Skip to main content
SpringerLink
Log in

Elevated Na+–H+ Exchanger Expression and Its Role in Myocardial Disease

  • Chapter
  • First Online:
Molecular Defects in Cardiovascular Disease

  • 601 Accesses

Abstract

The mammalian Na+–H+ exchanger isoform 1 (NHE1) is a plasma ­membrane protein that regulates intracellular pH in the myocardium by removing one intracellular hydrogen ion in exchange for one extracellular sodium ion. While NHE1 regulates intracellular pH, it is also involved in the damage that occurs to the myocardium with ischemia and reperfusion. Additionally, NHE1 levels are elevated in cardiac diseases such as hypertrophy, and NHE1 inhibition can reduce ischemia–reperfusion damage and prevent heart hypertrophy in animal models. Recently, it has been demonstrated that elevation of NHE1 levels occurs in several kinds of hearts disease. Surprisingly, the effect of elevation of these levels is ­varied, sometimes having beneficial and sometimes detrimental effects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fliegel L. The Na+/H+ exchanger isoform 1. Int J Biochem Cell Biol. 2005;37:33–7.

    Article  PubMed  CAS  Google Scholar 

  2. Fliegel L, Dyck JRB, Wang H, et al. Cloning and analysis of the human myocardial Na+/H+ exchanger. Mol Cell Biochem. 1993;125:137–43.

    Article  PubMed  CAS  Google Scholar 

  3. Fliegel L, Sardet C, Pouysségur J, et al. Identification of the protein and cDNA of the cardiac Na+/H+ exchanger. FEBS Lett. 1991;279:25–9.

    Article  PubMed  CAS  Google Scholar 

  4. Fliegel L. Functional and cellular regulation of the myocardial Na+/H+ exchanger. J Thromb Thrombolysis. 1999;8:9–14.

    Article  PubMed  CAS  Google Scholar 

  5. Orlowski J, Kandasamy RA, Shull GE. Molecular cloning of putative members of the Na+/H+ exchanger gene family. J Biol Chem. 1992;267:9331–9.

    PubMed  CAS  Google Scholar 

  6. Takaichi K, Wang D, Balkovetz DF, et al. Cloning, sequencing, and expression of Na+/H+ antiporter cDNAs from human tissues. Am J Physiol Cell Physiol. 1992;262:C1069–76.

    CAS  Google Scholar 

  7. Orlowski J, Grinstein S. Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflugers Arch. 2004;447:549–65.

    Article  PubMed  CAS  Google Scholar 

  8. Karmazyn M, Gan T, Humphreys RA, et al. The myocardial Na+–H+ exchange. Structure, regulation, and its role in heart disease. Circ Res. 1999;85:777–86.

    PubMed  CAS  Google Scholar 

  9. Malo ME, Fliegel L. Physiological role and regulation of the Na+/H+ exchanger. Can J Physiol Pharmacol. 2006;84:1081–95.

    Article  PubMed  CAS  Google Scholar 

  10. Sardet C, Franchi A, Pouysségur J. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell. 1989;56:271–80.

    Article  PubMed  CAS  Google Scholar 

  11. Wakabayashi S, Pang T, Su X, et al. A novel topology model of the human Na+/H+ exchanger isoform 1. J Biol Chem. 2000;275:7942–9.

    Article  PubMed  CAS  Google Scholar 

  12. Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982;157:105–32.

    Article  PubMed  CAS  Google Scholar 

  13. Landau M, Herz K, Padan E, et al. Model structure of the Na+/H+ exchanger 1 (NHE1): functional and clinical implications. J Biol Chem. 2007;282:37854–63.

    Article  PubMed  CAS  Google Scholar 

  14. Fliegel L, Haworth RS, Dyck JRB. Characterization of the placental brush border membrane Na+/H+ exchanger: Identification of thiol-dependent transitions in apparent molecular size. Biochem J. 1993;289:101–7.

    PubMed  CAS  Google Scholar 

  15. Fafournoux P, Noel J, Pouysségur J. Evidence that Na+/H+ exchanger isoforms NHE1 and NHE3 exist as stable dimers in membranes with a high degree of specificity for homodimers. J Biol Chem. 1994;269:2589–96.

