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Regulation of cardiac malonyl-CoA content and fatty acid oxidation during increased cardiac power

¹Department of Physiology and Biophysics and ²Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and ³Department of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada

Submitted 4 March 2005 ; accepted in final form 8 April 2005

	ABSTRACT

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Myocardial fatty acid oxidation is regulated by carnitine palmitoyltransferase I (CPT I), which is inhibited by malonyl-CoA. Increased cardiac power causes a fall in malonyl-CoA content and accelerated fatty acid oxidation; however, the mechanism for the decrease in malonyl-CoA is unclear. Malonyl-CoA is formed by acetyl-CoA carboxylase (ACC) and degraded by malonyl-CoA decarboxylase (MCD); thus a fall in malonyl-CoA could be due to activation of MCD, inhibition of ACC, or both. This study assessed the effects of increased cardiac power on malonyl-CoA content and ACC and MCD activities. Anesthetized pigs were studied under control conditions and during increased cardiac power in response to dobutamine infusion and aortic constriction alone, under hyperglycemic conditions, or with the CPT I inhibitor oxfenicine. An increase in cardiac power was accompanied by increased myocardial O₂ consumption, decreased malonyl-CoA concentration, and increased fatty acid oxidation. There were no differences among groups in activity of ACC or AMP-activated protein kinase (AMPK), which physiologically inhibits ACC. There also were no differences in V_max or K_m of MCD. Previous studies have demonstrated that AMPK can be inhibited by protein kinase B (PKB); however, PKB was activated by dobutamine and the elevated insulin that accompanied hyperglycemia, but there was no effect on AMPK activity. In conclusion, the fall in malonyl-CoA and increase in fatty acid oxidization that occur with increased cardiac work were not due to inhibition of ACC or activation of MCD, suggesting alternative regulatory mechanisms for the work-induced decrease in malonyl-CoA concentration.

acetyl coenzyme A carboxylase; heart; malonyl coenzyme A decarboxylase; mitochondria; protein kinase B

An increase in cardiac workload and myocardial oxygen consumption (MO₂), such as occurs with physical exercise or catecholamine stress, increases fatty acid uptake and oxidation (8, 19, 35). Dobutamine infusion in pigs increases MO₂ and fatty acid uptake and decreases malonyl-CoA content (10, 11), suggesting that there is less malonyl-CoA inhibition of CPT I and accelerated fatty acid oxidation. This fall in malonyl-CoA content is not accompanied by activation of AMPK or reduced ACC activity (10). The fall in malonyl-CoA content with -adrenergic stimulation coincides with a reduced malonyl-CoA turnover that occurs in perfused rat hearts (28). There are conflicting results on the effects of -adrenergic stimulation on MCD activity: in the isolated rat heart, Goodwin and Taegtmeyer (9) observed a decrease in the K_m of MCD with no change in V_max with isoproterenol stimulation, whereas investigators in our laboratory (28) found no change in MCD activity with epinephrine stimulation.

Myocardial malonyl-CoA content and turnover also are determined by the supply of acetyl-CoA. Both parameters increase despite no change in the activities of ACC or MCD if acetyl-CoA levels increase, such as when the heart is perfused with the medium-chain fatty acid octanoate instead of with oleate or palmitate (20, 28). Cardiac malonyl-CoA content also is increased when acetyl-CoA levels are elevated by activation of pyruvate dehydrogenase with dichloroacetate, and this correlates with a decrease in fatty acid oxidation (31, 36). These observations suggest that increased availability of acetyl-CoA from the oxidation of either carbohydrate or fatty acids would increase malonyl-CoA content. Conversely, one would hypothesize that a reduction in acetyl-CoA production from fatty acid oxidation would decrease malonyl-CoA content.

Recent studies suggest that there is cross talk among cardiac workload, fatty acid metabolism, and the activation of protein kinase B (PKB) and AMPK (1, 17, 34). PKB is activated by an increase in cardiac afterload (1), and insulin activation of PKB is associated with inhibition of AMPK activity (17). A decrease in AMPK activity activates ACC, increases malonyl-CoA content, and reduces fatty acid oxidation. Studies in cultured mouse cardiac muscle cells show that the addition of palmitate to the medium partially prevents the insulin-induced increase in PKB activity (34). In addition, palmitate is able to prevent the inhibition of AMPK by insulin in isolated, perfused rat hearts (5).

