Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart



Nitric oxide (NO) produced in the heart by nitric oxide synthase (NOS) is a highly reactive signaling molecule and an important modulator of myocardial function. NOS catalyzes the conversion of l-arginine to l-citrulline and NO but under particular circumstances reactive oxygen species (ROS) can be formed instead of NO (uncoupling). In the heart, three NOS isoforms are present: neuronal NOS (nNOS, NOS1) and endothelial NOS (eNOS, NOS3) are constitutively present enzymes in distinct subcellular locations within cardiomyocytes, whereas inducible NOS (iNOS, NOS2) is absent in the healthy heart, but its expression is induced by pro-inflammatory mediators. In the tissue, NO has two main effects: (i) NO stimulates the activity of guanylate cyclase, leading to cGMP generation and activation of protein kinase G, and (ii) NO nitrosylates tyrosine and thiol-groups of cysteine in proteins. Upon nitrosylation, proteins may change their properties. Changes in (i) NOS expression and activity, (ii) subcellular compartmentation of NOS activity, and (iii) the occurrence of uncoupling may lead to multiple NO-induced effects, some of which being particularly evident during myocardial overload as occurs during aortic constriction and myocardial infarction. Many of these NO-induced effects are considered to be cardioprotective but particularly if NOS becomes uncoupled, formation of ROS in combination with a low NO bioavailability predisposes for cardiac damage.


Nitric oxide Hypertrophy Nitric oxide synthase Heart failure 



Nitric oxide


Neuronal nitric oxide synthase


Endothelial nitric oxide synthase


Inducible nitric oxide synthase






Cyclic guanosine monophosphate


Guanosine triphosphate


Protein kinase G


Left ventricle


Arg-gly-asp motif (in peptide)