    PubMed  CAS  Google Scholar 

  16. Hunte C, Screpanti E, Venturi M, et al. Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature. 2005;435:1197–202.

    Article  PubMed  CAS  Google Scholar 

  17. Brett CL, Donowitz M, Rao R. Evolutionary origins of eukaryotic sodium/proton exchangers. Am J Physiol Cell Physiol. 2005;288:C223–39.

    Article  PubMed  CAS  Google Scholar 

  18. Putney LK, Denker SP, Barber DL. The changing face of the Na+/H+ exchanger, NHE1: structure, regulation, and cellular actions. Annu Rev Pharmacol Toxicol. 2002;42:527–52.

    Article  PubMed  CAS  Google Scholar 

  19. Sardet C, Franchi A, Pouysségur J. Molecular cloning of the growth-factor-activatable human Na+/H+ antiporter. Cold Spring Harb Symp Quant Biol. 1988;LIII:1011–8.

    Google Scholar 

  20. Petrecca K, Atanasiu R, Grinstein S, et al. Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium. Am J Physiol Heart Circ Physiol. 1999;276:H709–17.

    CAS  Google Scholar 

  21. Malakooti J, Dahdal RY, Schmidt L, et al. Molecular cloning, tissue distribution, and functional expression of the human Na+/H+ exchanger NHE2. Am J Physiol Gen Physiol. 1999;277:G383–90.

    CAS  Google Scholar 

  22. Amemiya M, Loffing J, Lotscher M, et al. Expression of NHE-3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney Int. 1995;48:1206–15.

    Article  PubMed  CAS  Google Scholar 

  23. Biemesderfer D, Pizzonia J, Abu-Alfa A, et al. NHE3: a exchanger isoform of renal brush border. Am J Physiol Ren Physiol. 1993;265:F736–42.

    CAS  Google Scholar 

  24. Baird NR, Orlowski J, Szabo EZ, et al. Molecular cloning, genomic organization, and functional expression of Na+/H+ exchanger isoform 5 (NHE5) from human brain. J Biol Chem. 1999;274:4377–82.

    Article  PubMed  CAS  Google Scholar 

  25. Nakamura N, Tanaka S, Teko Y, et al. Four Na+/H+ exchanger isoforms are distributed to Golgi and post-Golgi compartments and are involved in organelle pH regulation. J Biol Chem. 2005;280:1561–72.

    Article  PubMed  CAS  Google Scholar 

  26. Numata M, Petrecca K, Lake N, et al. Identification of a mitochondrial Na+/H+ exchanger. J Biol Chem. 1998;273:6951–9.

    Article  PubMed  CAS  Google Scholar 

  27. Lee SH, Kim T, Park ES, et al. NHE10, an osteoclast-specific member of the Na+/H+ exchanger family, ­regulates osteoclast differentiation and survival ­[corrected]. Biochem Biophys Res Commun. 2008;369:320–6.

    Article  PubMed  CAS  Google Scholar 

  28. Xiang M, Feng M, Muend S, et al. A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension. Proc Natl Acad Sci USA. 2007;104:18677–81.

    Article  PubMed  CAS  Google Scholar 

  29. Schushan M, Xiang M, Bogomiakov P, et al. Model-guided mutagenesis drives functional studies of human NHA2, implicated in hypertension. J Mol Biol. 2010;396:1181–96.

    Article  PubMed  CAS  Google Scholar 

  30. Zerbini G, Maestroni A, Breviario D, et al. Alternative splicing of NHE-1 mediates Na–Li countertransport and associates with activity rate. Diabetes. 2003;52:1511–8.

    Article  PubMed  CAS  Google Scholar 

  31. Karmazyn M, Moffat MP. Role of Na/H exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox. Cardiovasc Res. 1993;27:915–24.

    Article  PubMed  CAS  Google Scholar 

  32. Haworth RS, Avkiran M. Receptor-mediated regulation of the cardiac sarcolemmal Na+/H+ exchanger. Mechanisms and (patho)physiological significance. In: Karmazyn M, Avkiran M, Fliegel L, editors. The Na+/H+ exchanger, from molecular to its role in disease. Boston: Kluwer; 2003. p. 191–209.

    Google Scholar 

  33. Moor AN, Fliegel L. Protein kinase mediated regulation of the Na+/H+ exchanger in the rat myocardium by MAP-kinase-dependent pathways. J Biol Chem. 1999;274:22985–92.