The mechanism for palmitate inhibition of insulin activation of PKB is unclear; however, it does not appear to be due to alterations in the mitochondrial oxidation of fatty acids, as evidenced by the lack of effect on CPT I inhibition or pyruvate dehydrogenase activation (34). It is not known whether -adrenergic stimulation activates PKB in the heart, and it is not clear whether there is a relationship between insulin activation of PKB and AMPK activity. In addition, the combined effects of -adrenergic stimulation, insulin stimulation, and fatty acid oxidation on PKB activation have not been evaluated.

In the present study we investigated the effects of an acute increase in left ventricular contractile power on key regulators of myocardial malonyl-CoA content. We hypothesized that 1) increased cardiac power results in activation of MCD (i.e., greater V_max and/or lower K_m); 2) hyperglycemia plus hyperinsulinemia during increased cardiac power elevates malonyl-CoA content; 3) suppression of fatty acid oxidation by CPT I inhibition reduces malonyl-CoA content; and 4) PKB activity increases during increased cardiac power and the elevated insulin that accompanies hyperglycemia and corresponds with a decrease in AMPK activity. Experiments were performed in anesthetized pigs under unstimulated conditions and with acute aortic constriction plus an infusion of dobutamine to increase cardiac power and MO₂. PKB activity was increased by hyperinsulinemia induced by an infusion of glucose, and fatty acid oxidation was blocked by CPT I inhibition with oxfenicine (2, 38). It is important to note that data on the regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates from these experiments have been reported separately (33).

	METHODS

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Studies were performed in anesthetized open-chest domestic swine (35–45 kg) in accordance with the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23). The protocol was approved by the Institutional Animal Care and Use Committee at Case Western Reserve University.

Surgical preparation. The surgical preparation was described in detail previously (33). Briefly, pigs fasted overnight were sedated with Telazol (6 mg/kg im), anesthetized with isoflurane by mask (5%), intubated by tracheotomy, ventilated with 100% O₂, and maintained on isoflurane (0.75–1.5%) and ketamine (4 mg·kg^–1·h^–1 iv). Ventilation was adjusted to maintain PCO₂ and pH in the normal range (35–45 mmHg and 7.35–7.45, respectively) (36). A midline sternotomy was performed, a femoral artery and vein were catheterized, and the pig was heparinized (200 U/kg iv). A 24-mm vascular hydraulic occluder (Harvard Apparatus) was placed around the ascending aorta, and the anterior interventricular vein was catheterized for coronary venous blood sampling. The left atrial appendage was cannulated for injection of microspheres for measurement of blood flow (4, 33).

Experimental protocol. Four experimental groups were studied: control (CON; n = 7) with sham instrumentation; dobutamine infusion (DOB; n = 6, 25 µg·kg^–1·min^–1); dobutamine and glucose infusion (DOB+GLU; n = 9, glucose infused at 15 mg·kg^–1·h^–1); and dobutamine, glucose, and oxfenicine infusion (DOB+GLU+OXF; n = 9, oxfenicine infused at 30 mg·kg^–1·h^–1). Each group underwent a 50-min equilibrium period followed by a 15-min treatment period. An infusion of [9,10-³H]oleate tracer (0.2 µCi/min) was initiated at the beginning of the equilibrium period to determine the free fatty acid oxidation rate. After 50 min of equilibration, animals received either no treatment (CON group) or were subject to a 15-min period of increased cardiac power induced by 1) a bolus injection of atropine (2 mg) to increase heart rate, 2) an infusion of dobutamine to increase cardiac contractility and further increase heart rate, and 3) inflation of the aortic cuff to maintain peak left ventricular (LV) systolic pressure at 170–180 mmHg. Arterial and coronary venous blood samples were taken immediately before treatment (at 42 and 47 min into the equilibration period) and during treatment (60 and 65 min) and were analyzed for blood oxygen content and plasma concentrations of free fatty acids, [³H]oleate, and ³H₂O. Cardiac function was recorded on a commercial online data acquisition system. Microspheres for flow measurement were injected into the left atrial appendage at 40 and 58 min, and a reference withdrawal sample was taken from the femoral artery (4 ml/min). After 15 min of treatment, a large punch biopsy (4–5 g) was rapidly obtained from the anterior free wall, freeze clamped, placed in liquid nitrogen, and stored at –80°C until analyzed.

