Pyruvate Dehydrogenase Activity and Malonyl CoA Levels in Normal and Ischemic Swine Myocardium: Effects of Dichloroacetate

Stanley, William C.; Hernandez, Lisa A.; Spires, Doreen A.; Bringas, John; Wallace, Sonja; McCormack, James G.

doi:10.1006/jmcc.1996.0085

Cited by 71 publications

(59 citation statements)

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“…Arterial and venous blood samples for measurement of blood glucose and lactate concentrations were taken before (Ϫ5 and Ϫ1 min) and during (20, 45, and 75 s and 2, 3, 4, and 5 min) dobutamine treatment, and samples were drawn for plasma free fatty acid and 3 H2O concentrations at Ϫ5 and Ϫ1 min and 3, 4, and 5 min of dobutamine infusion. After 5 min of increased workload, a large (ϳ3 g) punch biopsy was rapidly excised from the LAD bed, immediately freeze clamped on aluminum blocks precooled in liquid nitrogen, and stored at Ϫ80°C for later analysis (40). The CON group received the same infusion of [9, H]oleate, arterial and coronary venous blood samples were drawn at 50 -60 min, and a myocardial biopsy was immediately obtained as described for the other two groups.…”

Section: Methodsmentioning

confidence: 99%

“…Blood samples were analyzed for concentrations of glucose and lactate, and plasma was assayed for free fatty acids, [ 3 H]oleate, and 3 H2O, as previously described (24,38). Malonyl-CoA and adenine nucleotide contents were assayed by high-pressure liquid chromatography with UV detection, as previously described (40). All tissue concentrations were expressed per gram wet weight of tissue.…”

Section: Methodsmentioning

confidence: 99%

“…Myocardial blood flow was measured from the ultrasonic flowmeter and normalized by dividing by the weight of the heart being perfused by the LAD (34,40). The net uptakes ( mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) of glucose, lactate, free fatty acids, and oxygen were calculated as arterial-venous difference ϫ blood flow.…”

Section: Methodsmentioning

confidence: 99%

“…Fatty acid oxidation in the heart is regulated at the level of the mitochondrial outer membrane by the activity of carnitine palmitoyltransferase I (CPT-I), which is inhibited by malonyl-CoA on the cytosolic side of the enzyme (22, 44). Several studies have shown an inverse relationship between myocardial malonyl-CoA content and fatty acid oxidation (9,24,37,40,43) and, specifically, that adrenergic stimulation corresponds with a reciprocal increase in fatty acid oxidation and decrease in malonyl-CoA content (13-16, 24, 36). Malonyl-CoA is produced by acetylCoA carboxylase (ACC), which is inhibited when phosphorylated at serine 79 by AMP-activated protein kinase (AMPK), whereas AMPK is activated by phosphorylation at threonine 172 (10).…”

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Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Zhou¹,

Huang²,

Yuan³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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WC. Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation. Am J Physiol Heart Circ Physiol 294: H954-H960, 2008. First published December 14, 2007 doi:10.1152/ajpheart.00557.2007.-Inhibition of myocardial fatty acid oxidation can improve left ventricular (LV) mechanical efficiency by increasing LV power for a given rate of myocardial energy expenditure. This phenomenon has not been assessed at high workloads in nonischemic myocardium; therefore, we subjected in vivo pig hearts to a high workload for 5 min and assessed whether blocking mitochondrial fatty acid oxidation with the carnitine palmitoyltransferase-I inhibitor oxfenicine would improve LV mechanical efficiency. In addition, the cardiac content of malonyl-CoA (an endogenous inhibitor of carnitine palmitoyltransferase-I) and activity of acetyl-CoA carboxylase (which synthesizes malonyl-CoA) were assessed. Increased workload was induced by aortic constriction and dobutamine infusion, and LV efficiency was calculated from the LV pressure-volume loop and LV energy expenditure. In untreated pigs, the increase in LV power resulted in a 2.5-fold increase in fatty acid oxidation and cardiac malonyl-CoA content but did not affect the activation state of acetyl-CoA carboxylase. The activation state of the acetyl-CoA carboxylase inhibitory kinase AMP-activated protein kinase decreased by 40% with increased cardiac workload. Pretreatment with oxfenicine inhibited fatty acid oxidation by 75% and had no effect on cardiac energy expenditure but significantly increased LV power and LV efficiency (37 Ϯ 5% vs. 26 Ϯ 5%, P Ͻ 0.05) at high workload. In conclusion, 1) myocardial fatty acid oxidation increases with a short-term increase in cardiac workload, despite an increase in malonyl-CoA concentration, and 2) inhibition of fatty acid oxidation improves LV mechanical efficiency by increasing LV power without affecting cardiac energy expenditure.acetyl-CoA carboxylase; AMP-activated protein kinase; exercise; fatty acids; heart; mitochondria ONE OF THE MAJOR DETERMINANTS of myocardial oxygen consumption (MV O 2 ) at a given rate of left ventricular (LV) power generation is mitochondrial substrate selection (23, 44). Under normal resting conditions, fatty acid oxidation is the predominant source of energy for cardiac power generation (60 -80%); however, studies in humans (39), dogs (30, 31), and pigs (25) in vivo and in isolated perfused rat (3, 21) and mouse (20) hearts show that, with high rates fatty acid oxidation, the external power is reduced for a given MV O 2 (3,30,39). In the failing heart or during acute ischemia and/or reperfusion, pharmacological treatment with agents that inhibit myocardial fatty acid oxidation (5, 6) or directly activate carbohydrate oxidation (2, 28, 41) increases LV function without affecting MV O 2 and, therefore, improves LV mechanical efficiency (defined as the ratio of external LV power to LV energy expenditure). However, the effect of inhibition of fatty acid oxida...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Zhou¹,