    Article  PubMed  CAS  Google Scholar 

  34. Moor AN, Gan XT, Karmazyn M, et al. Activation of Na+/H+ exchanger-directed protein kinases in the ischemic and ischemic-reperfused rat myocardium. J Biol Chem. 2001;27:16113–22.

    Article  Google Scholar 

  35. Liu S, Piwnica-Worms D, Lieberman M. Intracellular pH regulation in cultured embryonic chick heart cells. Na+-dependent Cl−/HCO −3 exchange. J Gen Physiol. 1990;96:1247–69.

    Article  PubMed  CAS  Google Scholar 

  36. Lagadic-Gossmann D, Buckler KJ, Vaughan-Jones RD. Role of bicarbonate in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte. J Physiol. 1992;458:361–84.

    PubMed  CAS  Google Scholar 

  37. Lagadic-Gossmann D, Vaughan-Jones RD, Buckler KJ. Adrenaline and extracellular ATP switch between two modes of acid extrusion in the guinea-pig ventricular myocyte. J Physiol. 1992;458:385–407.

    PubMed  CAS  Google Scholar 

  38. Dart C, Vaughan-Jones RD. Na+–HCO −3 symport in the sheep cardiac purkinje fibre. J Physiol. 1992;451:365–85.

    PubMed  CAS  Google Scholar 

  39. Grace AA, Kirschenlohr HL, Metcalfe JC, et al. Regulation of intracellular pH in the perfused heart by external HCO −3 and Na+–H+ exchange. Am J Physiol Heart Circ Physiol. 1993;265:H289–98.

    CAS  Google Scholar 

  40. Vandenberg JI, Metcalfe JC, Grace AA. Mechanisms of pHi recovery after global ischemia in the perfused heart. Circ Res. 1993;72:993–1003.

    PubMed  CAS  Google Scholar 

  41. Vandenberg JI, Metcalfe JC, Grace AA. Intracellular pH recovery during respiratory acidosis in perfused hearts. Am J Physiol. 1994;266:C489–97.

    PubMed  CAS  Google Scholar 

  42. Meima ME, Mackley JR, Barber DL. Beyond ion translocation: structural functions of the sodium–hydrogen exchanger isoform-1. Curr Opin Nephrol Hypertens. 2007;16:365–72.

    Article  PubMed  CAS  Google Scholar 

  43. Pouyssegur J, Sardet C, Franchi A, et al. A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc Natl Acad Sci USA. 1984;81:4833–7.

    Article  PubMed  CAS  Google Scholar 

  44. Bell SM, Schreiner CM, Schultheis PJ, et al. Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures. Am J Physiol Cell Physiol. 1999;276:C788–95.

    CAS  Google Scholar 

  45. Cox GA, Lutz CM, Yang C-L, et al. Sodium/hydrogen exchanger gene defect in slow-wave epilepsy mice. Cell. 1997;91:139–48.

    Article  PubMed  CAS  Google Scholar 

  46. Putney LK, Barber DL. Na–H exchange-dependent increase in intracellular pH times G2/M entry and transition. J Biol Chem. 2003;278:44645–9.

    Article  PubMed  CAS  Google Scholar 

  47. Putney LK, Barber DL. Expression profile of genes regulated by activity of the Na–H exchanger NHE1. BMC Genomics. 2004;5:46–59.

    Article  PubMed  CAS  Google Scholar 

  48. Wang H, Singh D, Fliegel L. The Na+/H+ antiporter potentiates growth and retinoic- acid induced differentiation of P19 embryonal carcinoma cells. J Biol Chem. 1997;272:26545–9.

    Article  PubMed  CAS  Google Scholar 

  49. Rao GN, Sardet C, Pouyssegur J, et al. Na+/H+ antiporter gene expression increases during retinoic acid-induced granulocytic differentiation of HL60 cells. J Cell Physiol. 1992;151:361–6.

    Article  PubMed  CAS  Google Scholar 

  50. Khaled AR, Moor AN, Li A, et al. Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol Cell Biol. 2001;21:7545–57.

    Article  PubMed  CAS  Google Scholar 

  51. Reshkin SJ, Bellizzi A, Caldeira S, et al. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent ­transformation-associated phenotypes. FASEB J. 2000;14:2185–97.