Analytical methods. Hemoglobin concentration and saturation were measured spectrophotometrically with a hemoximeter (AVOXimeter 1000; A-VOX Systems, San Antonio, TX), and PO₂, PCO₂, and pH were measured with a blood gas meter (Nova Biomedical, Waltham, MA). Plasma concentrations of free fatty acid and ³H₂O and the ³H-fatty acid specific activity were measured as previously described (3, 24). Myocardial microsphere content was measured by neutron activation (25). Tissue malonyl-CoA concentration was determined by gas chromatography-mass spectroscopy as described by Reszko et al. (26). MCD activity was measured in triplicate at 37°C by using the radiochemical assay of Kerner et al. (16) at malonyl-CoA concentrations of 10, 30, 100, and 300 µM and a run time of 10 min. ACC activity was measured in the absence of citrate as previously described (18). AMPK activities were measured as previously described (18) with substitution of AMARA as the peptide substrate in the AMPK assay.

Immunoblot analysis. Myocardial PKB phosphorylation was determined in homogenates of myocardium that were subjected to SDS-PAGE and transferred to nitrocellulose as previously described (17). Membranes were blocked in 5% milk-Tris-buffered saline (TBS)-0.1% Tween 20 and then immunoblotted at 1:1,000 dilution with rabbit anti-phospho-PKB (Ser⁴⁷³) antibody or rabbit anti-PKB (Cell Signaling Technology) overnight at 4°C. After being washed, the membranes were incubated with peroxidase-conjugated goat anti-rabbit secondary antibodies in 5% milk-TBS-0.1% Tween 20. After being further washed, the antibodies were visualized using the Pharmacia enhanced chemiluminescence Western blotting detection system.

Calculations. MO₂, blood flow, and fatty acid oxidation were calculated as previously described (37). Rate-pressure product was calculated as heart rate x peak LV pressure. K_m and V_max values for MCD were calculated for each animal from Lineweaver-Burke plots.

Statistical analysis. Data are presented as means ± SE. Data for the CON and DOB groups were compared using a nonparametric t-test, and differences among data for the DOB, DOB+GLU, and DOB+GLU+OXF groups were determined using a Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks with a Dunn’s pairwise multiple comparison. A P value <0.05 was considered significant.

	RESULTS

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Before treatment, there were no differences in rate-pressure product or MO₂ among groups, and during the treatment period there was a significant increase in both parameters in all groups except CON (Table 1). Data on heart rate and blood pressure for these animal have been reported previously (33). MO₂ was similar before treatment in all groups and increased significantly and to the same extent in the DOB, DOB+GLU, and DOB+GLU+OXF groups (P < 0.01). As previously reported, the infusion of glucose in the DOB+GLU and DOB+GLU+OXF groups resulted in a 3.5-fold increase in arterial glucose concentration (from 4 to 14 mM) and a 9.0-fold increase in insulin concentration (from 15 to 135 pM) (33).

View this table: [in this window] [in a new window]   Table 1. Rate-pressure product and MO2 during treatment period

Malonyl-CoA content. There was a significant 35% decrease in malonyl-CoA content in the DOB group compared with the CON group (P < 0.006) (Fig. 1). The DOB+GLU group had significantly higher malonyl-CoA content than either the DOB (P < 0.004) or DOB+GLU+OXF groups (P < 0.001) (Fig. 1).

