Metabolic Profiling of Hearts Exposed to Sevoflurane and Propofol Reveals Distinct Regulation of Fatty Acid and Glucose Oxidation

Background Myocardial energy metabolism is a strong predictor of postoperative cardiac function. This study profiled the metabolites and metabolic changes in the myocardium exposed to sevoflurane, propofol, and Intralipid and investigated the underlying molecular mechanisms. Methods Sevoflurane (2 vol%) and propofol (10 and 100 microM) in the formulation of 1% Diprivan (AstraZeneca Inc., Mississauga, ON, Canada) were compared for their effects on oxidative energy metabolism and contractility in the isolated working rat heart model. Intralipid served as a control. Substrate flux through the major pathways for adenosine triphosphate generation in the heart, that is, fatty acid and glucose oxidation, was measured using [H]palmitate and [C]glucose. Biochemical analyses of nucleotides, acyl-CoAs, ceramides, and 32 acylcarnitine species were used to profile individual metabolites. Lipid rafts were isolated and used for Western blotting of the plasma membrane transporters CD36 and glucose transporter 4. Results Metabolic profiling of the hearts exposed to sevoflurane and propofol revealed distinct regulation of fatty acid and glucose oxidation. Sevoflurane selectively decreased fatty acid oxidation, which was closely related to a marked reduction in left ventricular work. In contrast, propofol at 100 microM but not 10 microM increased glucose oxidation without affecting cardiac work. Sevoflurane decreased fatty acid transporter CD36 in lipid rafts/caveolae, whereas high propofol increased pyruvate dehydrogenase activity without affecting glucose transporter 4, providing mechanisms for the fuel shifts in energy metabolism. Propofol increased ceramide formation, and Intralipid increased hydroxy acylcarnitine species. Conclusions Anesthetics and their solvents elicit distinct metabolic profiles in the myocardium, which may have clinical implications for the already jeopardized diseased heart.

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The Antianginal Drug Trimetazidine Shifts Cardiac Energy Metabolism From Fatty Acid Oxidation to Glucose Oxidation by Inhibiting Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase

Circulation Research ◽

10.1161/01.res.86.5.580 ◽

2000 ◽

Vol 86 (5) ◽

pp. 580-588 ◽

Cited By ~ 431

Author(s):

Paul F. Kantor ◽

Arnaud Lucien ◽

Raymond Kozak ◽

Gary D. Lopaschuk

Keyword(s):

Fatty Acid ◽

Energy Metabolism ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Coenzyme A ◽

Acid Oxidation ◽

Cardiac Energy Metabolism ◽

Cardiac Energy ◽

Long Chain

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Acetylation and succinylation contribute to maturational alterations in energy metabolism in the newborn heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00900.2015 ◽

2016 ◽

Vol 311 (2) ◽

pp. H347-H363 ◽

Cited By ~ 34

Author(s):

Arata Fukushima ◽

Osama Abo Alrob ◽

Liyan Zhang ◽

Cory S. Wagg ◽

Tariq Altamimi ◽

...

Keyword(s):

Fatty Acid ◽

Energy Metabolism ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Acid Oxidation ◽

Amino Acid Synthesis ◽

Oxidation Rates ◽

Cardiac Energy Metabolism ◽

Cardiac Energy ◽

The Impact

Dramatic maturational changes in cardiac energy metabolism occur in the newborn period, with a shift from glycolysis to fatty acid oxidation. Acetylation and succinylation of lysyl residues are novel posttranslational modifications involved in the control of cardiac energy metabolism. We investigated the impact of changes in protein acetylation/succinylation on the maturational changes in energy metabolism of 1-, 7-, and 21-day-old rabbit hearts. Cardiac fatty acid β-oxidation rates increased in 21-day vs. 1- and 7-day-old hearts, whereas glycolysis and glucose oxidation rates decreased in 21-day-old hearts. The fatty acid oxidation enzymes, long-chain acyl-CoA dehydrogenase (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD), were hyperacetylated with maturation, positively correlated with their activities and fatty acid β-oxidation rates. This alteration was associated with increased expression of the mitochondrial acetyltransferase, general control of amino acid synthesis 5 like 1 (GCN5L1), since silencing GCN5L1 mRNA in H9c2 cells significantly reduced acetylation and activity of LCAD and β-HAD. An increase in mitochondrial ATP production rates with maturation was associated with the decreased acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α, a transcriptional regulator for mitochondrial biogenesis. In addition, hypoxia-inducible factor-1α, hexokinase, and phosphoglycerate mutase expression declined postbirth, whereas acetylation of these glycolytic enzymes increased. Phosphorylation rather than acetylation of pyruvate dehydrogenase (PDH) increased in 21-day-old hearts, accounting for the low glucose oxidation postbirth. A maturational increase was also observed in succinylation of PDH and LCAD. Collectively, our data are the first suggesting that acetylation and succinylation of the key metabolic enzymes in newborn hearts play a crucial role in cardiac energy metabolism with maturation. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/acetylation-control-of-energy-metabolism-in-newborn-hearts/ .