Interleukin 6


Tumor necrosis factor alpha


Nω-nitro-l-arginine methyl ester


Angiotensin converting enzyme


Reactive oxygen species


Ryanodine receptor


Sarcoplasmic reticulum


Matrix metalloproteinase


Interleukin-1 beta


Sarcoplasmic reticulum calcium ATPase


Probability of a channel to be open


Right ventricle


Nicotinamide adenine dinucleotide phosphate


Congestive heart failure


N G-monomethyl-l-arginine


Xanthine oxidoreductase




  1. 1.
    Wang Y, Marsden PA (1995) Nitric oxide synthases: gene structure and regulation. Adv Pharmacol 34:71–90Google Scholar
  2. 2.
    Xie Q-W, Nathan C (1994) The high-output nitric oxide pathway: role and regulation. J Leukocyte Biol 56:576–582Google Scholar
  3. 3.
    Nathan C (1997) Inducible nitric oxide synthase: what difference does it make? J Clin Invest 100:2417–2423Google Scholar
  4. 4.
    Keira N, Tatsumi T, Matoba S et al (2002) Lethal effect of cytokine-induced nitric oxide and peroxynitrite on cultured rat cardiac myocytes. J Mol Cell Cardiol 34:583–596Google Scholar
  5. 5.
    Mannick JB, Schonhoff CM (2002) Nitrosylation: the next phosphorylation? Arch Biochem Biophys 408:1–6Google Scholar
  6. 6.
    Martinez-Ruiz A, Lamas S (2004) S-nitrosylation: a potential new paradigm in signal transduction. Cardiovasc Res 62:43–52Google Scholar
  7. 7.
    Hess DT, Matsumoto A, Kim SO et al (2005) Protein S-nitrosylation: purview and parameters. Nat Mol Cell Biol 6:150–166Google Scholar
  8. 8.
    Campbell DL, Stamler JS, Strauss HC (1996) Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols. J Gen Physiol 108:277–293Google Scholar
  9. 9.
    Hu H, Chiamvimonvat N, Yamagishi T et al (1997) Direct inhibition of expressed cardiac L-type Ca2+ channels by S-nitrosothiol nitric oxide donors. Circ Res 81:742–752Google Scholar
  10. 10.
    Sun J, Picht E, Ginsburg KS et al (2006) Hypercontractile female hearts exhibit increased S-nitrosylation of the L-type Ca2+ channel α1 subunit and reduced ischemia-reperfusion injury. Circ Res 98:403–411Google Scholar
  11. 11.
    Nunez L, Vaquero M, Gomez R et al (2006) Nitric oxide blocks hKv1.5 channels by S-nitrosylation and by a cyclic GMP-dependent mechanism. Cardiovasc Res 72:80–89Google Scholar
  12. 12.
    Lokuta AJ, Maertz NA, Vadakkadath Meethal S et al (2005) Increased nitration of sarcoplasmic reticulum Ca2+-ATPase in human heart failure. Circulation 111:988–995Google Scholar
  13. 13.
    Xu L, Eu JP, Meissner G et al (1998) Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation. Science 279:234–237Google Scholar
  14. 14.
    Eu JP, Xu L, Stamler JS et al (1999) Regulation of ryanodine receptors by reactive nitrogen species. Biochem Pharmacol 1079–1084Google Scholar
  15. 15.
    Liu L, Hausladen A, Zeng M et al (2001) A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410:490–494Google Scholar
  16. 16.
    Liu L, Yan Y, Zeng M et al (2004) Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell 116:617–628Google Scholar
  17. 17.
    Dimmeler S, Haendeler J, Nehls M et al (1997) Suppression of apoptosis by nitric oxide via inhibition of interleukin-1β-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases. J Exp Med 185:601–607Google Scholar
  18. 18.
    Nikitovic D, Holmgren A, Spyrou G (1998) Inhibition of AP-1 DNA binding by nitrix oxide involving conserved cysteine residues in Jun and Fos. Biochem Biophys Res Commun 242:109–112Google Scholar
  19. 19.
    Mannick JB, Hausladen A, Liu L et al (1999) Fas-induced caspase denitrosylation. Science 284:651–654Google Scholar
  20. 20.
    Park HS, Huh SH, Kim MS et al (2000) Nitric oxide negatively regulates c-Jun N-terminal kinase/stress-activated protein kinase by means of S-nitrosylation. Proc Natl Acad Sci USA 97:14382–14387Google Scholar
  21. 21.
    Park HS, Yu JW, Cho JH et al (2004) Inhibition of apoptosis signal-regulating kinase 1 by nitric oxide through a thiol redox mechanism. J Biol Chem 279:7584–7590Google Scholar
  22. 22.
    Paulus WJ, Bronzwaer JG (2004) Nitric oxide’s role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol 287:H8–H13Google Scholar
  23. 23.
    Seddon M, Shah AM, Casadei B (2007) Cardiomyocytes as effectors of nitric oxide signaling. Cardiovasc Res 75:315–326Google Scholar
  24. 24.
    Paulus WJ, Vantrimpont PJ, Shah AM (1995) Paracrine coronary endothelial control of left ventricular function in humans. Circulation 92:2119–2126Google Scholar
  25. 25.
    Shah AH, Spurgeon HA, Sollott SJ et al (1994) 8-Bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res 74:970–978Google Scholar
  26. 26.
    Layland J, Li J-M, Shah AM (2002) Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes. J Physiol (Lond) 540:457–467Google Scholar
  27. 27.
    Martin SR, Emanuel K, Sears CE et al (2006) Are myocardial eNOS and nNOS involved in the β-adrenergic and muscarinic regulation of inotropy? A systematic investigation. Cardiovasc Res 70:97–106Google Scholar
  28. 28.
    Gyurko R, Kuhlencordt P, Fishman MC et al (2000) Modulation of mouse cardiac function in vivo by eNOS and ANP. Am J Physiol Heart Circ Physiol 278:H971–H981Google Scholar
  29. 29.
    Khan SA, Skaf MW, Harrison RW et al (2003) Nitric oxide regulation of myocardial contractility and calcium cycling: independent impact of neuronal and endothelial nitric oxide synthases. Circ Res 92:1322–1329Google Scholar
  30. 30.
    Shaul PW (2002) Regulation of endothelial nitric oxide synthase: location, location, location. Annu Rev Physiol 64:749–774Google Scholar
  31. 31.
    Barouch LA, Harrison RW, Skaf MW et al (2002) Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 416:337–340Google Scholar
  32. 32.
    Brunner F, Andrew P, Wölkart G et al (2001) Myocardial contractile function and heart rate in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Circulation 104:3097–3102Google Scholar
  33. 33.
    Martinez-Moreno M, Alvarez-Barrientos A, Roncal F et al (2005) Direct interaction between the reductase domain of the endothelial nitric oxide synthase and the ryanodine receptor. FEBS Lett 579:3159–3163Google Scholar
  34. 34.
    Vila-Petroff MG, Kim SH, Pepe S et al (2001) Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Nat Cell Biol 3:867–873Google Scholar
  35. 35.
    Linz W, Wohlfart P, Schölkens BA et al (1999) Review. Interactions among ACE, kinins and NO. Cardiovasc Res 43:549–561Google Scholar
  36. 36.
    Cornwell TL, Arnold E, Boerth NJ et al (1994) Inhibition of smooth muscle cell growth by nitric oxide and activation of cAMP-dependent protein kinase by cGMP. Am J Physiol Cell Physiol 267:C1405–C1413Google Scholar
  37. 37.
    Bath PMW, Hassall DG, Gladwin A-M et al (1991) Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb 11:254–260Google Scholar
  38. 38.
    Radomski MW, Palmer RMJ, Moncada S (1990) An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 87:5193–5197Google Scholar
  39. 39.
    Garg UC, Hassid A (1990) Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB/c 3T3 fibroblasts by a cyclic GMP-dependent mechanism. Biochem Biophys Res Commun 171:474–479Google Scholar
  40. 40.
    Arstall MA, Sawyer DB, Fukazawa R et al (1999) Cytokine-mediated apoptosis in cardiac myocytes: the role of inducible nitric oxide synthase induction and peroxynitrite generation. Circ Res 85:829–840Google Scholar
  41. 41.
    Mungrue IN, Gros R, You X et al (2002) Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109:735–743Google Scholar
  42. 42.
    Heger J, Gödecke A, Flögel U et al (2002) Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 90:93–99Google Scholar
  43. 43.
    Flögel U, Merx MW, Gödecke A et al (2001) Myoglobin: a scavenger of bioactive NO. Proc Natl Acad Sci USA 98:735–740Google Scholar
  44. 44.
    Gödecke A, Molojavyi A, Heger J et al (2003) Myoglobin protects the heart from inducible nitric-oxide synthase (iNOS)-mediated nitrosative stress. J Biol Chem 278:21761–21766Google Scholar
  45. 45.
    Funakoshi H, Kubota T, Kawamura N et al (2002) Disruption of inducible nitric oxide synthase improves β-adrenergic inotropic responsiveness but not the survival of mice with cytokine-induced cardiomyopathy. Circ Res 90:959–965Google Scholar
  46. 46.
    Xu KY, Huso DL, Dawson TM et al (1999) Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 96:657–662Google Scholar
  47. 47.
    Sears CE, Bryant SM, Ashley EA et al (2003) Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling. Circ Res 92:e52–e59Google Scholar
  48. 48.
    Meissner G (2004) Molecular regulation of cardiac ryanodine receptor ion channel. Cell Calcium 35:621–628Google Scholar
  49. 49.
    Danson EJ, Choate JK, Paterson DJ (2005) Cardiac nitric oxide: emerging role for nNOS in regulating physiological function. Pharmacol Ther 106:57–74Google Scholar
  50. 50.
    Dawson D, Lygate CA, Zhang MH et al (2005) nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation 112:3729–3737Google Scholar
  51. 51.
    Ashley EA, Sears CE, Bryant SM et al (2002) Cardiac nitric oxide synthase 1 regulates basal and β-adrenergic contractility in murine ventricular myocytes. Circulation 105:3011–3016Google Scholar
  52. 52.
    Khan SA, Lee K, Minhas KM et al (2004) Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc Natl Acad Sci USA 101:15944–15948Google Scholar
  53. 53.
    Burkard N, Rokita AG, Kaufmann SG et al (2007) Conditional neuronal nitric oxide synthase overexpression impairs myocardial contractility. Circ Res 100:e32–e44Google Scholar
  54. 54.
    Stoyanovsky D, Murphy T, Anno PR et al (1997) Nitric oxide activates skeletal and cardiac ryanodine receptors. Cell Calcium 21:19–29Google Scholar
  55. 55.
    Jaffrey SR, Erdjument-Bromage H, Ferris CD et al (2001) Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 3:193–197Google Scholar
  56. 56.
    Nakane M, Mitchell J, Förstermann U et al (1991) Phosphorylation by calcium calmodulin-dependent protein kinase II and protein kinase C modulates the activity of nitric oxide synthase. Biochem Biophys Res Commun 180:1396–1402Google Scholar
  57. 57.
    Loyer X, Heymes C, Samuel JL (2008) Constitutive nitric oxide synthases in the heart from hypertrophy to failure. Clin Exp Pharmacol Physiol 35:483–488Google Scholar
  58. 58.
    Takimoto E, Champion HC, Li M et al (2005) Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodelling from chronic pressure load. J Clin Invest 115:1221–1231Google Scholar
  59. 59.
    Kuzkaya N, Weissmann N, Harrison DG et al (2003) Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric oxide synthase. J Biol Chem 278:22546–22554Google Scholar
  60. 60.
    Xia Y, Dawson VL, Dawson TM et al (1996) Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. Proc Natl Acad Sci USA 93:6770–6774Google Scholar
  61. 61.
    Rosen GM, Tsai P, Weaver J et al (2002) The role of tetrahydrobiopterin in the regulation of neuronal nitric-oxide synthase-generated superoxide. J Biol Chem 277:40275–40280Google Scholar
  62. 62.
    Hyndman ME, Verma S, Rosenfeld RJ et al (2002) Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 282:H2167–H2172Google Scholar
  63. 63.
    Stroes ES, van Faassen EE, Yo M et al (2000) Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 86:1129–1134Google Scholar
  64. 64.
    Bayraktutan U, Yang Z-K, Shah AM (1998) Selective dysregulation of nitric oxide synthase type 3 in cardiac myocytes but not coronary microvascular endothelial cells of spontaneously hypertensive rats. Cardiovasc Res 38:719–726Google Scholar
  65. 65.
    Sanada S, Node K, Minamino T et al (2003) Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats. Hypertension 41:963–967Google Scholar
  66. 66.
    Wenzel S, Rohde C, Wingerning S et al (2007) Lack of endothelial nitric oxide synthase-derived nitric oxide formation favors hypertrophy in adult ventricular cardiomyocytes. Hypertension 49:193–200Google Scholar
  67. 67.
    Huang PL, Huang ZH, Mashimo H et al (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239–242Google Scholar
  68. 68.
    Ichinose F, Bloch KD, Wu JC et al (2004) Pressure overload-induced hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency. Am J Physiol Heart Circ Physiol 286:H1070–H1075Google Scholar
  69. 69.
    Buys ES, Raher MJ, Blake SL et al (2007) Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodelling after chronic pressure overload. Am J Physiol Heart Circ Physiol 293:H620–H627Google Scholar
  70. 70.
    Bubikat A, de Windt LJ, Zetsche B et al (2005) Local ANP signalling prevents hypertensive cardiac hypertrophy in endothelial NO synthase (eNOS)-deficient mice. J Biol Chem 280:21594–21599Google Scholar
  71. 71.
    Moens AL, Takimoto E, Tocchetti CG et al (2008) Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin. Efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation 117:2626–2636Google Scholar
  72. 72.
    Ozaki M, Kawashima S, Yamashita T et al (2002) Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion. Circ J 66:851–856Google Scholar
  73. 73.
    Janssens S, Pokreisz P, Schoonjams L et al (2004) Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res 94:1256–1262Google Scholar
  74. 74.
    Massion PB, Balligand JL (2007) Relevance of nitric oxide for myocardial remodeling. Curr Heart Fail Rep 4:18–25Google Scholar
  75. 75.
    Massion PB, Feron O, Dessy C et al (2003) Nitric oxide and cardiac function: ten years after, and continuing. Circ Res 93:388–398Google Scholar
  76. 76.
    Umar S, van der Valk EJ, Schalij MJ et al (2009) Integrin stimulation-induced hypertrophy in neonatal rat cardiomyocytes is NO-dependent. Mol Cell Biochem 320:75–84Google Scholar
  77. 77.
    Umar S, Hessel M, Steendijk P et al (2007) Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension. Pathol Res Pract 203:863–872Google Scholar
  78. 78.
    Zhang P, Xu X, Hu X et al (2007) Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res 100:1089–1098Google Scholar
  79. 79.
    Pacher P, Schulz R, Liaudet L et al (2005) Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol Sci 26:302–310Google Scholar
  80. 80.
    Takimoto E, Kass DA (2007) Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49:241–248Google Scholar
  81. 81.
    Mollnau H, Wendt M, Szöcs K et al (2002) Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. Circ Res 90:e58–e65Google Scholar
  82. 82.
    Turko IV, Murad F (2002) Protein nitration in cardiovascular diseases. Pharmacol Rev 54:619–634Google Scholar
  83. 83.
    Mihm MJ, Coyle CM, Schanbacher BL et al (2001) Peroxynitrite induced nitration and inactivation of myofibillar creatine kinase in experimental heart failure. Cardiovasc Res 49:798–807Google Scholar
  84. 84.
    Ferdinandy P, Danial H, Ambrus I et al (2000) Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87:241–247Google Scholar
  85. 85.
    Vaziri ND, Ni Z, Oveisi F et al (2002) Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 39:135–141Google Scholar
  86. 86.
    Szabo C (2003) Multiple pathways of peroxynitrite cytotoxicity. Toxicol Lett 140–141:105–112Google Scholar
  87. 87.
    Wang W, Sawicki G, Schulz R (2002) Peroxynitrite-induced myocardial injury is mediated through matrix metalloproteinase-2. Cardiovasc Res 53:165–174Google Scholar
  88. 88.
    Shiomi T, Tsutsui H, Matsusaka H et al (2004) Overexpression of glutathione peroxidase prevents left ventricular remodeling and failure after myocardial infarction in mice. Circulation 109:544–549Google Scholar
  89. 89.
    Moens AL, Champion HC, Claeys MJ et al (2008) High-dose folic acid pretreatment blunts cardiac dysfunction during ischemia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation 117:1810–1819Google Scholar
  90. 90.
    Piech A, Massart PE, Dessy C et al (2002) Decreased expression of myocardial eNOS and caveolin in dogs with hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 282:H219–H231Google Scholar
  91. 91.
    Drexler H, Kästner S, Strobel A et al (1998) Expression, activity and functional significance of inducible nitric oxide synthase in the failing human heart. J Am Coll Cardiol 32:955–963Google Scholar
  92. 92.
    Damy T, Ratajczak P, Shah AM et al (2004) Increased neuronal nitric oxide synthase-derived NO production in the failing human heart. Lancet 363:1365–1367Google Scholar
  93. 93.
    Stein B, Eschenhagen T, Rüdiger J et al (1998) Increased expression of constitutive nitric oxide synthase III, but not inducible nitric oxide synthase II, in human heart failure. J Am Coll Cardiol 32:1179–1186Google Scholar
  94. 94.
    Fukuchi M, Hussain SNA, Giaid A (1998) Heterogeneous expression and activity of endothelial and inducible nitric oxide synthases in end-stage human heart failure. Their relation to lesion site and β-adrenergic receptor therapy. Circulation 98:132–139Google Scholar
  95. 95.
    Gealekman O, Abassi Z, Rubinstein I et al (2002) Role of myocardial inducible nitric oxide synthase in contractile dysfunction and β-adrenergic hyporesponsiveness in rats with experimental volume-overload heart failure. Circulation 105:236–243Google Scholar
  96. 96.
    Smith RS Jr, Agata J, Xia C-F et al (2005) Human endothelial nitric oxide synthase gene delivery protects against cardiac remodeling and reduces oxidative stress after myocardial infarction. Life Sci 76:2457–24571Google Scholar
  97. 97.
    Jones SP, Greer JJM, van Haperen R et al (2003) Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci USA 100:4891–4896Google Scholar
  98. 98.
    Scherrer-Crosbie M, Ullrich R, Bloch KD et al (2001) Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 104:1286–1291Google Scholar
  99. 99.
    Liu Y-H, Xu J, Yang X-P et al (2002) Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension 39:375–381Google Scholar
  100. 100.
    Feng Q, Fortin AJ, Lu X et al (1999) Effects of L-arginine on endothelial and cardiac function in rats with heart failure. Eur J Pharmacol 376:37–44Google Scholar
  101. 101.
    Haywood GA, Tsao PS, von der Leyen HE et al (1996) Expression of inducible nitric oxide synthase in human heart failure. Circulation 93:1087–1094Google Scholar
  102. 102.
    Vejlstrup NG, Bouloumie A, Boesgaard S et al (1998) Inducible nitric oxide synthase (iNOS) in the human heart: expression and localization in congestive heart failure. J Mol Cell Cardiol 30:1215–1223Google Scholar
  103. 103.
    Chen Y, Traverse JH, Du R et al (2002) Nitric oxide modulates myocardial oxygen consumption in the failing heart. Circulation 106:273–279Google Scholar
  104. 104.
    Thoenes M, Förstermann U, Tracey WR et al (1996) Expression of inducible nitric oxide synthase in failing and non-failing human heart. J Mol Cell Cardiol 28:165–169Google Scholar
  105. 105.
    Heymes C, Vanderheyden M, Bronzwaer JGF et al (1999) Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy. Circulation 99:3009–3016Google Scholar
  106. 106.
    Feng Q, Lu X, Jones DL et al (2001) Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104:700–704Google Scholar
  107. 107.
    Sam F, Sawyer DB, Xie Z et al (2001) Mice lacking inducible nitric oxide synthase have improved left ventricular contractile function and reduced apoptotic cell death late after myocardial infarction. Circ Res 89:351–356Google Scholar
  108. 108.
    Jones SP, Greer JJ, Ware PD et al (2005) Deficiency of iNOS does not attenuate severe congestive heart failure in mice. Am J Physiol Heart Circ Physiol 288:H365–H370Google Scholar
  109. 109.
    Liu Y-H, Carretero OA, Cingolani OH et al (2005) Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction. Am J Physiol Heart Circ Physiol 289:H2616–H2623Google Scholar
  110. 110.
    West MB, Rokosh G, Obal D et al (2008) Cardiac myocyte-specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition. Circulation 118:1970–1978Google Scholar
  111. 111.
    Narula J, Haider N, Virmani R et al (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189Google Scholar
  112. 112.
    Olivetti G, Abbi R, Quaini F et al (1997) Apoptosis in the failing human heart. N Engl J Med 336:1131–1141Google Scholar
  113. 113.
    Damy T, Ratajczak P, Robidel E et al (2003) Up-regulation of cardiac nitric oxide synthase 1-derived nitric oxide after myocardial infarction in senescent rats. FASEB J 17:1934–1936Google Scholar
  114. 114.
    Bendall JK, Damy T, Ratajczak P et al (2004) Role of myocardial neuronal nitric oxide synthase-derived nitric oxide in β-adrenergic hyporesponsiveness after myocardial infarction-induced heart failure in rat. Circulation 110:2368–2375Google Scholar
  115. 115.
    Kawakami M, Okabe E (1998) Superoxide anion radical-triggered Ca2+ release from cardiac sarcoplasmic reticulum through ryanodine receptor Ca2+ channel. Mol Pharmacol 53:497–503Google Scholar
  116. 116.
    Seddon M, Looi YH, Shah AM (2007) Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93:903–907Google Scholar
  117. 117.
    Keith M, Geranmayegan A, Sole MJ et al (1998) Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 31:1352–1356Google Scholar
  118. 118.
    Belch JJF, Bridges AB, Scott N et al (1991) Oxygen free radicals and congestive heart failure. Br Heart J 65:245–248Google Scholar
  119. 119.
    Saraiva RM, Minhas KM, Raju SVY et al (2005) Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction. Role of nitroso-redox equilibrium. Circulation 112:3415–3422Google Scholar
  120. 120.
    Casadei B (2006) The emerging role of neuronal nitric oxide synthase in the regulation of myocardial infarction. Exp Physiol 91:943–955Google Scholar
  121. 121.
    Kinugawa S, Huang H, Wang Z et al (2005) A defect of neuronal nitric oxide synthase increases xanthine oxidase-derived superoxide anion and attenuates the control of myocardial oxygen consumption by nitric oxide derived from endothelial nitric oxide synthase. Circ Res 96:355–362Google Scholar
  122. 122.
    Gonzalez DR, Beigi F, Treuer AV et al (2007) Deficient ryanodine receptor S-nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes. Proc Natl Acad Sci USA 104:20612–20617Google Scholar
  123. 123.
    Saraiva RM, Hare JM (2006) Nitric oxide signaling in the cardiovascular system: implications for heart failure. Curr Opin Cardiol 21:221–228Google Scholar
  124. 124.
    Barouch LA, Cappola TP, Harrison RW et al (2003) Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice. J Mol Cell Cardiol 35:637–644Google Scholar
  125. 125.
    Loyer X, Gómez AM, Milliez P et al (2008) Cardiomyocyte overexpression of neuronal nitric oxide synthase delays transition toward heart failure in response to pressure overload by preserving calcium cycling. Circulation 117:3187–3198Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  1. 1.Department of CardiologyLeiden University Medical CenterLeidenThe Netherlands

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