View larger version (19K): [in this window] [in a new window]   Fig. 1. Myocardial malonyl-CoA content at the end of the protocol. Four experimental groups were studied: control (CON; n = 7) with sham instrumentation; dobutamine infusion (DOB; n = 6); dobutamine and glucose infusion (DOB+GLU; n = 9); and dobutamine, glucose, and oxfenicine infusion (DOB+GLU+OXF; n = 9).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Myocardial protein kinase B (PKB) phosphorylation at the end of the protocol. Whole heart homogenates from the different treatment groups were subjected to immunoblot analysis using anti-phospho-PKB (Ser473) and anti-total-PKB antibodies. Blots were scanned, and data were quantified, expressed as phospho-PKB/PKB ratios, and presented as a fraction of the mean of the CON group. *P < 0.05, PKB in the DOB group was significantly greater than in the CON group.

	DISCUSSION

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The results of the present investigation support the concept that the increase in fatty acid oxidation that occurs with an increase in cardiac energy expenditures is due to a fall in malonyl-CoA content and less inhibition of CPT I (10, 11, 28); however, the mechanism for the reduction in malonyl-CoA remains elusive. It is important to note that the inhibitory site for malonyl-CoA is on the cytosolic side of CPT I (12, 15, 22, 40) and that malonyl-CoA is found in both the cytosol and the mitochondria (12, 15, 22, 40). It is possible that adrenergic stimulation and/or high rates of cardiac energy expenditure cause a selective decrease in cytosolic acetyl-CoA or result in selective alterations in the activity or cellular location of cytosolic ACC or MCD, which lead to reduced production or greater clearance of cytosolic malonyl-CoA. However, we cannot draw conclusions regarding cytosolic levels from the whole tissue contents. On the other hand, we can estimate the cytosolic concentration on the basis of assumed mitochondrial and cytosolic volumes and malonyl-CoA distribution between the two compartments. If we assume that 1) the mitochondrial and the cytosolic compartments comprise 20 and 80% of the intracellular volume, 2) under normal cardiac work conditions malonyl-CoA concentration is the same in both compartments, and 3) there is no change in malonyl-CoA concentration in the mitochondria during increased cardiac work, we can then estimate that the cytosolic malonyl-CoA content in the cytosol will decrease by 44% with dobutamine [compared with only a 35% decrease in whole tissue content (Fig. 1)]. Furthermore, if we assume that dobutamine stimulation results in a doubling of mitochondrial malonyl-CoA [secondary to an increase in acetyl-CoA concentration (13)], then we would predict a 69% decrease in cytosolic malonyl-CoA concentration. Thus, if the mitochondrial pool of malonyl-CoA does not change or if it increases when cardiac work is increased, there is a greater change in cytosolic malonyl-CoA. Future studies should assess the cellular distribution of malonyl-CoA by rapidly separating the cytosolic and mitochondrial compartments and measuring malonyl-CoA content in the two fractions.

The supply of acetyl-CoA in the cytosol is thought to be a major regulator of cytosolic malonyl-CoA concentration. Cytosolic malonyl-CoA is formed in the cytosol from acetyl-CoA by ACC (9–11, 18, 30, 31, 39); however, most of the acetyl-CoA in cardiomyocytes resides in the mitochondria (14). In the present experiment we did not observe any significant differences in total tissue acetyl-CoA content among groups (5.6 ± 0.4, 7.1 ± 1.2, 7.7 ± 0.8, and 8.5 ± 0.8 nmol/g for CON, DOB, DOB+GLU, and DOB+GLU+OXF groups, respectively). There are three sources of cytosolic acetyl-CoA: 1) cleavage of citrate via the ATP-citrate lyase reaction (23, 32), 2) acetylcarnitine that has been exported out of the mitochondrial matrix (21, 31), and 3) peroxisomal -oxidation. Reszko et al. (27) recently provided convincing evidence that the latter process predominates in the heart. Clearly, additional work is needed before the role of cellular compartmentation in the regulation of malonyl-CoA kinetics and CPT I inhibition is understood.