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Barth Syndrome-Related Cardiomyopathy is Associated with a Reduction in Myocardial Glucose Oxidation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00873.2020 ◽

2021 ◽

Author(s):

Amanda A. Greenwell ◽

Keshav Gopal ◽

Tariq Altamimi ◽

Christina T. Saed ◽

Faqi Wang ◽

...

Keyword(s):

Heart Failure ◽

Energy Metabolism ◽

Glucose Oxidation ◽

Genetic Disorder ◽

Left Ventricular ◽

Barth Syndrome ◽

Acid Oxidation ◽

Functional Impairments ◽

Myocardial Energy Metabolism ◽

Oxidation Rates

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS (doxycycline-inducible Taz knockdown (TazKD) mice). In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared to their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired prior to the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS.

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Dietary Calanus oil recovers metabolic flexibility and rescues postischemic cardiac function in obese female mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00191.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. H290-H299 ◽

Cited By ~ 3

Author(s):

Kirsten M. Jansen ◽

Sonia Moreno ◽

Pablo M. Garcia-Roves ◽

Terje S. Larsen

Keyword(s):

Fatty Acid ◽

Cardiac Function ◽

Glucose Oxidation ◽

Myocardial Metabolism ◽

Dietary Supplementation ◽

Left Ventricular ◽

Lv Function ◽

Marine Oil ◽

Normal Chow ◽

Postischemic Recovery

The aim of this study was to find out whether dietary supplementation with Calanus oil (a novel marine oil) or infusion of exenatide (an incretin mimetic) could counteract obesity-induced alterations in myocardial metabolism and improve postischemic recovery of left ventricular (LV) function. Female C57bl/6J mice received high-fat diet (HFD, 45% energy from fat) for 12 wk followed by 8-wk feeding with nonsupplemented HFD, HFD supplemented with 2% Calanus oil, or HFD plus exenatide infusion (10 µg·kg−1·day−1). A lean control group was included, receiving normal chow throughout the whole period. Fatty acid and glucose oxidation was measured in ex vivo perfused hearts during baseline conditions, while LV function was assessed with an intraventricular fluid-filled balloon before and after 20 min of global ischemia. HFD-fed mice receiving Calanus oil or exenatide showed less intra-abdominal fat deposition than mice receiving nonsupplemented HFD. Both treatments prevented the HFD-induced decline in myocardial glucose oxidation. Somewhat surprising, recovery of LV function was apparently better in hearts from mice fed nonsupplemented HFD relative to hearts from mice fed normal chow. More importantly however, postischemic recovery of hearts from mice receiving HFD with Calanus oil was superior to that of mice receiving nonsupplemented HFD and mice receiving HFD with exenatide, as expressed by better pressure development, contractility, and relaxation properties. In summary, dietary Calanus oil and administration of exenatide counteracted obesity-induced derangements of myocardial metabolism. Calanus oil also protected the heart from ischemia, which could have implications for the prevention of obesity-related cardiac disease. NEW & NOTEWORTHY This article describes for the first time that dietary supplementation with a low amount (2%) of a novel marine oil (Calanus oil) in mice is able to prevent the overreliance of fatty acid oxidation for energy production during obesity. The same effect was observed with infusion of the incretin mimetic, exanatide. The improvement in myocardial metabolism in Calanus oil-treated mice was accompanied by a significantly better recovery of cardiac performance following ischemia-reperfusion. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/dietary-calanus-oil-energy-metabolism-and-cardiac-function/ .

