored during surgery by pH and lactate levels. Transcription analysis of the pyruvate kinase, lactate dehydrogenase and phosphoenolpyruvate carboxykinase enzymes were performed by qRT-PCR, and glycogen quantification was determined enzymatically. Pyruvate kinase transcription increased during ischemia, followed by glycogen consumption content. The gluconeogenesis increased in control and ischemia moments, suggesting a relationship between gluconeogenesis and glycogen metabolism. This result shows the significant contribution of these substrates in the organ energy supply and demonstrates the capacity of the heart to adapt the metabolism after this injury, sustaining the homeostasis during shortterm myocardial ischemia.
Relation between lipolysis and glycolysis during ischemia in the isolated rat heart
Basic Research in Cardiology, 1986
The relation between lipolysis and glycolysis during ischemia was investigated in isolated perfused rat hearts. In hearts perfused with 11 mM glucose, ischemia caused a marked increase of glycerol release from 10 to 33 nmol/g wt weight/rain. Substrate-free perfusion induced an initial stimulation of glycerol release, but lipolysis was subsequently reduced to values comparable to normoxic conditions. Neither did perfusion in the presence of acetate (10 mM) and [~-hydroxybutyrate (10 raM) stimulate lipolysis. Inhibition of glycolysis by pyruvate prevented the increase of glycerol release during ischemia. These data suggest a tight link between glycolysis and lipolysis during ischemia which is probably mediated by the availability of glycolytically produced glycerol-3-phosphate for reesterification. In the absence of glycerol-3-phosphate, the lipolysis is regulated by product inhibition. As a consequence, the tissue triglyceride levels after perfusion remained fairly constant in all groups of hearts.
Glucose requirement for postischemic recovery of perfused working heart
European Journal of Biochemistry, 1990
The quantitative importance of glycolysis in cardiomyocyte reenergization and contractile recovery was examined in postischemic, preload-controlled, isolated working guinea pig hearts. A 25-min global but low-flow ischemia with concurrent norepinephrine infusion to exhaust cellular glycogen stores was followed by a 15-min reperfusion. With 5 mM pyruvate as sole reperfusion substrate, severe contractile failure developed despite normal sarcolemmal pyruvate transport rate and high intracellular pyruvate concentrations near 2 mM. Reperfusion dysfunction was characterized by a low cytosolic phosphorylation potential ([ATP]/([ADP][P,]) due to accumulations of inorganic phosphate (Pi) and lactate. In contrast, with 5 mM glucose plus pyruvate as substrates, but not with glucose as sole substrate, reperfusion phosphorylation potential and function recovered to near normal. During the critical ischemia-reperfusion transition at 30 s reperfusion the cytosolic creatine kinase appeared displaced from equilibrium, regardless of the substrate supply. When under these conditions glucose and pyruvate were coinfused, glycolytic flux was near maximum, the glyceraldehyde-3-phosphate dehydrogenase13phosphoglycerate kinase reaction was enhanced, accumulation of Pi was attenuated, ATP content was slightly increased, and adenosine release was low. Thus, glucose prevented deterioration of the phosphorylation potential to levels incompatible with reperfusion recovery. Immediate energetic support due to maximum glycolytic ATP production and enhancement of the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase reaction appeared to act in concert to prevent detrimental collapse of [ATP]/([ADP][P,]) during creatine kinase dysfunction in the ischemia-reperfusion transition. Dichloroacetate (2 mM) plus glucose stimulated glycolysis but failed fully to reenergize the reperfused heart; conversely, 10 mM 2-deoxyglucose plus pyruvate inhibited glycolysis and produced virtually instantaneous de-energization during reperfusion. The following conclusions were reached. (1) A functional glycolysis is required to prevent energetic and contractile collapse of the low-flow ischemic or reperfused heart (2). Glucose stabilization of energetics in pyruvate-perfused hearts is due in part to intensification of glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase activity.
Circulation, 2005
Background-It is believed that increasing cardiac glucose metabolism in the setting of ischemia and reperfusion is protective because of the resulting decrease in fatty acid oxidation, which improves cardiac efficiency and increases glucose oxidation relative to glycolysis; however, these conclusions are based primarily on studies in which glucose is the only carbohydrate provided. The goal of this study was to examine the effect of stimulating myocardial carbohydrate use either by increasing glucose and insulin levels or by using dichloroacetate on the response to ischemia and reperfusion in hearts perfused with physiological concentrations of lactate and pyruvate plus glucose and fatty acids. Methods and Results-Metabolic fluxes were determined in hearts from male Sprague-Dawley rats perfused with 13 C-labeled substrates using 13 C/ 1 H-NMR isotopomer analysis after 30 minutes of low-flow ischemia (0.3 mL/min) and 60 minutes of reperfusion. Measurements were made under control conditions: 5 mmol/L glucose, 1 mmol/L lactate, 0.1 mmol/L pyruvate, 0.3 mmol/L palmitate, and 50 U/mL insulin plus dichloroacetate 5 mmol/L or glucose and insulin increased to 30 mmol/L and 1000 U/mL, respectively. Dichloroacetate increased carbohydrate oxidation and the ratio of glucose oxidation to glycolysis but did not improve functional recovery or cardiac efficiency; however, elevated glucose and insulin levels improved functional recovery and cardiac efficiency but did not increase carbohydrate oxidation or the ratio of glucose oxidation to glycolysis. Conclusions-These data support the notion that increasing myocardial glucose use is beneficial in the setting of ischemia and reperfusion; however, the protective effect appears not to be mediated by shifting the balance between carbohydrate and fatty acid oxidation.
Impairment of glucose metabolism and energy transfer in the hypertriglyceridemic rat heart
Journal of Molecular and Cellular Cardiology, 2001
The metabolic pathways involved in ATP production in hypertriglyceridemic rat hearts were evaluated. Hearts from male Wistar rats with sugar-induced hypertriglyceridemia were perfused in an isolated organ system. Mechanical performance, oxygen uptake and beat rate were evaluated under perfusion with different oxidizable substrates. Age-and weight-matched animals were used as control. The hypertriglyceridemic (HTG) hearts showed a decrease in the mechanical work and slight diminution in the oxygen uptake when perfused with glucose, pyruvate or lactate. No differences were found when perfused with palmitate, octanoate or β-hydroxybutyrate. The glycolytic flux in HTG hearts was 2.4 times lower than in control hearts. Phosphofructokinase-I (PFK-I) was 16% decreased in HTG hearts, whereas pyruvate kinase activity did not change. The increased levels of glucose-6-phosphate in HTG heart, suggested a flux limitation by the PFK-I. Pyruvate dehydrogenase in its active form (PDHa) diminished as well. The PDHa level in the HTG hearts was restored to control values by dichloroacetate; however, this addition did not significantly improve the mechanical performance. Levels of ATP and phosphocreatine as well as total creatine kinase activity and the MB fraction were significant lower in the HTG hearts perfused with glucose. The data suggested that supply of ATP by glucose oxidation did not suffice to support cardiac work in the HTG hearts; this impairment was exacerbated by the diminution of the creatine kinase system output. (Mol Cell Biochem 249: 157-165, 2003)
Detrimental effects of acute hyperglycaemia on the rat heart
Acta Physiologica, 2014
Aim: Hyperglycaemia is an important risk factor for acute myocardial infarction. It can lead to increased induction of non-oxidative glucose pathways (NOGPs)polyol and hexosamine biosynthetic pathways, advanced glycation end products and protein kinase C -that may contribute to cardiovascular diseases onset. However, the precise underlying mechanisms remain poorly understood. Here we hypothesized that acute hyperglycaemia increases myocardial oxidative stress and NOGP activation resulting in cardiac dysfunction during ischaemia-reperfusion and that inhibition of, and/or shunting flux away from NOGPs [by benfotiamine (BFT) treatment], leads to cardioprotection. Methods: We employed several experimental systems: (i) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) AE global ischaemia and reperfusion AE BFT (first 20 min of reperfusion); (ii) Infarct size determination as per the ischaemic protocol, but with regional ischaemia and reperfusion AE BFT treatment; in separate experiments, NOGP inhibitors were also employed for (i) and (ii); and (iii) In vivo coronary ligations performed on streptozotocin-treated rats AE BFT treatment (early reperfusion). Results: Acute hyperglycaemia generated myocardial oxidative stress, NOGP activation and apoptosis, but caused no impairment of cardiac function during pre-ischaemia, thereby priming hearts for later damage. Following ischaemia-reperfusion (under hyperglycaemic conditions), such effects were exacerbated together with cardiac contractile dysfunction. Moreover, inhibition of respective NOGPs and shunting away by BFT treatment (in part) improved cardiac function during ischaemia-reperfusion. Conclusion: Coordinate NOGP activation in response to acute hyperglycaemia results in contractile dysfunction during ischaemia-reperfusion, allowing for the development of novel cardioprotective agents.
Glycogen metabolism in rat heart muscle cultures after hypoxia
Molecular and cellular biochemistry, 2003
Elevated glycogen levels in heart have been shown to have cardioprotective effects against ischemic injury. We have therefore established a model for elevating glycogen content in primary rat cardiac cells grown in culture and examined potential mechanisms for the elevation (glycogen supercompensation). Glycogen was depleted by exposing the cells to hypoxia for 2 h in the absence of glucose in the medium. This was followed by incubating the cells with 28 mM glucose in normoxia for up to 120 h. Hypoxia decreased glycogen content to about 15% of control, oxygenated cells. This was followed by a continuous increase in glycogen in the hypoxia treated cells during the 120 h recovery period in normoxia. By 48 h after termination of hypoxia, the glycogen content had returned to baseline levels and by 120 h glycogen was about 150% of control. The increase in glycogen at 120 h was associated with comparable relative increases in glucose uptake (approximately 180% of control) and the protein ...