There are several limitations in the present study that need to be addressed. First, our protocol did not include groups under normal workload conditions treated with hyperglycemia or hyperglycemia plus oxfenicine, because the goal of this study was to assess the effects of increased cardiac energy expenditure on malonyl-CoA content and the role of substrate supply on malonyl-CoA content during increased work. Ideally, one would also assess the effects of hyperglycemia and oxfenicine under normal workload conditions; however, this was not the primary goal of this study, and therefore we did not include these groups. A second limitation was the lack of measurement of the cytosolic concentration of malonyl-CoA. Future studies should rapidly separate the cytosol and mitochondria and measure malonyl-CoA content in the two compartments.

In conclusion, the results of the present study show that an acute increase in LV contractile power and MO₂ reduces myocardial malonyl-CoA content independently of changes in the activities of MCD, ACC, and AMPK. These findings run counter to other situations, such as diabetes, ischemia-reperfusion, or maturation, where the activities of MCD, ACC, and AMPK clearly regulate malonyl-CoA content. On the other hand, the results of the present study show that the supply of substrate was a major determinant of malonyl-CoA levels under increased work conditions, with an increase in malonyl-CoA content with hyperglycemia plus hyperinsulinemia and a significant decrease in malonyl-CoA content with inhibition of fatty acid oxidation via CPT I inhibition. In addition, PKB activity was increased by an increase in cardiac power; however, this did not correspond with a decrease in AMPK activity, suggesting that there is no interaction between the two enzymes under these conditions.

	GRANTS

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This work was supported by the Center for Modeling Integrate Metabolic Systems at Case Western Reserve University [National Institutes of Health (NIH) Grant P50-GM-066309] and by NIH Grant P01-HL-074237.

	FOOTNOTES

 