    Article  PubMed  CAS  Google Scholar 

  52. McLean LA, Roscoe J, Jorgensen NK, et al. Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am J Physiol Cell Physiol. 2000;278:C676–88.

    PubMed  CAS  Google Scholar 

  53. Rich IN, Worthington-White D, Garden OA, et al. Apoptosis of leukemic cells accompanies reduction in intracellular pH after targeted inhibition of the Na+/H+ exchanger. Blood. 2000;95:1427–34.

    PubMed  CAS  Google Scholar 

  54. Reshkin SJ, Bellizzi A, Albarani V, et al. Phosphoinositide 3-kinase is involved in the tumor-specific activation of human breast cancer cell Na+/H+ exchange, motility, and invasion induced by serum deprivation. J Biol Chem. 2000;275:5361–9.

    Article  PubMed  CAS  Google Scholar 

  55. Cardone RA, Bagorda A, Bellizzi A, et al. Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. Mol Biol Cell. 2005;16:3117–27.

    Article  PubMed  CAS  Google Scholar 

  56. Paradiso A, Cardone RA, Bellizzi A, et al. The Na+–H+ exchanger-1 induces cytoskeletal changes involving reciprocal RhoA and Rac1 signaling, resulting in motility and invasion in MDA-MB-435 cells. Breast Cancer Res. 2004;6:R616–28.

    Article  PubMed  CAS  Google Scholar 

  57. Allen DG, Xiao XH. Role of the cardiac Na+/H+ exchanger during ischemia and reperfusion. Cardiovasc Res. 2003;57:934–41.

    Article  PubMed  CAS  Google Scholar 

  58. Lazdunski M, Frelin C, Vigne P. The sodium/hydrogen exchange system in cardiac cells. Its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol. 1985;17:1029–42.

    Article  PubMed  CAS  Google Scholar 

  59. Avkiran M. Protection of the ischaemic myocardium by Na+/H+ exchange inhibitors: potential mechanisms of action. Basic Res Cardiol. 2001;96:306–11.

    Article  PubMed  CAS  Google Scholar 

  60. Karmazyn M, Sawyer M, Fliegel L. The Na+/H+ exchanger: a target for cardiac therapeutic intervention. Curr Drug Targets Cardiovasc Haematol Disord. 2005;5:323–35.

    Article  PubMed  CAS  Google Scholar 

  61. Avkiran M, Marber MS. Na+/H+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol. 2002;39:747–53.

    Article  PubMed  CAS  Google Scholar 

  62. Karmazyn M. Amiloride enhances post ischemic recovery: possible role of Na+/H+ exchange. Am J Physiol Heart Circ Physiol. 1988;255:H608–15.

    CAS  Google Scholar 

  63. Scholz W, Albus U, Counillon L, et al. Protective effects of HOE642, a selective sodium–hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res. 1995;29:260–8.

    PubMed  CAS  Google Scholar 

  64. Gumina RJ, Mizumura T, Beier N, et al. A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. J Pharmacol Exp Ther. 1998;286:175–83.

    PubMed  CAS  Google Scholar 

  65. Coccaro E, Karki P, Cojocaru C, et al. Phenylephrine and sustained acidosis activate the neonatal rat cardiomyocyte Na+/H+ exchanger through phosphorylation of amino acids Ser770 and Ser771. Am J Physiol Heart Circ Physiol. 2009;297:H846–58.

    Article  PubMed  CAS  Google Scholar 

  66. Kusumoto K, Haist JV, Karmazyn M. Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2001;280:H738–45.

    PubMed  CAS  Google Scholar 

  67. Yoshida H, Karmazyn M. Na+/H+ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium. Am J Physiol Heart Circ Physiol. 2000;278:H300–4.

    PubMed  CAS  Google Scholar 

  68. Kilic A, Velic A, De Windt LJ, et al. Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Circulation. 2005;112:2307–17.

    Article  PubMed  CAS  Google Scholar 

  69. Karmazyn M, Liu Q, Gan XT, et al. Aldosterone increases NHE-1 expression and induces NHE-1-dependent hypertrophy in neonatal rat ventricular myocytes. Hypertension. 2003;42:1171–6.

