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Nitric oxide synthases in the pathogenesis of cardiovascular disease

Lessons from genetically modified mice

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Abstract

Nitric oxide (NO) is produced in almost all tissues and organs, exerting a variety of biological actions under both physiological and pathological conditions. NO is synthesized by three distinct NO synthase (NOS) isoforms (neuronal, inducible, and endothelial NOS), all of which are expressed in the human cardiovascular system. Although the regulatory roles of NOSs in cardiovascular diseases have been described in pharmacological studies with selective and non-selective NOS inhibitors, the specificity of the NOS inhibitors continues to be an issue of debate. To overcome this issue, genetically engineered animals have been used. All types of NOS gene-deficient animals, including singly, doubly, and triply NOS-deficient mice, and various types of NOS gene-transgenic (TG) animals, including conditional and non-conditional TG mice bearing endothelium-specific or cardiomyocyte-specific overexpression of each NOS gene, have thus been developed. The roles of individual NOS isoforms as well as the entire NOS system in the cardiovascular system have been extensively investigated in those mice, providing pivotal insights into an understanding of the pathophysiology of NOSs in human cardiovascular diseases. Based on studies with the murine NOS genetic models, this review briefly summarizes the latest knowledge of NOSs and cardiovascular diseases.

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References

  1. Antman EM, Braunwald E (2005) ST-elevation myocardial infarction: pathology, pathophysiology, and clinical features. In: Zipes DP, Libby P, Bonow RO, Braunwald E (eds) Braunwald's heart disease, 7th edn. Elsevier Saunders, Philadelphia, pp 1141–1166

    Google Scholar 

  2. Boulanger CM, Heymes C, Benessiano J, Geske RS, Levy BI, Vanhoutte PM (1998) Neuronal nitric oxide synthase is expressed in rat vascular smooth muscle cells: activation by angiotensin II in hypertension. Circ Res 83:1271–1278

    CAS  PubMed  Google Scholar 

  3. Brunner F, Andrew P, Wolkart G, Zechner R, Mayer B (2001) Myocardial contractile function and heart rate in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Circulation 104:3097–3102

    Article  CAS  PubMed  Google Scholar 

  4. Buchwalow IB, Podzuweit T, Bocker W, Samoilova VE, Thomas S, Wellner M et al (2002) Vascular smooth muscle and nitric oxide synthase. FASEB J 16:500–508

    Article  CAS  PubMed  Google Scholar 

  5. Burkard N, Rokita AG, Kaufmann SG, Hallhuber M, Wu R, Hu K et al (2007) Conditional neuronal nitric oxide synthase overexpression impairs myocardial contractility. Circ Res 100:e32–e44

    Article  CAS  PubMed  Google Scholar 

  6. Casadei B (2006) The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function. Exp Physiol 91:943–955

    Article  CAS  PubMed  Google Scholar 

  7. Chyu KY, Dimayuga P, Zhu J, Nilsson J, Kaul S, Shah PK et al (1999) Decreased neointimal thickening after arterial wall injury in inducible nitric oxide synthase knockout mice. Circ Res 85:1192–1198

    CAS  PubMed  Google Scholar 

  8. Dawson D, Lygate CA, Zhang MH, Hulbert K, Neubauer S, Casadei B (2005) nNOS gene deletion exacerbates pathological left ventricular remodeling and functional deterioration after myocardial infarction. Circulation 112:3729–3737

    Article  CAS  PubMed  Google Scholar 

  9. Dudzinski DM, Igarashi J, Greif D, Michel T (2006) The regulation and pharmacology of endothelial nitric oxide synthase. Annu Rev Pharmacol Toxicol 46:235–276

    Article  CAS  PubMed  Google Scholar 

  10. Feng Q, Lu X, Jones DL, Shen J, Arnold JM (2001) Increased inducible nitric oxide synthase expression contributes to myocardial dysfunction and higher mortality after myocardial infarction in mice. Circulation 104:700–704

    Article  CAS  PubMed  Google Scholar 

  11. Forstermann U, Boissel JP, Kleinert H (1998) Expressional control of the constitutive isoforms of nitric oxide synthase (NOS I and NOS III). FASEB J 12:773–790

    CAS  PubMed  Google Scholar 

  12. Furchgott RF (1984) The role of endothelium in the responses of vascular smooth muscle to drugs. Annu Rev Pharmacol Toxicol 24:175–197