Address for reprint requests and other correspondence: W. C. Stanley, Dept. of Physiology and Biophysics, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106-4970 (e-mail: WCS4{at}case.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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1. Beauloye C, Marsin AS, Bertrand L, Vanoverschelde JL, Rider MH, and Hue L. The stimulation of heart glycolysis by increased workload does not require AMP-activated protein kinase but a wortmannin-sensitive mechanism. FEBS Lett 531: 324–328, 2002.[CrossRef][Web of Science][Medline]
2. Bielefeld DR, Vary TC, and Neely JR. Inhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle. J Mol Cell Cardiol 17: 619–625, 1985.[Web of Science][Medline]
3. Chandler MP, Huang H, McElfresh TA, and Stanley WC. Increased nonoxidative glycolysis despite continued fatty acid uptake during demand-induced myocardial ischemia. Am J Physiol Heart Circ Physiol 282: H1871–H1878, 2002.[Abstract/Free Full Text]
4. Chandler MP, Kerner J, Huang H, Vazquez E, Reszko A, Martini WZ, Hoppel CL, Imai M, Rastogi S, Sabbah HN, and Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 287: H1538–H1543, 2004.[Abstract/Free Full Text]
5. Clark H, Carling D, and Saggerson D. Covalent activation of heart AMP-activated protein kinase in response to physiological concentrations of long-chain fatty acids. Eur J Biochem 271: 2215–2224, 2004.[Web of Science][Medline]
6. Dyck JR, Barr AJ, Barr RL, Kolattukudy PE, and Lopaschuk GD. Characterization of cardiac malonyl-CoA decarboxylase and its putative role in regulating fatty acid oxidation. Am J Physiol Heart Circ Physiol 275: H2122–H2129, 1998.[Abstract/Free Full Text]
7. Dyck JR, Cheng JF, Stanley WC, Barr R, Chandler MP, Brown S, Wallace D, Arrhenius T, Harmon C, Yang G, Nadzan AM, and Lopaschuk GD. Malonyl coenzyme a decarboxylase inhibition protects the ischemic heart by inhibiting fatty acid oxidation and stimulating glucose oxidation. Circ Res 94: e78–e84, 2004.[Abstract/Free Full Text]
8. Gertz EW, Wisneski JA, Stanley WC, and Neese RA. Myocardial substrate utilization during exercise in humans. Dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 82: 2017–2025, 1988.[Web of Science][Medline]
9. Goodwin GW and Taegtmeyer H. Regulation of fatty acid oxidation of the heart by MCD and ACC during contractile stimulation. Am J Physiol Endocrinol Metab 277: E772–E777, 1999.[Abstract/Free Full Text]
10. Hall JL, Lopaschuk GD, Barr A, Bringas J, Pizzurro RD, and Stanley WC. Increased cardiac fatty acid uptake with dobutamine infusion in swine is accompanied by a decrease in malonyl CoA levels. Cardiovasc Res 32: 879–885, 1996.[CrossRef][Web of Science][Medline]
11. Hall JL, Stanley WC, Lopaschuk GD, Wisneski JA, Pizzurro RD, Hamilton CD, and McCormack JG. Impaired pyruvate oxidation but normal glucose uptake in diabetic pig heart during dobutamine-induced work. Am J Physiol Heart Circ Physiol 271: H2320–H2329, 1996.[Abstract/Free Full Text]
12. Hamilton C and Saggerson ED. Malonyl-CoA metabolism in cardiac myocytes. Biochem J 350: 61–67, 2000.
13. Hansford RG and Cohen L. Relative importance of pyruvate dehydrogenase interconversion and feed-back inhibition in the effect of fatty acids on pyruvate oxidation by rat heart mitochondria. Arch Biochem Biophys 191: 65–81, 1978.[CrossRef][Web of Science][Medline]
14. Idell-Wenger JA, Grotyohann LW, and Neely JR. Coenzyme A and carnitine distribution in normal and ischemic hearts. J Biol Chem 253: 4310–4318, 1978.[Abstract/Free Full Text]
15. Kerner J and Hoppel C. Fatty acid import into mitochondria. Biochim Biophys Acta 1486: 1–17, 2000.[Medline]
16. Kerner J and Hoppel CL. Radiochemical malonyl-CoA decarboxylase assay: activity and subcellular distribution in heart and skeletal muscle. Anal Biochem 306: 283–289, 2002.[CrossRef][Web of Science][Medline]
17. Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, and Dyck JR. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278: 39422–39427, 2003.[Abstract/Free Full Text]
18. Kudo N, Barr AJ, Barr RL, Desai S, and Lopaschuk GD. High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5'-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 270: 17513–17520, 1995.[Abstract/Free Full Text]
19. Lassers BW, Wahlqvist ML, Kaijser L, and Carlson LA. Effect of nicotinic acid on myocardial metabolism in man at rest and during exercise. J Appl Physiol 33: 72–80, 1972.[Free Full Text]
20. Longnus SL, Wambolt RB, Barr RL, Lopaschuk GD, and Allard MF. Regulation of myocardial fatty acid oxidation by substrate supply. Am J Physiol Heart Circ Physiol 281: H1561–H1567, 2001.[Abstract/Free Full Text]
21. Lysiak W, Toth PP, Suelter CH, and Bieber LL. Quantitation of the efflux of acylcarnitines from rat heart, brain, and liver mitochondria. J Biol Chem 261: 13698–13703, 1986.[Abstract/Free Full Text]
22. McGarry JD, Mills SE, Long CS, and Foster DW. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. Biochem J 214: 21–28, 1983.[Web of Science][Medline]
23. Poirier M, Vincent G, Reszko AE, Bouchard B, Kelleher JK, Brunengraber H, and Des Rosiers C. Probing the link between citrate and malonyl-CoA in perfused rat hearts. Am J Physiol Heart Circ Physiol 283: H1379–H1386, 2002.[Abstract/Free Full Text]
24. Recchia FA, Osorio JC, Chandler MP, Xu X, Panchal AR, Lopaschuk GD, Hintze TH, and Stanley WC. Reduced synthesis of NO causes marked alterations in myocardial substrate metabolism in conscious dogs. Am J Physiol Endocrinol Metab 282: E197–E206, 2002.[Abstract/Free Full Text]
25. Reinhardt CP, Dalhberg S, Tries MA, Marcel R, and Leppo JA. Stable labeled microspheres to measure perfusion: validation of a neutron activation assay technique. Am J Physiol Heart Circ Physiol 280: H108–H116, 2001.[Abstract/Free Full Text]
26. Reszko AE, Kasumov T, Comte B, Pierce BA, David F, Bederman IR, Deutsch J, Des Rosiers C, and Brunengraber H. Assay of the concentration and ¹³C-isotopic enrichment of malonyl-coenzyme A by gas chromatography-mass spectrometry. Anal Biochem 298: 69–75, 2001.[CrossRef][Web of Science][Medline]
27. Reszko AE, Kasumov T, David F, Jobbins KA, Thomas KR, Hoppel CL, Brunengraber H, and Des Rosiers C. Peroxisomal fatty acid oxidation is a substantial source of the acetyl moiety of malonyl-CoA in rat heart. J Biol Chem 279: 19574–19579, 2004.[Abstract/Free Full Text]
28. Reszko AE, Kasumov T, David F, Thomas KR, Jobbins KA, Cheng JF, Lopaschuk GD, Dyck JR, Diaz M, Des Rosiers C, Stanley WC, and Brunengraber H. Regulation of malonyl-CoA concentration and turnover in the normal heart. J Biol Chem 279: 34298–34301, 2004.[Abstract/Free Full Text]
29. Ruderman N and Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 3: 340–351, 2004.[CrossRef][Web of Science][Medline]
30. Ruderman NB, Saha AK, Vavvas D, and Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol Endocrinol Metab 276: E1–E18, 1999.[Abstract/Free Full Text]
31. Saddik M, Gamble J, Witters LA, and Lopaschuk GD. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 268: 25836–25845, 1993.[Abstract/Free Full Text]
32. Saha AK, Vavvas D, Kurowski TG, Apazidis A, Witters LA, Shafrir E, and Ruderman NB. Malonyl-CoA regulation in skeletal muscle: its link to cell citrate and the glucose-fatty acid cycle. Am J Physiol Endocrinol Metab 272: E641–E648, 1997.[Abstract/Free Full Text]
33. Sharma N, Okere IC, Brunengraber DZ, McElfresh TA, King KL, Sterk JP, Huang H, Chandler MP, and Stanley WC. Regulation of pyruvate dehydrogenase activity and citric acid cycle intermediates during high cardiac power generation. J Physiol 562: 593–603, 2005.[Abstract/Free Full Text]
34. Soltys CL, Buchholz L, Gandhi M, Clanachan AS, Walsh K, and Dyck JR. Phosphorylation of cardiac protein kinase B is regulated by palmitate. Am J Physiol Heart Circ Physiol 283: H1056–H1064, 2002.[Abstract/Free Full Text]
35. Soto PF, Herrero P, Kates AM, Dence CS, Ehsani AA, Davila-Roman V, Schechtman KB, and Gropler RJ. Impact of aging on myocardial metabolic response to dobutamine. Am J Physiol Heart Circ Physiol 285: H2158–H2164, 2003.[Abstract/Free Full Text]
36. Stanley WC, Hernandez LA, Spires D, Bringas J, Wallace S, and McCormack JG. Pyruvate dehydrogenase activity and malonyl CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate. J Mol Cell Cardiol 28: 905–914, 1996.[CrossRef][Web of Science][Medline]
37. Stanley WC, Meadows SR, Kivilo KM, Roth BA, and Lopaschuk GD. -Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content. Am J Physiol Heart Circ Physiol 285: H1626–H1631, 2003.[Abstract/Free Full Text]
38. Stephens TW, Higgins AJ, Cook GA, and Harris RA. Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem J 227: 651–660, 1985.[Web of Science][Medline]
39. Thampy KG. Formation of malonyl coenzyme A in rat heart. Identification and purification of an isozyme of A carboxylase from rat heart. J Biol Chem 264: 17631–17634, 1989.[Abstract/Free Full Text]
40. Zammit VA, Fraser F, and Orstorphine CG. Regulation of mitochondrial outer-membrane carnitine palmitoyltransferase (CPT I): role of membrane-topology. Adv Enzyme Regul 37: 295–317, 1997.[CrossRef][Web of Science][Medline]

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