Research Article
Volume 4 Issue 2 - 2020
Global No-Flow Ischemia and Chemical Stress Condition Effects on D-3-hydroxybutyrate and Glucose Utilization in the Isolated Perfused Heart
Abdurazzaq Mohammed Sultan1*, Qusai A Sultan2, Abdulwahab H Bin Melaih2, Tareq H Al Kaabi2 and Belal S Barogaan2
1Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Saudi Arabia
2Faculty of Medicine, Umm Al-Qura University, Saudi Arabia
*Corresponding Author: Abdurazzaq Mohammed Sultan, Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Received: January 09, 2020; Published: January 21, 2020


The heart utilizes ketone bodies in preference to fatty acids and glucose under normal condition. This study was carried out to investigate the effect of global no-flow ischemia and chemical stress condition on the utilization of D-3-hydroxybutyrate (D-3-HB) and glucose with reference to the AMP-activated protein kinase (AMPK) and p38 mitogen activated protein kinase (p38 MAPK) signaling cascades in the isolated perfused heart. 2,4-dinitrophenol (DNP) and anisomycin (Aniso) are used to mimic hypoxia and ischemia respectively. DNP stimulated D-3-HB and glucose utilization. D-3-HB decreased the DNP-and Insulin-stimulated glucose utilization. The stimulatory effects of Insulin and DNP on glucose utilization were additive. Insulin and DNP enhanced D-3-HB utilization and the stimulatory effects of Insulin and DNP were not additive. Global no-flow ischemia-reperfusion, ionomycin (Iono) an activator of Ca2+-calmodulin-dependent protein kinase kinase (CaMKK) and anisomycin an activator of p38 MAPK stimulate the utilization of D-3-HB. STO-609 and PD-169316 are a selective inhibitor of CaMKK and p38 MAPK respectively. STO-609 and PD-169316 abolished the increase in D-3-HB utilization in response to ionomycin, anisomycin, and global no-flow ischemia-reperfusion. We conclude that these results indicate the involvement of AMPK and p38 MAPK in the regulation of D-3-HB and glucose utilization during stress, and global no-flow ischemia. Stimulatory effect on D-3-HB utilization could be mediated via the AMPK and p38 MAPK signaling cascades.

Keywords: D-3-hydroxybutyrate; Glucose; AMPK; p38 MAPK; Cardiac Metabolism; Ischemia


  1. Stanley WC., et al. “β-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content”. American Journal of Physiology-Heart and Circulatory Physiology 285 (2003): H1626-H1631.
  2. Aubert G., et al. “The Failing Heart Relies on Ketone Bodies as a Fuel”. Circulation 133.8 (2016): 698-705.
  3. Bedi KC Jr., et al. “Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure”. Circulation 133.8 (2016): 706-716. 
  4. Ho K., et al. “The contribution of fatty acid and keton body oxidation to energy production increases in the failing heart and is associated with a decrease in cardiac efficiency”. Journal of Molecular and Cellular Cardiology (2017): 112-143.
  5. Horton JL., et al. “The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense”. JCI Insight 4.4 (2019): 124079. 
  6. Pelletier A and Coderre L. “Ketone bodies alter dinitrophenol-induced glucose uptake through AMPK inhibition and oxidative stress generation in adult cardiomyocytes”. American Journal of Physiology-Endocrinology and Metabolism 292 (2007): E1325-E1332.
  7. Stanley WC., et al. “β-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content”. American Journal of Physiology-Heart and Circulatory Physiology 285 (2003P: H1626-H1631.
  8. Russell RR., et al. “AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury”. Journal of Clinical Investigation 114 (2004): 495-503.
  9. Kudo N., et al. “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”. Journal of Biological Chemistry 270 (1995): 17513-17520.
  10. Pelletier A., et al. “Adenosine 5'-monophosphate-activated protein kinase and p38 mitogen-activated protein kinase participate in the stimulation of glucose uptake by dinitrophenol in adult cardiomyocytes”. Endocrinology 146 (2005): 2285-2294.
  11. Russell RR., et al. “Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR”. American Journal of Physiology-Heart and Circulatory Physiology 277 (1999): H643-H649.
  12. Sambandam N and Lopaschuk GD. “AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart”. Progress in Lipid Research 42 (2003): 238-256.
  13. Young LH., et al. “AMP-activated protein kinase: A key stress signaling pathway in the heart”. Trends in Cardiovascular Medicine 15 (2005): 110-118.
  14. Hayashi T., et al. “Metabolic Stress and Altered Glucose Transport activation of AMP-activated protein kinase as a unifying coupling mechanism”. Diabetes 49 (2000): 527-531.
  15. Kulisz A., et al. “Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes”. American Journal of Physiology-Lung Cellular and Molecular Physiology 282.6 (2002): L1324-1329.
  16. Bogoyevitch MA., et al. “Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion”. Circulation Research 79 (1996): 162-173.
  17. Sultan AMN. “D-3-hydroxybutyrate metabolism in the perfused rat heart”. Molecular and Cellular Biochemistry 79 (1988): 113-118.
  18. Sultan AMN. “Effects of diabetes and insulin on ketone bodies metabolism in heart”. Molecular and Cellular Biochemistry 110 (1992): 17-23.
  19. Zou Z., et al. “dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts”. American Journal of Physiology-Heart and Circulatory Physiology 283 (2002): H1968-H1974.
  20. Williamson DH and Mellanby J. “D-(-)-3-hydroxybutyrate”. In: Hans Ulrich Bergmeyer (ed). Methods of Enzymatic Analysis. 4 (1974): 1836-1839.
  21. Mellanby J and Williamson DH. “Acetoacetate”. In: Hans Ulrich Bergmeyer (ed). Methods of Enzymatic Analysis. 4 (1974): 1841-1843.
  22. Gutmann I and Wahlefeld A. “L-(+)-lactate determination with lactate dehydrogenase and NAD”. In: Bergmeyer H, editor. Methods of Enzymatic Analysis (2nd edition) (1974): 1464-1468.
  23. Sultan AMN. “Utilization of D-3-hydroxybutyrate by the isolated perfused heart under global no-flow ischemia and stress condition”. UMM AL-QURA Medical Journal 5.1 (2014): 1-17.
  24. Newby AC., et al. “The control of adenosine concentration in polymorphonuclear leucocytes, cultured heart cells and isolated perfused heart from the rat”. Biochemical Journal 214 (1983): 317-323.
  25. Musi N., et al. “AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle”. American Journal of Physiology-Endocrinology and Metabolism 280 (2001): E677-E684.
  26. Morgan AJ and Jacob R. “Ionomycin enhances Ca2+ influx by stimulating store-regulated cation entry and not by a direct action at the plasma membrane”. Biochemical Journal 300 (1994): 665-672.
  27. Hawley SA., et al. “Calmodulin-dependent protein kinase kinase-βeta is an alternative upstream kinase for AMP-activated protein kinase”. Cell Metabolism 2 (2005): 9-19.
  28. Hurley RL., et al. “The Ca2+/Calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases”. Journal of Biological Chemistry 280.32 (2005): 29060-29066.
  29. Tokumitsu H., et al. “STO-609, a specific inhibitor of the Ca2+/Calmodulin-dependent protein kinase kinase”. Journal of Biological Chemistry 277 (2002): 15813-15818.
  30. Hudman D., et al. “The origin of calcium overload in rat cardiac myocytes following metabolic inhibition with 2,4-dinitrophenol”. Journal of Molecular and Cellular Cardiology 34 (2002): 859-871
  31. Kang S., et al. “Changes of cytosolic Ca+2 under metabolic inhibition in isolated rat ventricular myocytes”. The Korean Journal of Physiology and Pharmacology 9 (2005): 291-298.
  32. Rodrigo GC., et al. “Dinitrophenol pretreatment of rat ventricular myocytes protects against damage by metabolic inhibition and reperfusion”. Journal of Molecular and Cellular Cardiology 34 (2002): 555-569.
  33. Li J., et al. “AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart”. Circulation Research 97 (2005): 872-879.
  34. Kummer JL., et al. “Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase”. Journal of Biological Chemistry 272 (1997): 20490-20494.
  35. Khayat ZA., et al. “Rapid stimulation of glucose transport by mitochondrial uncoupling depends in part on cytosolic Ca2+ and cPKC”. American Journal of Physiology 5.6 (1998): C1487-1497. 
  36. Marsin AS., et al. “Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia”. Current Biology 10.20 (2000): 1247-1255.
  37. Hardie DG and Carling D. “The AMP-activated protein kinase--fuel gauge of the mammalian cell?”. European Journal of Biochemistry 246.2 (1997): 259-273.
  38. Denton RM., et al. “Stimulation by calcium ions of pyruvate dehydrogenase phosphate phosphatase”. Biochemical Journal 8.1 (1972): 161-163.
  39. Glancy Brian and Robert S Balaban. “Role of mitochondrial Ca2+ in the regulation of cellular energetics.” Biochemistry 51.14 (2012): 2959-2973. 
  40. Konrad D., et al. “Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells”. Diabetologia 48 (2005): 954-966.
  41. Ray J., et al. “Long-chain fatty acids increase basal metabolism and depolarize mitochondria in cardiac muscle cells”. American Journal of Physiology-Heart and Circulatory Physiology 282 (2002): H1495-H1501.
  42. Musi N., et al. “AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle”. American Journal of Physiology-Endocrinology and Metabolism 280 (2001): E677-E684.
  43. Dyck JR., et al. “Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5'-AMP activated protein kinase”. European Journal of Biochemistry 262 (1999): 184-190.
  44. Stapleton D., et al. “Mammalian AMP-activated protein kinase subfamily”. Journal of Biological Chemistry 271 (1996): 611-614.
  45. Hayashi T., et al. “Metabolic Stress and Altered Glucose Transport activation of AMP-activated protein kinase as a unifying coupling mechanism”. Diabetes 49 (2000): 527-531.
  46. Parkinson FE and Geiger JD. “Effects of iodotubercidin on adenosine kinase activity and nucleoside transport in DDT1 MF-2 smooth muscle cells”. Journal of Pharmacology and Experimental Therapeutics 277 (1996): 1397-1401.
  47. Aymerich I., et al. “Extracellular adenosine activates AMP-dependent protein kinase (AMPK)”. Journal of Cell Science 119 (2006): 1612-1621.
  48. Woods A., et al. “Ca2+/Calmodulin-dependent protein kinase kinase-βeta acts upstream of AMP-activated protein kinase in mammalian cells”. Cell Metabolism 2 (2005): 21-33.
  49. Sakamoto K., et al. “Deficiency of LKB1 in heart prevents ischemia-mediated activation of AMPKα2 but not AMPKα1”. American Journal of Physiology-Endocrinology and Metabolism 290 (2006): E780-E788.
  50. Da Silva CG., et al. “Extracellular nucleotides and adenosine independently activate AMP-activated protein kinase in endothelial cells: involvement of P2 receptors and adenosine transporters”. Circulation Research 98 (2006): e39-e47.
  51. Alekseev AE., et al. “Opening of cardiac sarcolemmal KATP channels by dinitrophenol separate from metabolic inhibition”. The Journal of Membrane Biology 157 (1997): 203-214.
  52. Jilkina O., et al. “Effects of K(ATP) channel openers, P-1075, pinacidil, and diazoxide, on energetics and contractile function in isolated rat hearts”. Journal of Molecular and Cellular Cardiology 34 (2002): 427-440.
  53. Sasaki N., et al. “ATP consumption by uncoupled mitochondria activates sarcolemmal K(ATP) channels in cardiac myocytes”. American Journal of Physiology-Heart and Circulatory Physiology280 (2001): H1882-H1888.
  54. Chai W., et al. “Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury”. American Journal of Physiology-Endocrinology and Metabolism 294 (2008): E183-E189.
  55. Armstrong SC. “Protein kinase activation and myocardial ischemia/reperfusion injury”. Cardiovascular Research 61 (2004): 427-436.
  56. Bogoyevitch MA., et al. “Cellular stresses differentially activate c-Jun N-terminal protein kinases and extracellular signal-regulated protein kinases in cultured ventricular myocytes”. Journal of Biological Chemistry 270 (1995): 29710-29717.
  57. Jacquet S., et al. “The relationship between p38 mitogen-activated protein kinase and AMP-activated protein kinase during myocardial ischemia”. Cardiovascular Research 76 (2007): 465-472.
  58. Stoppa GR., et al. “Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling”. Journal of Endocrinology 198 (2008): 157-168.
  59. Abdelmegeed MA., et al. “Acetoacetate activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in primary cultured rat hepatocytes: role of oxidative stress”. Journal of Pharmacology and Experimental Therapeutics 310 (2004): 728-736.
  60. Abdurazzaq MN Sultan., et al. “The Effect of Diabetes on Acetoacetate Metabolism in Heart”. International Journal of Advanced Research 5.1 (2017): 2877-2882.
  61. Rafaeloff-Phail R., et al. “Biochemical regulation of mammalian AMP-activated protein kinase activity by NAD and NADH”. Journal of Biological Chemistry 279 (2004): 52934-52939.
  62. Suter M., et al. “Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase”. Journal of Biological Chemistry 281 (2006): 32207-32216.
  63. Sultan AMN. “The effect of fasting on D-3-hydroxybutyrate metabolism in the perfused rat heart”. Molecular and Cellular Biochemistry 93 (1990): 107-118.
  64. An D Pulinilkunnil T., et al. “The metabolic "switch" AMPK regulates cardiac heparin-releasable lipoprotein lipase”. American Journal of Physiology-Endocrinology and Metabolism 288 (2005): E246-E253.
  65. Matsui Y., et al. “Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy”. Circulation Research 100 (2007): 914-922.
  66. Salt I., et al. “AMP-activated protein kinase: greater AMP dependence, and preferential nuclear localization, of complexes containing the α2 isoform”. Biochemical Journal 334 (1998): 177-187.
Citation: Abdurazzaq Mohammed Sultan., et al. “Global No-Flow Ischemia and Chemical Stress Condition Effects on D-3-hydroxybutyrate and Glucose Utilization in the Isolated Perfused Heart”. EC Emergency Medicine and Critical Care 4.2 (2020): 01-15.

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