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Regulation of and intervention into the oxidative pentose phosphate pathway and adenine nucleotide metabolism in the heart

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Abstract

The capacity of the oxidative pentose phosphate pathway (PPP) in the heart is limited, since the activity of glucose-6-phosphate dehydrogenase (G-6-PD), the first and regulating enzyme of this pathway, is very low. Two mechanisms are involved in the regulation of this pathway. Under normal conditions, G-6-PD is inhibited by NADPH. This can be overcome in the isolated perfused rat heart by increasing the oxidized glutathione and by elevating the NADP+/NADPH ratio. Besides this rapid control mechanism, there is a long-term regulation which involves the synthesis of G-6-PD. The activity of G-6-PD was elevated in the rat heart during the development of cardiac hypertrophy due to constriction of the abdominal aorta and in the non-ischemic part of the rat heart subsequent to myocardial infarction. The catecholamines isoproterenol and norepinephrine stimulated the activity of myocardial G-6-PD in a time- and dose-dependent manner. The isoproterenol-induced stimulation was cAMP-dependent and due to increased new synthesis of enzyme protein. The G-6-PD mRNA was elevated by norepinephrine. As a consequence of the stimulation of the oxidative PPP, the available pool of 5-phosphoribosyl-l-pyrophosphate (PRPP) was expanded. PRPP is an important precursor substrate for purine and pyrimidine nucleotide synthesis. The limiting step in the oxidative PPP, the G-6-PD reaction, can be bypassed with ribose. This leads to an elevation of the cardiac PRPP pool. The decline in ATP that is induced in many pathophysiological conditions was attenuated or even entirely prevented by i.v. infusion of ribose. In two in vivo rat models, the overloaded and catecholamine-stimulated heart and the infarcted heart, the normalization of the cardiac adenine nucleotide pool by ribose was accompanied by an improvement of global heart function. Combination of ribose with adenine or inosine in isoproterenol-treated rats was more effective to restore completely the cardiac ATP level within a short period of time than either intervention alone. (Mol Cell Biochem 160/161: 101–109, 1996)

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References

  1. Reimer KA, Hill ML, Jennings RB: Prolonged depletion of ATP and of the adenine nucleotide pool due to delayed resynthesis of adenine nucleotides following reversible myocardial ischemic injury in dogs. J Mol Cell Cardiol 13: 229–239, 1981

    Google Scholar 

  2. Zimmer H-G, Ibel H: Ribose accelerates the repletion of the ATP pool during recovery from reversible ischemia of the rat myocardium. J Mol Cell Cardiol 16: 863–866, 1984

    Google Scholar 

  3. Gerlach E, Deuticke B, Dreisbach: Der Nucleotid-Abbau im Herzen bei Sauerstoffmangel und seine mögliche Bedeutung für die Coronardurchblutung. Naturwiss 50: 228–229, 1963

    Google Scholar 

  4. Imai S, Riley AL, Berne RM: Effect of ischemia on adenine nucleotides in cardiac and skeletal muscle. Circ Res 15: 443–450, 1964

    Google Scholar 

  5. Zimmer H-G, Trendelenburg C, Kammermeier H, Gerlach E: De novo synthesis of myocardial adenine nucleotides in the rat. Acceleration during recovery from oxygen deficiency. Circ Res 32; 635–642, 1973

    Google Scholar 

  6. Zimmer H-G, Ibel H, Suchner U: β-Adrenergic agonists stimulate the oxidative pentose phosphate pathway in the rat heart. Circ Res 67: 1525–1534, 1990

    Google Scholar 

  7. Eggleston LV, Krebs HA: Regulation of the pentose phosphate cycle. Biochem J 138: 425–435, 1974

    Google Scholar 

  8. Glock GE, McLean P: Further studies on the properties and assay of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase of rat liver. Biochem J 55: 400–408, 1953

    Google Scholar 

  9. Glock GE, McLean P: Levels of enzymes of the direct oxidative pathway of carbohydrate metabolism in mammalian tissues and tumours. Biochem J 56: 171–175, 1954

    Google Scholar 

  10. Zimmer H-G, Gerlach E: Stimulation of myocardial adenine nucleotide biosynthesis by pentoses and pentitols. Pflügers Arch 376: 223–227, 1978

    Google Scholar 

  11. Zimmer H-G, Ibel H, Suchner U, Schad H: Ribose intervention in the cardiac pentose phosphate pathway is not species-specific. Science 223: 712–714, 1984