    Article  CAS  PubMed  Google Scholar 

  13. Godecke A, Decking UK, Ding Z, Hirchenhain J, Bidmon HJ, Godecke S et al (1998) Coronary hemodynamics in endothelial NO synthase knockout mice. Circ Res 82:186–194

    CAS  PubMed  Google Scholar 

  14. Gyurko R, Leupen S, Huang PL (2002) Deletion of exon 6 of the neuronal nitric oxide synthase gene in mice results in hypogonadism and infertility. Endocrinology 143:2767–2774

    Article  CAS  PubMed  Google Scholar 

  15. Hafezi-Moghadam A, Simoncini T, Yang Z, Limbourg FP, Plumier JC, Rebsamen MC et al (2002) Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8:473–479

    Article  CAS  PubMed  Google Scholar 

  16. Heger J, Godecke A, Flogel U, Merx MW, Molojavyi A, Kuhn-Velten WN et al (2002) Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 90:93–99

    Article  CAS  PubMed  Google Scholar 

  17. Huang A, Sun D, Shesely EG, Levee EM, Koller A, Kaley G (2002) Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice. Am J Physiol 282:H429–H436

    CAS  Google Scholar 

  18. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75:1273–1286

    Article  CAS  PubMed  Google Scholar 

  19. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA et al (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377:239–242

    Article  CAS  PubMed  Google Scholar 

  20. Ichinose F, Bloch KD, Wu JC, Hataishi R, Aretz HT, Picard MH et al (2004) Pressure overload-induced LV hypertrophy and dysfunction in mice are exacerbated by congenital NOS3 deficiency. Am J Physiol 286:H1070–H1075

    CAS  Google Scholar 

  21. Ignarro LJ (1990) Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol 30:535–560

    Article  CAS  PubMed  Google Scholar 

  22. Janssens S, Pokreisz P, Schoonjans L, Pellens M, Vermeersch P, Tjwa M et al (2004) Cardiomyocyte-specific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res 94:1256–1262

    Article  CAS  PubMed  Google Scholar 

  23. Jones SP, Greer JJ, van Haperen R, Duncker DJ, de Crom R, Lefer DJ (2003) Endothelial nitric oxide synthase overexpression attenuates congestive heart failure in mice. Proc Natl Acad Sci USA 100:4891–4896

    Article  CAS  PubMed  Google Scholar 

  24. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792

    Article  CAS  PubMed  Google Scholar 

  25. Kawashima S, Yamashita T, Ozaki M, Ohashi Y, Azumi H, Inoue N et al (2001) Endothelial NO synthase overexpression inhibits lesion formation in mouse model of vascular remodeling. Arterioscler Thromb Vasc Biol 21:201–207

    CAS  PubMed  Google Scholar 

  26. Knowles JW, Reddick RL, Jennette JC, Shesely EG, Smithies O, Maeda N (2000) Enhanced atherosclerosis and kidney dysfunction in eNOS−/−Apoe−/− mice are ameliorated by enalapril treatment. J Clin Invest 105:451–458

    Article  CAS  PubMed  Google Scholar 

  27. Koglin J, Glysing-Jensen T, Mudgett JS, Russell ME (1998) Exacerbated transplant arteriosclerosis in inducible nitric oxide-deficient mice. Circulation 97:2059–2065

    CAS  PubMed  Google Scholar 

  28. Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai R (2008) Demographics and changes in medical/interventional treatment of coronary artery disease patients over a 3.5-year period in Japan: The Japanese Coronary Artery Disease Study: Trend examination. Circ J 72:1397–1402

    Article  PubMed  Google Scholar 

  29. Kuhlencordt PJ, Chen J, Han F, Astern J, Huang PL (2001) Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Circulation 103:3099–3104

    CAS  PubMed  Google Scholar 

  30. Kuhlencordt PJ, Gyurko R, Han F, Scherrer-Crosbie M, Aretz TH, Hajjar R et al (2001) Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 104:448–454

    Article  CAS  PubMed  Google Scholar 

  31. Kuhlencordt PJ, Hotten S, Schodel J, Rutzel S, Hu K, Widder J et al (2006) Atheroprotective effects of neuronal nitric oxide synthase in apolipoproteine knockout mice. Arterioscler Thromb Vasc Biol 26:1539–1544