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Glucose metabolism in perfused mouse hearts overexpressing human GLUT-4 glucose transporter

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.3.e420 ◽

2001 ◽

Vol 280 (3) ◽

pp. E420-E427 ◽

Cited By ~ 32

Author(s):

Darrel D. Belke ◽

Terje S. Larsen ◽

E. Michael Gibbs ◽

David L. Severson

Keyword(s):

Heart Rate ◽

Cardiac Output ◽

Fatty Acid ◽

Coronary Flow ◽

Glucose Oxidation ◽

Glucose Transporter ◽

Acid Metabolism ◽

Glut 4 ◽

Cardiac Power ◽

Glycolytic Rate

Glucose and fatty acid metabolism was assessed in isolated working hearts from control C57BL/KsJ- m+/+db mice and transgenic mice overexpressing the human GLUT-4 glucose transporter ( db/+-hGLUT-4). Heart rate, coronary flow, cardiac output, and cardiac power did not differ between control hearts and hearts overexpressing GLUT-4. Hearts overexpressing GLUT-4 had significantly higher rates of glucose uptake and glycolysis and higher levels of glycogen after perfusion than control hearts, but rates of glucose and palmitate oxidation were not different. Insulin (1 mU/ml) significantly increased glycogen levels in both groups. Insulin increased glycolysis in control hearts but not in GLUT-4 hearts, whereas glucose oxidation was increased by insulin in both groups. Therefore, GLUT-4 overexpression increases glycolysis, but not glucose oxidation, in the heart. Although control hearts responded to insulin with increased rates of glycolysis, the enhanced entry of glucose in the GLUT-4 hearts was already sufficient to maximally activate glycolysis under basal conditions such that insulin could not further stimulate the glycolytic rate.

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Caffeamide 36-13 Regulates the Antidiabetic and Hypolipidemic Signs of High-Fat-Fed Mice on Glucose Transporter 4, AMPK Phosphorylation, and Regulated Hepatic Glucose Production

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/821569 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Yueh-Hsiung Kuo ◽

Cheng-Hsiu Lin ◽

Chun-Ching Shih

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Glucose Transporter ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hypolipidemic Effect ◽

Glucose Transporter 4 ◽

High Fat ◽

Amide Derivatives ◽

Hepatic Glucose

This study was to investigate the antidiabetic and antihyperlipidemic effects of (E)-3-[3, 4-dihydroxyphenyl-1-(piperidin-1-yl)prop-2-en-1-one] (36-13) (TS), one of caffeic acid amide derivatives, on high-fat (HF-) fed mice. The C57BL/6J mice were randomly divided into the control (CON) group and the experimental group, which was firstly fed a HF diet for 8 weeks. Then, the HF group was subdivided into four groups and was given TS orally (including two doses) or rosiglitazone (Rosi) or vehicle for 4 weeks. Blood, skeletal muscle, and tissues were examined by measuring glycaemia and dyslipidemia-associated events. TS effectively prevented HF diet-induced increases in the levels of blood glucose, triglyceride, insulin, leptin, and free fatty acid (FFA) and weights of visceral fa; moreover, adipocytes in the visceral depots showed a reduction in size. TS treatment significantly increased the protein contents of glucose transporter 4 (GLUT4) in skeletal muscle; TS also significantly enhanced Akt phosphorylation in liver, whereas it reduced the expressions of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, TS enhanced phosphorylation of AMP-activated protein kinase (phospho-AMPK) both in skeletal muscle and liver tissue. Therefore, it is possible that the activation of AMPK by TS resulted in enhanced glucose uptake in skeletal muscle, contrasting with diminished gluconeogenesis in liver. TS exhibits hypolipidemic effect by decreasing the expressions of fatty acid synthase (FAS). Thus, antidiabetic properties of TS occurred as a result of decreased hepatic glucose production by PEPCK and G6Pase downregulation and improved insulin sensitization. Thus, amelioration of diabetic and dyslipidemic state by TS in HF-fed mice occurred by regulation of GLUT4, G6Pase, and FAS and phosphorylation of AMPK.

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Role of Metabolic Modulation in the Management of Chronic Ischemic Heart Disease

Clinical Medicine Insights Therapeutics ◽

10.4137/cmt.s3159 ◽

2010 ◽

Vol 2 ◽

pp. CMT.S3159

Author(s):

Anna Salerno ◽

Gabriele Fragasso ◽

Claudia Montanaro ◽

Michela Cera ◽

Camilla Torlasco ◽

...

Keyword(s):

Heart Disease ◽

Fatty Acid ◽

Ischemic Heart Disease ◽

Glucose Oxidation ◽

Left Ventricular ◽

Ischemic Heart ◽

Severe Left Ventricular Dysfunction ◽

Atp Production ◽

Conventional Medical Therapy ◽

Cpt I

Coronary artery disease (CAD) is a major cause of morbidity and mortality in the world. Therapy for stable CAD is currently based on conventional medical therapy, including nitrates, β-blockers and calcium-channels antagonists and, more recently, metabolic therapy, of which a pivotal therapeutic role is increasingly recognized. Under normoxic condition, the healthy heart derives 2/3 of its energy from the free fatty acid (FFA) pathway, the other source of energy being derived from glucose oxidation. However, glycolysis requires less O2 per mole of ATP generated compared with FFA oxidation. On this basis, shifting energy substrate utilization from fatty acid metabolism to glucose metabolism can be more efficient in terms of ATP production per mole of oxygen utilized. A number of different approaches have been used to manipulate energy metabolism in the heart. These approaches include direct agents, such as dichloroacetate, L-carnitine, ribose or lipoic acid which directly increase glucose oxidation, or indirect methods, through the inhibition of free fatty acids oxidation. Among these, the most important are carnitil-palmitoyl-transpherase I (CPT-I) inhibitors, which inhibit FFA mitochondrial uptake (e.g. etomoxir, perhexiline, oxphenicine), or 3-ketoacyl-coenzyme-A thiolase (3-KAT) inhibitors, such as trimetazidine, which inhibits the last enzyme involved in β-oxidation. In most patients with ischemic heart disease metabolic abnormalities, if not adequately treated, will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. In this paper, all possible metabolic approaches to ischemic heart disease are reviewed and discussed.

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Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01185.2009 ◽

2011 ◽

Vol 300 (5) ◽

pp. H1637-H1644 ◽

Cited By ~ 34

Author(s):

Yukihiro Ohta ◽

Shintaro Kinugawa ◽

Shouji Matsushima ◽

Taisuke Ono ◽

Mochamad A. Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Diastolic Pressure ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Glucose Transporter 4

Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) ( 30 ). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

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Inhibition of angiotensin II-induced hypertrophy and cardiac dysfunction by North American ginseng (Panax quinquefolius)

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2020-0480 ◽

2020 ◽

Author(s):

Xilan Tang ◽

Tracey Gan ◽

Chian Ju Jong ◽

Venkatesh Rajapurohitam ◽

Morris Karmazyn

Keyword(s):

Gene Expression ◽

Fatty Acid ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

North American ◽

Glucose Oxidation ◽

American Ginseng ◽

Left Ventricular ◽

Neonatal Rat ◽

Expression Levels

We determined whether North American ginseng mitigates the effect of angiotensin II on hypertrophy and heart failure. Angiotensin II (0.3 mg/kg) was administered to rats for 2 or 4 weeks in the presence or absence of ginseng pretreatment. The effect of ginseng (10 μg/mL) on angiotensin II (100 nM) induced hypertrophy was also determined in neonatal rat ventricular myocytes. We also determined effects of ginseng on fatty acid and glucose oxidation by measuring gene and protein expression levels of key factors. Angiotensin II treatment for 2 and 4 weeks induced cardiac hypertrophy as evidenced by increased heart weights as well as the upregulation of the hypertrophy-related fetal gene expression levels with all effects being abolished by ginseng. Ginseng also reduced abnormalities in left ventricular function as well as the angiotensin-induced increased blood pressure. In myocytes, ginseng abolished the hypertrophic response to angiotensin II as assessed by surface area and gene expression of molecular markers of hypertrophy. Ginseng modulated angiotensin II-induced abnormalities in gene expression and protein levels of CD36, CPT1M, Glut4 and PDK4 in vivo and in vitro. In conclusion, ginseng suppresses angiotensin II induced cardiac hypertrophy and dysfunction which is related to normalization of fatty acid and glucose oxidation.

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