Huang²,

Yuan³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The activities of enzymes involved in mitochondrial transfer of acetyl units via citrate or acetylcarnitine are small compared with the CAC flux rate (1,4,10,27,36). However, these activities could be sufficient to maintain the very small pool of malonyl-CoA (between 0.2 and 4 nmol/g wet wt) (4,17,20,23,37).…”

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confidence: 99%

Probing the link between citrate and malonyl-CoA in perfused rat hearts

Poirier¹,

Vincent²,

Reszko

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Little is known about the sources of cytosolic acetyl-CoA used for the synthesis of malonyl-CoA, a key regulator of fatty acid oxidation in the heart. We tested the hypothesis that citrate provides acetyl-CoA for malonyl-CoA synthesis after its mitochondrial efflux and cleavage by cytosolic ATP-citrate lyase. We expanded on a previous study where we characterized citrate release from perfused rat hearts (Vincent G, Comte B, Poirier M, and Des Rosiers C. Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis. Am J Physiol Endocrinol Metab 278: E846-E856, 2000). In the present study, we show that citrate release rates, ranging from 6 to 22 nmol/min, can support a net increase in malonyl-CoA concentrations induced by changes in substrate supply, at most 0.7 nmol/min. In experiments with [U-13 C](lactate ϩ pyruvate) and [1-13 C]oleate, we show that the acetyl moiety of malonyl-CoA is derived from both pyruvate and long-chain fatty acids. This 13 Clabeling of malonyl-CoA occurred without any changes in its concentration. Hydroxycitrate, an inhibitor of ATP-citrate lyase, prevents increases in malonyl-CoA concentrations and decreases its labeling from [U-13 C](lactate ϩ pyruvate). Our data support at least a partial role of citrate in the transfer from the mitochondria to cytosol of acetyl units for malonylCoA synthesis. In addition, they provide a dynamic picture of malonyl-CoA metabolism: even when the malonyl-CoA concentration remains constant, there appears to be a constant need to supply acetyl-CoA from various carbon sources, both carbohydrates and lipids, for malonyl-CoA synthesis.gas chromatography-mass spectrometry; adenosine 5Ј-triphosphate-citrate lyase; hydroxycitrate; acetyl-coenzyme A; citric acid cycle; 13 C-substrate; isotopomer analysis THE INTRACELLULAR CONCENTRATION of malonyl-CoA modulates a number of physiological and pathophysiological events. These effects of malonyl-CoA are related to its inhibition of carnitine palmitoyl transferase 1. The latter controls the entry of long-chain acyl-CoA into mitochondria, where they are ␤-oxidized for energy production. In addition, carnitine palmitoyl transferase 1 activity affects cytosolic concentrations of longchain acyl-CoAs, which influence signal transduction and binding of nuclear transcription factors (5,16,19,42). In lipogenic tissues such as the liver, malonyl-CoA is both a modulator of fatty acid oxidation and an intermediate of fatty acid synthesis (25). In nonlipogenic tissues such as the heart and skeletal muscle, cytosolic malonyl-CoA modulates fatty acid oxidation and is a component of a fuel-sensing and signaling mechanism that responds to changes in the cell's substrate supply and energy expenditure (31, 33). Recently, a dysregulated malonyl-CoA metabolism has been implicated in insulin resistance (33), apoptosis (19), and functional recovery of the heart after ischemia (20). In the heart, the regulatory role of cytosolic malonylCoA is supported by the kinetic and regulatory properties of enzymes involved in its meta...