    Google Scholar 

  12. Negelein E, Haas E: Über die Wirkungsweise des Zwischenferments. Biochem Z 282: 206–220, 1935

    Google Scholar 

  13. Zimmer H-G, Bünger R, Koschine H, Steinkopff G: Rapid stimulation of the hexose monophosphate shunt in the isolated perfused rat heart: Possible involvement of oxidized glutathione. J Mol Cell Cardiol 13: 531–535, 1981

    Google Scholar 

  14. Borregaard N, Schwartz JH, Tauber AI: Proton secretion by stimulated neutrophils. Significance of hexose monophosphate shunt activity as source of electrons and proteins for the respiratory burst. J Clin Invest 74: 455–459, 1984

    Google Scholar 

  15. Zimmer H-G, Ibel H, Gerlach E: Significance of the hexose monophosphate shunt in experimentally induced cardiac hypertrophy. Basic Res Cardiol 75: 207–213, 1980

    Google Scholar 

  16. Bechtelsheimer H, Zimmer H-G, Gedigk P: Histologische und histochemische Untersuchungen am nicht-infarzierten Myokardanteil beim experimentellen Herzinfarkt der Ratte. Virchows Arch. Abt. B Zellpath. 9: 115–124, 1971

    Google Scholar 

  17. Zimmer H-G, Gerlach E: Some metabolic features of the development of experimentally induced cardiac hypertrophy. Eur Heart J 3 (Suppl A):83–92, 1982

    Google Scholar 

  18. Zierhut W, Zimmer H-G: Significance of myocardial α- and β-adrenoceptors in catecholamine-induced cardiac hypertrophy. Circ Res 65:1417–1425, 1989

    Google Scholar 

  19. Zimmer H-G, Lankat-Buttgereit B, Kolbeck-Rühmkorff C, Nagano T, Zierhut W: Effects of norepinephrine on the oxidative pentose phosphate pathway in the rat heart. Circ Res 71: 451–459, 1992

    Google Scholar 

  20. Riabowol KT, Fink JS, Gilman MZ, Walsh DA, Goodman RH, Feramisco JR: The catalytic subunit of cAMP-dependent protein kinase induces expression of genes containing cAMP-responsive enhancer elements. Nature 336: 83–86, 1988

    Google Scholar 

  21. Sassone-Corsi P, Visvader J, Ferland L, Mellon PL, Verma IM: Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-responsive element. Genes and Development 2: 1529–1538, 1988

    Google Scholar 

  22. Berridge MJ, Irvine RF: Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315–321, 1984

    Google Scholar 

  23. Nishizuka Y: The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334: 661–665, 1988

    Google Scholar 

  24. Iwaki K, Sukhatme VP, Shubeita HE, Chien KR: α- and β-Adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. J Biol Chem 265: 13809–13817, 1990

    Google Scholar 

  25. Kolbeck-Rühmkorff C, Horban A, Zimmer H-G: Effect of pressure and volume overload on proto-oncogene expression in the isolated working rat heart. Cardiovasc Res 27: 1998–2004, 1993

    Google Scholar 

  26. Seymour A-ML, Eldar H, Radda GK: Hyperthyroidism results in increased glycolyticcapacity in the rat heart. A 31P-NMR study. Biochim Biophys Acta 1055: 107–116, 1990

    Google Scholar 

  27. Wagner KR, Kauffman FC, Max SR: The Penrose phosphate pathway in regenerating skeletal muscle. Biochem J 170: 17–22, 1978

    Google Scholar 

  28. Glock GE, McLean P: Levels of oxidized and reduced diphosphopyridine nucleotide and triphosphopyridine nucleotide in animals tissues. Biochem J 61: 388–390, 1955

    Google Scholar 

  29. Dow JW, Nigdikar S, Bowditch J: Adenine nucleotide synthesis de novo in mature rat cardiac myocytes. Biochim Biophys Acta 847: 223–227, 1985

    Google Scholar 

  30. Zimmer H-G, Ibel H, Steinkopff G, Korb G: Reduction of the isoproterenol-induced alterations in cardiac adenine nucleotides and morphology by ribose. Science 207: 319–321, 1980

    Google Scholar 

  31. Zimmer H-G, Peffer H: Metabolic aspects of the development of experimental cardiac hypertrophy. Basic Res Cardiol 81 (Suppl. 1): 127–137, 1986

    Google Scholar 

  32. Chatham JC, Challiss RAJ, Radda GK, Seymour A-ML: Studies on the protective effect of ribose in myocardial ischaemia by using 31P-nuclear-magnetic-resonance spectroscopy. Biochem Soc Trans 13: 885–886, 1985