    Article  PubMed  CAS  Google Scholar 

  70. Karmazyn M. Role of NHE-1 in cardiac hypertrophy and heart failure. In: Karmazyn M, Avkiran M, Fliegel L, editors. The Na+/H+ exchanger, from molecular to its role in disease. Boston: Kluwer; 2003. p. 211–9.

    Google Scholar 

  71. Cingolani HE, Alvarez BV, Ennis IL, et al. Stretch-induced alkalinization of feline papillary muscle: an autocrine-paracrine system. Circ Res. 1998;83:775–80.

    PubMed  CAS  Google Scholar 

  72. Cingolani HE, Ennis IL. Sodium–hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation. 2007;115:1090–100.

    Article  PubMed  Google Scholar 

  73. Dulce RA, Hurtado C, Ennis IL, et al. Endothelin-1 induced hypertrophic effect in neonatal rat cardiomyocytes: involvement of Na+/H+ and Na+/Ca2+ exchangers. J Mol Cell Cardiol. 2006;41:807–15.

    Article  PubMed  CAS  Google Scholar 

  74. Dumont EA, Reutelingsperger CP, Smits JF, et al. Real-time imaging of apoptotic cell-membrane changes at the single-cell level in the beating murine heart. Nat Med. 2001;7:1352–5.

    Article  PubMed  CAS  Google Scholar 

  75. Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest. 1996;74:86–107.

    PubMed  CAS  Google Scholar 

  76. Dumont EA, Hofstra L, van Heerde WL, et al. Cardiomyocyte death induced by myocardial ischemia and reperfusion: measurement with recombinant human annexin-V in a mouse model. Circulation. 2000;102:1564–8.

    PubMed  CAS  Google Scholar 

  77. Saraste A, Pulkki K, Kallajoki M, et al. Apoptosis in human acute myocardial infarction. Circulation. 1997;95:320–3.

    PubMed  CAS  Google Scholar 

  78. Veinot JP, Gattinger DA, Fliss H. Early apoptosis in human myocardial infarcts. Hum Pathol. 1997;28:485–92.

    Article  PubMed  CAS  Google Scholar 

  79. Sun HY, Wang NP, Halkos ME, et al. Involvement of Na+/H+ exchanger in hypoxia/re-oxygenation-induced neonatal rat cardiomyocyte apoptosis. Eur J Pharmacol. 2004;486:121–31.

    Article  PubMed  CAS  Google Scholar 

  80. Jung YS, Kim MY, Kim MJ, et al. Pharmacological profile of KR-33028, a highly selective inhibitor of Na+/H+ exchanger. Eur J Pharmacol. 2006;535:220–7.

    Article  PubMed  CAS  Google Scholar 

  81. Chakrabarti S, Hoque AN, Karmazyn M. A rapid ­ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium–hydrogen exchange inhibitor HOE 642 (cariporide). J Mol Cell Cardiol. 1997;29:3169–74.

    Article  PubMed  CAS  Google Scholar 

  82. Javadov S, Choi A, Rajapurohitam V, et al. NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res. 2008;77:416–24.

    Article  PubMed  CAS  Google Scholar 

  83. Garg S, Hofstra L, Reutelingsperger C, et al. Apoptosis as a therapeutic target in acutely ischemic myocardium. Curr Opin Cardiol. 2003;18:372–7.

    Article  PubMed  Google Scholar 

  84. Aker S, Snabaitis AK, Konietzka I, et al. Inhibition of the Na+/H+exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits. Cardiovasc Res. 2004;63:273–82.

    Article  PubMed  CAS  Google Scholar 

  85. Humphreys RA, Haist JV, Chakrabarti S, et al. Orally administered NHE1 inhibitor cariporide reduces acute responses to coronary occlusion and reperfusion. Am J Physiol Heart Circ Physiol. 1999;276:H749–57.

    CAS  Google Scholar 

  86. Maekawa N, Abe J, Shishido T, et al. Inhibiting p90 ribosomal S6 kinase prevents Na+–H+ exchanger-mediated cardiac ischemia-reperfusion injury. Circulation. 2006;113:2516–23.

    Article  PubMed  CAS  Google Scholar 

  87. Avkiran M, Cook AR, Cuello F. Targeting Na+/H+ exchanger regulation for cardiac protection: a RSKy approach? Curr Opin Pharmacol. 2008;8(2):133–40.