    Article  CAS  PubMed  Google Scholar 

  32. Laine P, Kaartinen M, Penttila A, Panula P, Paavonen T, Kovanen PT (1999) Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation 99:361–369

    CAS  PubMed  Google Scholar 

  33. Lamping KG, Nuno DW, Shesely EG, Maeda N, Faraci FM (2000) Vasodilator mechanisms in the coronary circulation of endothelial nitric oxide synthase-deficient mice. Am J Physiol 279:H1906–H1912

    CAS  Google Scholar 

  34. Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A et al (2004) Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 110:1933–1939

    Article  CAS  PubMed  Google Scholar 

  35. Laubach VE, Shesely EG, Smithies O, Sherman PA (1995) Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharideinduced death. Proc Natl Acad Sci USA 92:10688–10692

    Article  CAS  PubMed  Google Scholar 

  36. Liu YH, Xu J, Yang XP, Yang F, Shesely E, Carretero OA (2002) Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension 39:375–381

    Article  CAS  PubMed  Google Scholar 

  37. Loyer X, Gomez AM, Milliez P, Fernandez-Velasco M, Vangheluwe P, Vinet L 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 117:3187–3198

    Article  CAS  PubMed  Google Scholar 

  38. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M et al (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641–650

    Article  CAS  PubMed  Google Scholar 

  39. Massion PB, Balligand JL (2003) Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): Lessons from genetically modified mice. J Physiol 546:63–75

    Article  CAS  PubMed  Google Scholar 

  40. Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A (2000) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 106:1521–1530

    Article  CAS  PubMed  Google Scholar 

  41. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I (2004) Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 24:29–33

    Article  CAS  PubMed  Google Scholar 

  42. Morikawa K, Shimokawa H, Matoba T, Kubota H, Akaike T, Talukder MA, Hatanaka M, Fujiki T, Maeda H, Takahashi S, Takeshita A (2003) Pivotal role of Cu, Zn-superoxide dismutase in endothelium-dependent hyperpolarization. J Clin Invest 112:1871–1879

    CAS  PubMed  Google Scholar 

  43. Morishita T, Tsutsui M, Shimokawa H, Horiuchi M, Tanimoto A, Suda O et al (2002) Vasculoprotective roles of neuronal nitric oxide synthase. FASEB J 16:1994–1996

    CAS  PubMed  Google Scholar 

  44. Morishita T, Tsutsui M, Shimokawa H, Sabanai K, Tasaki H, Suda O et al (2005) Nephrogenic diabetes insipidus in mice lacking all nitric oxide synthase isoforms. Proc Natl Acad Sci USA 102:10616–10621

    Article  CAS  PubMed  Google Scholar 

  45. Moroi M, Zhang L, Yasuda T, Virmani R, Gold HK, Fishman MC et al (1998) Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 101:1225–1232

    Article  CAS  PubMed  Google Scholar 

  46. Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T et al (2002) Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 109:735–743

    CAS  PubMed  Google Scholar 

  47. Mungrue IN, Husain M, Stewart DJ (2002) The role of NOS in heart failure: lessons from murine genetic models. Heart Fail Rev 7:407–422

    Article  CAS  PubMed  Google Scholar 

  48. Murad F (1997) What are the molecular mechanisms for the antiproliferative effects of nitric oxide and cGMP in vascular smooth muscle? Circulation 95:1101–1103

    CAS  PubMed  Google Scholar 

  49. Nakamura T, Tsubono Y, Kameda-Takemura K, Funahashi T, Yamashita S, Hisamichi S et al (2001) Magnitude of sustained multiple risk factors for ischemic heart disease in Japanese employees: a case-control study. Jpn Circ J 65:11–17

    Article  CAS  PubMed  Google Scholar 

  50. Nakata S, Tsutsui M, Shimokawa H, Suda O, Morishita T, Shibata K et al (2008) Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation 117:2211–2223

    Article  CAS  PubMed  Google Scholar 

  51. Nakata S, Tsutsui M, Shimokawa H, Tamura M, Tasaki H, Morishita T et al (2005) Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor. Arterioscler Thromb Vasc Biol 25:2502–2508