    Google Scholar 

  33. Pasque MK, Spray TL, Pellom GL, van Trigt P, Peyton RB, Currie W, Wechsler AS: Ribose-enhanced myocardial recovery following ischemia in the isolated working rat heart. J Thorac Cardiovac Surg 83:390–398, 1982

    Google Scholar 

  34. Seifart HI, Delabar U, Siess M: The influence of various precursors on the concentration of energy-rich phosphates and pyridine nucleotides in cardiac tissue and its possible meaning for anoxic survival. Basic Res Cardiol 75: 57–61, 1980

    Google Scholar 

  35. Haas GS, DeBoer LWV, O'Keefe DD, Bodenhamer RM, Geffin GA, Drop LJ, Teplick RS, Daggett WM: Reduction of postischemic myocardial dysfunction by substrate repletion during reperfusion. Circulation 70 (suppl I): 165–174, 1984

    Google Scholar 

  36. Mauser M, Hoffmeister HM, Nienaber C, Schaper W: Influence of ribose, adenosine, and ‘AICAR’ on the rate of myocardial adenosine triphosphate synthesis during reperfusion after coronary artery occlusion in the dog. Circ Res 56: 220–230, 1985

    Google Scholar 

  37. Ward HB, St.Cyr JA, Cogordan JA, Alyono D, Bioanco RW, Kriett JM, Foker JE: Recovery of adenine nucleotide levels after global ischemia in dogs. Surgery 96: 248–253, 1984

    Google Scholar 

  38. Wyatt DA, Ely SW, Lasley RD, Walsh R, Mainwaring R, Berne RM, Mentzer RM: Purine-enriched asanguineous cardioplegia retards adenosine triphosphate degradation during ischemia and improves postischemic ventricular function. J Thorac Cardiovasc Surg 97: 771–778, 1989

    Google Scholar 

  39. Zimmer H-G, Martins PA, Marschner G: Myocardial infarction in rats: Effects of metabolic and pharmacologic interventions. Basic Res Cardiol 84: 332–343, 1989

    Google Scholar 

  40. Clay MA, Stewart-Richardson P, Tasset DM, Williams JF: Chronic alcoholic cardiomyopathy. Protection of the isolated ischaemic working heart by ribose. Biochem Internat 17: 791–800, 1988

    Google Scholar 

  41. Zoref-Shani E, Shainberg A, Sperling O: Characterization of purine nucleotide metabolism in primary rat muscle cultures. Biochim Biophys Acta 716: 324–330, 1982

    Google Scholar 

  42. Zimmer H-G: Measurement of left ventricular hemodynamic parameters in closed-chest rats under control and various pathophysiologic conditions. Basic Res Cardiol 78: 77–84, 1983

    Google Scholar 

  43. Zimmer H-G: Normalization of depressed heart function in rats by ribose. Science 220: 81–82, 1983

    Google Scholar 

  44. Zimmer H-G, Zierhut W, Marschner G: Combination of ribose with calcium antagonist and β-blocker treatment in closed-chest rats. J Mol Cell Cardiol 19: 635–639, 1987

    Google Scholar 

  45. Isselhard W, Hamaji M, Mäurer W, Erkens H, Welter H: Adenosine-induced increase in myocardial adenine nucleotides without adenosine-induced systemic hypotension. Basic Res Cardiol 80: 47–61, 1985

    Google Scholar 

  46. Seesko RC, Zimmer H-G: Hemodynamic effects of inosine in combination with positive and negative inotropic drugs: Studies on rats in vivo. J Cardiovasc Pharmacol 16: 249–256, 1990

    Google Scholar 

  47. Zimmer H-G, Schneider A: Nucleotide precursors modify the effects of isoproterenol. Studies on heart function and cardiac adenine nucleotide content in intact rats. Circ Res 69: 1575–1582, 1991

    Google Scholar 

  48. Lee RGL, Springer C, Kasulis P, Lanir A, Frazer J, Clouse ME: Nuclear magnetic resonance assessment of adenosine triphosphate (ATP) dynamics in ischemic mouse livers perfused with adenine and ribose. Invest Rachel 22: 685–687, 1987

    Google Scholar 

  49. McAnulty JF, Southard JH, Belzer FO: Improved maintenance of adenosine triphosphate in five-day perfused kidneys with adenine and ribose. Transplant Proc 19: 1376–1379, 1987

    Google Scholar 

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  1. Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstr. 27, D-04103, Leipzig, Germany

    Heinz-Gerd Zimmer

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Zimmer, HG. Regulation of and intervention into the oxidative pentose phosphate pathway and adenine nucleotide metabolism in the heart. Mol Cell Biochem 160, 101–109 (1996). https://doi.org/10.1007/BF00240038

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