    Article  PubMed  CAS  Google Scholar 

  88. Grenier AL, Abu-ihweij K, Zhang G, et al. Apoptosis-induced alkalinization by the Na+/H+ exchanger isoform 1 is mediated through phosphorylation of amino acids Ser726 and Ser729. Am J Physiol Cell Physiol. 2008;295:C883–96.

    Article  PubMed  CAS  Google Scholar 

  89. Dilley RJ, Farrelly CA, Allen TJ, et al. Diabetes induces Na/H exchange activity and hypertrophy of rat mesenteric but not basilar arteries. Diab Res Clin Pract. 2005;70:201–8.

    Article  CAS  Google Scholar 

  90. Little PJ, Dilley RJ. Role of Na–H exchanger in vascular remodelling in diabetes. In: Karmazyn M, Avkiran M, Fliegel L, editors. The Na+/H+ exchanger, from molecular to its role in disease. Boston: Kluwer; 2003. p. 159–75.

    Google Scholar 

  91. Vial G, Dubouchaud H, Couturier K, et al. Na+/H+ exchange inhibition with cariporide prevents alterations of coronary endothelial function in streptozotocin-induced diabetes. Mol Cell Biochem. 2008;310:93–102.

    Article  PubMed  CAS  Google Scholar 

  92. Phillis JW, Pilitsis JG, O’Regan MH. The potential role of the Na+/H+ exchanger in ischemia/reperfusion injury of the central nervous system. In: Karmazyn M, Avkiran M, Fliegel L, editors. The Na+/H+ exchanger, from molecular to its role in disease. Boston: Kluwer; 2003. p. 177–89.

    Google Scholar 

  93. Gumina RJ, Daemmgen J, Gross GJ. Inhibition of the Na+/H+ exchanger attenuates phase 1b ischemic arrhythmias and reperfusion-induced ventricular fibrillation. Eur J Pharmacol. 2000;396:119–24.

    Article  PubMed  CAS  Google Scholar 

  94. Aye NN, Komori S, Hashimoto K. Effects and interaction, of cariporide and preconditioning on cardiac arrhythmias and infarction in rat in vivo. Br J Pharmacol. 1999;127:1048–55.

    Article  PubMed  CAS  Google Scholar 

  95. Gazmuri RJ, Ayoub IM, Hoffner E, et al. Successful ventricular defibrillation by the selective sodium–hydrogen exchanger isoform-1 inhibitor cariporide. Circulation. 2001;104:234–9.

    PubMed  CAS  Google Scholar 

  96. Gumina RJ, Gross GJ. If ischemic preconditioning is the gold standard, has a platinum standard of cardioprotection arrived? Comparison with NHE inhibition. J Thromb Thrombolysis. 1999;8:39–44.

    Article  PubMed  CAS  Google Scholar 

  97. Gumina RJ, Buerger E, Eickmeier C, et al. Inhibition of the Na+/H+ exchanger confers greater cardioprotection against 90 minutes of myocardial ischemia than ischemic preconditioning in dogs. Circulation. 1999;100:2519–26, discussion 469–472.

    PubMed  CAS  Google Scholar 

  98. Myers ML, Karmazyn M. Improved cardiac function after prolonged hypothermic ischemia with the exchange Na+/H+ inhibitor HOE 694. Ann Thorac Surg. 1996;61:1400–6.

    Article  PubMed  CAS  Google Scholar 

  99. Kim YI, Herijgers P, Laycock SK, et al. Na+/H+ exchange inhibition improves long-term myocardial preservation. Ann Thorac Surg. 1998;66:436–42.

    Article  PubMed  CAS  Google Scholar 

  100. Kim YI, Herijgers P, Van Lommel A, et al. Na+/H+ exchange inhibition improves post-transplant myocardial compliance in 4-hour stored donor hearts. Cardiovasc Surg. 1998;6:67–75.

    Article  PubMed  CAS  Google Scholar 

  101. Gazmuri RJ, Ayoub IM. NHE-1 inhibition: a ­potential new treatment for resuscitation from ­cardiac arrest. In: Karmazyn M, Avkiran M, Fliegel L, editors. The Na+/H+ exchanger, from molecular to its role in ­disease. Boston: Kluwer; 2003. p. 291–308.