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Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized ¹³CO₂ and H¹³CO

Merritt

Harrison

Storey

et al. 2008

Magnetic Resonance in Med

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Isolated rat hearts were studied by 31 P NMR and 13 C NMR. Hyperpolarized [1-13 C]pyruvate was supplied to control normoxic hearts and production of [1-13 C]lactate, [1-13 C]alanine, 13 CO 2 and H 13 CO 3 ؊ was monitored with 1-s temporal resolution. Hearts were also subjected to 10 min of global ischemia followed by reperfusion. Developed pressure, heart rate, oxygen consumption, [ Myocardial oxygen consumption is sensitive to the ratio of fatty acid versus carbohydrate metabolism (1-3). Fatty acid utilization increases oxygen consumption. This is considered insignificant to physiology in the normoxic heart, but in the setting of ischemia or ischemia-reperfusion, increased metabolism of fatty acids impairs contractility and recovery (1,2). Diverse metabolic (4,5) and pharmacologic (6 -8) interventions share a common featureincreased oxidation of carbohydrates relative to fatty acids improves outcome after myocardial ischemia. Although these benefits have been demonstrated repeatedly, the mechanism is poorly understood and the clinical utility of increased carbohydrate oxidation remains controversial (9).Glucose, pyruvate, and lactate are important substrates for oxidation by the heart. The product of lactate and glucose metabolism, pyruvate, is decarboxylated by pyruvate dehydrogenase (PDH) to produce acetyl-CoA for subsequent oxidation in the citric acid cycle. The other major substrates for energy production, fatty acids and ketones, are metabolized through ␤ oxidation and bypass PDH for generation of acetyl-CoA. Because of the importance of PDH in cardiac metabolism, the classic radiotracer method for assessing PDH flux, 14 CO 2 release from [1-14 C]pyruvate (10 -13), has been extensively developed and widely accepted. Applications, however, are limited in vivo because of radiation containment requirements and the difficulty of collecting blood from the vessels draining the ischemic region. Consequently, there is considerable interest in direct metabolic mapping using hyperpolarized [1-13 C]pyruvate (7,14). 13 C MR images of [1-13 C]lactate, [1-13 C]alanine and H 13 CO 3 Ϫ ([ 13 C]bicarbonate) were relatively homogeneous in the normal myocardium, but reduced signal from [ 13 C]bicarbonate compared with the normal myocardium was observed 2 hr after transient ischemia (15). In the presence of [1-13 C]pyruvate, the appearance of H 13 CO 3 Ϫ in heart tissue is due exclusively to PDH flux (16). When carbohydrates are the only source of acetyl-CoA for oxidation in the TCA cycle, the rate of production of H 13 CO 3 Ϫ is proportional to citric acid cycle flux. However, the heart can derive much of its acetyl-CoA from long chain fatty acids or ketones. It would be expected that reduced bicarbonate signal may be due to reduced flux through the TCA cycle, a switch to oxidation of fats or ketones, or a combination of these two factors.In the present study, oxidation of hyperpolarized [1-13 C]pyruvate was examined in a model widely used for evaluation of tracer kinetics in ischemia and reperfusion, the isolated rat heart...

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Pyruvate Dehydrogenase Activity and Malonyl CoA Levels in Normal and Ischemic Swine Myocardium: Effects of Dichloroacetate

Cited by 71 publications

References 2 publications

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Probing the link between citrate and malonyl-CoA in perfused rat hearts

Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized ¹³CO₂ and H¹³CO

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Pyruvate Dehydrogenase Activity and Malonyl CoA Levels in Normal and Ischemic Swine Myocardium: Effects of Dichloroacetate

Cited by 71 publications

References 2 publications

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Metabolic response to an acute jump in cardiac workload: effects on malonyl-CoA, mechanical efficiency, and fatty acid oxidation

Probing the link between citrate and malonyl-CoA in perfused rat hearts

Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized 13CO2 and H13CO

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Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized ¹³CO₂ and H¹³CO