    Article  CAS  PubMed  Google Scholar 

  52. Nakata S, Tsutsui M, Shimokawa H, Yamashita T, Tanimoto A, Tasaki H et al (2007) Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-κB pathway. Arterioscler Thromb Vasc Biol 27:92–98

    Article  CAS  PubMed  Google Scholar 

  53. Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N et al (1998) Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 102:2061–2071

    Article  CAS  PubMed  Google Scholar 

  54. Ozaki M, Kawashima S, Yamashita T, Hirase T, Namiki M, Inoue N et al (2002) Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 110:331–340

    CAS  PubMed  Google Scholar 

  55. Packer MA, Hemish J, Mignone JL, John S, Pugach I, Enikolopov G (2005) Transgenic mice overexpressing nNOS in the adult nervous system. Cell Mol Biol 51:269–277

    CAS  PubMed  Google Scholar 

  56. Packer MA, Stasiv Y, Benraiss A, Chmielnicki E, Grinberg A, Westphal H, Goldman SA, Enikolopov G (2003) Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci USA 100:9566–9571

    Article  CAS  PubMed  Google Scholar 

  57. Park CS, Park R, Krishna G (1996) Constitutive expression and structural diversity of inducible isoform of nitric oxide synthase in human tissues. Life Sci 59:219–225

    Article  CAS  PubMed  Google Scholar 

  58. Prabhu SD (2004) Nitric oxide protects against pathological ventricular remodeling: Reconsideration of the role of NO in the failing heart. Circ Res 94:1155–1157

    Article  CAS  PubMed  Google Scholar 

  59. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101:731–736

    Article  CAS  PubMed  Google Scholar 

  60. Sam F, Sawyer DB, Xie Z, Chang DL, Ngoy S, Brenner DA 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 89:351–356

    Article  CAS  PubMed  Google Scholar 

  61. Saraiva RM, Hare JM (2006) Nitric oxide signaling in the cardiovascular system: implications for heart failure. Curr Opin Cardiol 21:221–228

    Article  PubMed  Google Scholar 

  62. Saraiva RM, Minhas KM, Raju SV, Barouch LA, Pitz E, Schuleri KH et al (2005) Deficiency of neuronal nitric oxide synthase increases mortality and cardiac remodeling after myocardial infarction: role of nitroso-redox equilibrium. Circulation 112:3415–3422

    Article  CAS  PubMed  Google Scholar 

  63. Scherrer-Crosbie M, Ullrich R, Bloch KD, Nakajima H, Nasseri B, Aretz HT et al (2001) Endothelial nitric oxide synthase limits left ventricular remodeling after myocardial infarction in mice. Circulation 104:1286–1291

    Article  CAS  PubMed  Google Scholar 

  64. Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE et al (1996) Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci USA 93:13176–13181

    Article  CAS  PubMed  Google Scholar 

  65. Shimokawa H (1999) Primary endothelial dysfunction: atherosclerosis. J Mol Cell Cardiol 31:23–37

    Article  CAS  PubMed  Google Scholar 

  66. Shimokawa H, Morikawa K (2005) Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Mol Cell Cardiol 39:725–732

    Article  CAS  PubMed  Google Scholar 

  67. Shioji K, Moriwaki S, Takeuchi Y, Uegaito T, Mutsuo S, Matsuda M (2007) Relationship of serum adiponectin level to adverse cardiovascular events in patients who undergo percutaneous coronary intervention. Circ J 71:675–680

    Article  CAS  PubMed  Google Scholar 

  68. Son H, Hawkins RD, Martin K, Kiebler M, Huang PL, Fishman MC et al (1996) Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell 87:1015–1023

    Article  CAS  PubMed  Google Scholar 

  69. Takaki A, Morikawa K, Tsutsui M, Murayama Y, Takes E, Yamagishi H, Ohashi J, Yada T, Yanagihara N, Shimokawa H (2008) Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice. J Exp Med 205:2053–2063

    Article  CAS  PubMed  Google Scholar 

  70. Takamura T, Kato I, Kimura N, Nakazawa T, Yonekura H, Takasawa S et al (1998) Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic beta cells develop insulin-dependent diabetes without insulitis. J Biol Chem 273:2493–2496

    Article  CAS  PubMed  Google Scholar 

  71. Takeno M, Yasuda S, Otsuka Y, Morii I, Kawamura A, Yano K et al (2008) Impact of metabolic syndrome on the long-term survival of patients with acute myocardial infarction: potential association with C-reactive protein. Circ J 72:415–419

    Article  CAS  PubMed  Google Scholar 

  72. Tranguch S, Huet-Hudson Y (2003) Decreased viability of nitric oxide synthase double knockout mice. Mol Reprod Dev 65:175–179

    Article  CAS  PubMed  Google Scholar 

  73. Tsutsui M (2004) Neuronal nitric oxide synthase as a novel anti-atherogenic factor. J Atheroscler Thromb 11:41–48

    CAS  PubMed  Google Scholar 

  74. Tsutsui M, Nakata S, Shimokawa H, Otsuji Y, Yanagihara N (2008) Spontaneous myocardial infarction and nitric oxide synthase. Trends Cardiovasc Med 18:275–279

    Article  CAS  PubMed  Google Scholar 

  75. Tsutsui M, Shimokawa H, Morishita T, Nakashima Y, Yanagihara N (2006) Development of genetically engineered mice lacking all three nitric oxide synthases. J Pharmacol Sci 102:147–154

    Article  CAS  PubMed  Google Scholar 

  76. Tsutsui M, Shimokawa H, Otsuji Y, Ueta Y, Sasaguri Y, Yanagihara N (2009) Nitric oxide synthases and cardiovascular diseases. Insights from genetically modified mice. Circ J 73:986–993

    Article  CAS  PubMed  Google Scholar 

  77. van Haperen R, de Waard M, van Deel E, Mees B, Kutryk M, van Aken T et al (2002) Reduction of blood pressure, plasma cholesterol, and atherosclerosis by elevated endothelial nitric oxide. J Biol Chem 277:48803–48807

    Article  PubMed  Google Scholar 

  78. Vanhoutte PM (2009) Endothelial dysfunction. The first step toward coronary arteriosclerosis. Circ J 73:595–601

    Article  CAS  PubMed  Google Scholar 

  79. Vanhoutte PM, Shimokawa H (1989) Endothelium-derived relaxing factor and coronary vasospasm. Circulation 80:1–9

    CAS  PubMed  Google Scholar 

  80. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H et al (1998) Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 95:9220–9225

    Article  CAS  PubMed  Google Scholar 

  81. Wang W, Wang S, Yan L, Madara P, Del Pilar CA, Wesley RA et al (2000) Superoxide production and reactive oxygen species signaling by endothelial nitric-oxide synthase. J Biol Chem 275:16899–16903

    Article  CAS  PubMed  Google Scholar 

  82. Ward ME, Toporsian M, Scott JA, Teoh H, Govindaraju V, Quan A et al (2005) Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant. J Clin Invest 115:3128–3139

    Article  CAS  PubMed  Google Scholar 

  83. Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP et al (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375:408–411

    Article  CAS  PubMed  Google Scholar 

  84. Wilcox JN, Subramanian RR, Sundell CL, Tracey WR, Pollock JS, Harrison DG et al (1997) Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 17:2479–2488

    CAS  PubMed  Google Scholar 

  85. Yogo K, Shimokawa H, Funakoshi H, Kandabashi T, Miyata K, Okamoto S et al (2000) Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol 20:E96–E100

    CAS  PubMed  Google Scholar 

  86. Zhang P, Xu X, Hu X, van Deel ED, Zhu G, Chen Y (2007) Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure. Circ Res 100:1089–1098

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by the Grant-in-Aid for Scientific Research on Innovative Areas (Signaling Functions of Reactive Oxygen Species), the Grant-in-Aid for Tohoku University Global COE for Conquest of Signal Transduction Diseases with Network Medicine, and the Grants-in-Aid for Scientific Research, all of which are from the Ministry of Education, Culture, Sports, Science and Technology, Tokyo, Japan.

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  1. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Hiroaki Shimokawa

  2. Department of Pharmacology, Ryukyu University, Okinawa, Japan

    Masato Tsutsui

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  1. Hiroaki Shimokawa
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Correspondence to Hiroaki Shimokawa.

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Shimokawa, H., Tsutsui, M. Nitric oxide synthases in the pathogenesis of cardiovascular disease. Pflugers Arch - Eur J Physiol 459, 959–967 (2010). https://doi.org/10.1007/s00424-010-0796-2

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