    Google Scholar 

  102. Wu D, Arias J, Bassuk J, et al. Na+/H+ exchange inhibition delays the onset of hypovolemic circulatory shock in pigs. Shock. 2008;29:519–25.

    PubMed  CAS  Google Scholar 

  103. Rupprecht HJ, vom Dahl J, Terres W, et al. Cardioprotective effects of the Na+/H+ exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA. Circulation. 2000;101:2902–8.

    PubMed  CAS  Google Scholar 

  104. Zeymer U, Suryapranata H, Monassier JP, et al. The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial. J Am Coll Cardiol. 2001;38:1644–50.

    Article  PubMed  CAS  Google Scholar 

  105. Boyce SW, Bartels C, Bolli R, et al. Impact of sodium–hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: results of the CABG surgery cohort of the GUARDIAN study. J Thorac Cardiovasc Surg. 2003;126:420–7.

    Article  PubMed  CAS  Google Scholar 

  106. Fleisher LA, Newman MF, St. Aubin LB, et al. Efficacy of zoniporide, an Na/H exchange ion inhibitor, for reducing perioperative cardiovascular events in vascular surgery patients. J Cardiothorac Vasc Anesth. 2005;19:570–6.

    Article  PubMed  CAS  Google Scholar 

  107. Dyck JRB, Maddaford T, Pierce GN, et al. Induction of expression of the sodium–hydrogen exchanger in rat myocardium. Cardiovasc Res. 1995;29:203–8.

    PubMed  CAS  Google Scholar 

  108. Gan XT, Chakrabarti S, Karmazyn M. Modulation of Na+/H+ exchange isoform 1 mRNA expression in isolated rat hearts. Am J Physiol Heart Circ Physiol. 1999;277:H993–8.

    CAS  Google Scholar 

  109. Yokoyama H, Gunasegaram S, Harding S, Avkiran M. Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium. J Am Coll Cardiol. 2000;36:534–40.

    Article  PubMed  CAS  Google Scholar 

  110. Chen L, Gan XT, Haist JV, et al. Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced ­pulmonary vascular injury by the Na+–H+ exchange inhibitor cariporide. J Pharmacol Exp Ther. 2001;298:469–76.

    PubMed  CAS  Google Scholar 

  111. Engelhardt S, Hein L, Keller U, et al. Inhibition of Na+–H+ exchange prevents hypertrophy, fibrosis, and heart failure in beta(1)-adrenergic receptor transgenic mice. Circ Res. 2002;90:814–9.

    Article  PubMed  CAS  Google Scholar 

  112. Jandeleit-Dahm K, Hannan KM, Farrelly CA, et al. Diabetes-induced vascular hypertrophy is accompanied by activation of Na+–H+ exchange and prevented by Na+–H+ exchange inhibition. Circ Res. 2000;87:1133–40.

    PubMed  CAS  Google Scholar 

  113. Cook AR, Bardswell SC, Pretheshan S, et al. Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress? J Mol Cell Cardiol. 2009;46:225–33.

    Article  PubMed  CAS  Google Scholar 

  114. Imahashi K, Mraiche F, Steenbergen C, et al. Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium. Am J Physiol Heart Circ Physiol. 2007;292:H2237–47.

    Article  PubMed  CAS  Google Scholar 

  115. Nakamura TY, Iwata Y, Arai Y, et al. Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res. 2008;103:891–9.

    Article  PubMed  CAS  Google Scholar 

  116. Xue J, Mraiche F, Zhou D, et al. Elevated myocardial Na+/H+ exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy. Physiol Genomics. 2010;42:374–83.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Larry Fliegel

Authors
  1. Larry Fliegel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Larry Fliegel .

Editor information

Editors and Affiliations

  1. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

  2. Jikei University School of Medicine, Shibuya-ku, Ebisu 3-31-6, Tokyo, 150-0013, Japan

    Makoto Nagano

  3. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Fliegel, L. (2011). Elevated Na+–H+ Exchanger Expression and Its Role in Myocardial Disease. In: Dhalla, N., Nagano, M., Ostadal, B. (eds) Molecular Defects in Cardiovascular Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7130-2_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-7130-2_4

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-7129-6

  • Online ISBN: 978-1-4419-7130-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation