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The Role of NOS in Heart Failure: Lessons from Murine Genetic Models

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Abstract

Nitric Oxide Synthases (NOSs) are a group of related proteins that produce nitric oxide (NO). In mammals, there are three known members of this gene family: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). Each has been disrupted by targeted gene ablation in mice and the corresponding phenotypes examined. These mice have allowed an examination of the contribution of each NOS in a variety of experimental models and continue to provided insights into the patho-physiological role of NOS and NO. With increasing sophistication, murine transgenic approaches continue to offer a wealth of information, and invaluable tools to further study the NOS system. The focus of this review will be an examination of the tools available, and the insights gained from studies done on murine NOS genetic models in the context of heart failure.

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References

  1. Bredt DS, Snyder SH. Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc Natl Acad Sci USA 1990;87:68–685.

    Google Scholar 

  2. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351:71–718.

    Google Scholar 

  3. Yui Y, Hattori R, Kosuga K, Eizawa H, Hiki K, Kawai C. Purification of nitric oxide synthase from rat macrophages. J Biol Chem 1991;266:1254–12547.

    Google Scholar 

  4. Stuehr DJ, Cho HJ, Kwon NS, Weise MF, Nathan CF. Purification and characterization of the cytokineinduced macrophage nitric oxide synthase: An FAD-and FMN-containing flavoprotein. Proc Natl Acad Sci USA 1991;88:777–7777.

    Google Scholar 

  5. Hevel JM, White KA, Marletta MA. Purification of the inducible murine macrophage nitric oxide synthase. Identification as a flavoprotein. J Biol Chem 1991;266:2278– 22791.

    Google Scholar 

  6. Forstermann U, Pollock JS, Schmidt HH, Heller M, Murad F. Calmodulindependent endothelium-derived relaxing factor/nitric oxide synthase activity is present in the particulate and cytosolic fractions of bovine aortic endothelial cells. Proc Natl Acad Sci USA 1991;88:178– 1792.

    Google Scholar 

  7. Pollock JS, Forstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, Murad F. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci USA 1991;88:1048– 10484.

    Google Scholar 

  8. Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 1992;256:22–228.

    Google Scholar 

  9. Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 1992;267:1451–14522.

    Google Scholar 

  10. Sessa WC, Harrison JK, Barber CM, Zeng D, Durieux ME, D'Angelo DD, Lynch KR, Peach MJ. Molecular cloning and expression of a cDNA encoding endothelial cell nitric oxide synthase. J Biol Chem 1992;267:1527–15276.

    Google Scholar 

  11. Nishida K, Harrison DG, Navas JP, Fisher AA, Dockery SP, Uematsu M, Nerem RM, Alexander RW, Murphy TJ. Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 1992;90:209–2096.

    Google Scholar 

  12. Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH. Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci USA 1992;89:671–6715.

    Google Scholar 

  13. Lyons CR, Orloff GJ, Cunningham JM.Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 1992;267:637–6374.

    Google Scholar 

  14. Stuehr DJ. Structure-function aspects in the nitric oxide synthases. Annu Rev Pharmacol Toxicol 1997;37:33– 359.

    Google Scholar 

  15. Marletta MA. Nitric oxide synthase: Aspects concerning structure and catalysis. Cell 1994;78:92–930.

    Google Scholar 

  16. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: Structure, function and inhibition. Biochem J 2001;357:59–615.

    Google Scholar 

  17. Crane BR, Arvai AS, Gachhui R, Wu C, Ghosh DK, Getzoff ED, Stuehr DJ, Tainer JA. The structure of nitric oxide synthase oxygenase domain and inhibitor complexes. Science 1997;278:42–431.

    Google Scholar 

  18. Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA. Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science 1998;279:212–2126.

    Google Scholar 

  19. Raman CS, Li H, Martasek P, Kral V, Masters BS, Poulos TL. Crystal structure of constitutive endothelial nitric oxide synthase: A paradigm for pterin function involving a novel metal center. Cell 1998;95:93–950.

    Google Scholar 

  20. Abu-Soud HM, Gachhui R, Raushel FM, Stuehr DJ. The ferrous-dioxy complex of neuronal nitric oxide synthase. Divergent effects of L-arginine and tetrahydrobiopterin on its stability. J Biol Chem 1997;272:1734– 17353.

    Google Scholar 

  21. Korth HG, Sustmann R, Thater C, Butler AR, Ingold KU. On the mechanism of the nitric oxide synthase-catalyzed conversion of N omega-hydroxyl-L-arginine to citrulline and nitric oxide. J Biol Chem 1994;269:1777–17779.

    Google Scholar 

  22. Busse R, Fleming I. Regulation and functional consequences of endothelial nitric oxide formation. Ann Med 1995;27:33–340.

    Google Scholar 

  23. Bredt DS, Snyder SH. Nitric oxide: A physiologic messenger molecule. Annu Rev Biochem 1994;63:17–195.

    Google Scholar 

  24. Son H, Hawkins RD, Martin K, Kiebler M, Huang PL, Fishman MC, Kandel ER. Long-term potentiation is reduced in mice that are doubly mutant in endothelial and neuronal nitric oxide synthase. Cell 1996;87:101–1023.

    Google Scholar 

  25. Xie Q, Nathan C. The high-output nitric oxide pathway: Role and regulation. J Leukoc Biol 1994;56:57–582.

    Google Scholar 

  26. Moilanen E, Vapaatalo H. Nitric oxide in inflammation and immune response. Ann Med 1995;27:35–367.

    Google Scholar 

  27. Nava E, Noll G, Luscher TF. Nitric oxide in cardiovascular diseases. Ann Med 1995;27:34–351.

    Google Scholar 

  28. Dusting GJ, Macdonald PS. Endogenous nitric oxide in cardiovascular disease and transplantation. Ann Med 1995;27:39–406.

    Google Scholar 

  29. Hare JM, Colucci WS. Role of nitric oxide in the regulation of myocardial function. Prog Cardiovasc Dis 1995;38:15– 166.

    Google Scholar 

  30. Christopherson KS, Bredt DS. Nitric oxide in excitable tissues: Physiological roles and disease. J Clin Invest 1997;100:242–2429.

    Google Scholar 

  31. Nathan C. Inducible nitric oxide synthase: What difference does it make? J Clin Invest 1997;100:241–2423.

    Google Scholar 

  32. Kim PK, Zamora R, Petrosko P, Billiar TR. The regulatory role of nitric oxide in apoptosis. Int Immunopharmacol 2001;1:142–1441.

    Google Scholar 

  33. Ziche M, Morbidelli L. Nitric oxide and angiogenesis. J Neurooncol 2000;50:13–148.

    Google Scholar 

  34. Burnett AL. Nitric oxide control of lower genitourinary tract functions: A review. Urology 1995;45:107–1083.

    Google Scholar 

  35. Frank S, Kampfer H, Wetzler C, Pfeilschifter J. Nitric oxide drives skin repair: Novel functions of an established mediator. Kidney Int 2002;61:88–888.

    Google Scholar 

  36. Kobzik L, Reid MB, Bredt DS, Stamler JS. Nitric oxide in skeletal muscle. Nature 1994;372:54–548.

    Google Scholar 

  37. Eu JP, Sun J, Xu L, Stamler JS, Meissner G. The skeletal muscle calcium release channel: Coupled O2 sensor and NO signaling functions. Cell 2000;102:49–509.

    Google Scholar 

  38. Roberts CK, Barnard RJ, Scheck SH, Balon TW. Exercisestimulated glucose transport in skeletal muscle is nitric oxide dependent. Am J Physiol 1997;273:E22–E225.

    Google Scholar 

  39. Bredt DS, Snyder SH. Transient nitric oxide synthase neurons in embryonic cerebral cortical plate, sensory ganglia, and olfactory epithelium. Neuron 1994;13:30– 313.

    Google Scholar 

  40. Cork RJ, Perrone ML, Bridges D, Wandell J, Scheiner CA, Mize RR. A web-accessible digital atlas of the distribution of nitric oxide synthase in the mouse brain. Prog Brain Res 1998;118:3–50.

    Google Scholar 

  41. Nozaki K, Moskowitz MA, Maynard KI, Koketsu N, Dawson TM, Bredt DS, Snyder SH. Possible origins and distribution of immunoreactive nitric oxide synthasecontaining nerve fibers in cerebral arteries. J Cereb Blood Flow Metab 1993;13:7–79.

    Google Scholar 

  42. Xu KY, Huso DL, Dawson TM, Bredt DS, Becker LC. Nitric oxide synthase in cardiac sarcoplasmic reticulum. Proc Natl Acad Sci USA 1999;96:65–662.

    Google Scholar 

  43. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC. Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993;75:127–1286.

    Google Scholar 

  44. Nelson RJ, Demas GE, Huang PL, Fishman MC, Dawson VL, Dawson TM, Snyder SH. Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. Nature 1995;378:38–386.

    Google Scholar 

  45. Shankar RR, Wu Y, Shen HQ, Zhu JS, Baron AD. Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes 2000;49:68–687.

    Google Scholar 

  46. Barouch LA, Harrison RW, Skaf MW, Rosas GO, Cappola TP, Kobeissi ZA, Hobai IA, Lemmon CA, Burnett AL, O'Rourke B, et al. Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms. Nature 2002;416:33–339.

    Google Scholar 

  47. Brenman JE, Chao DS, Gee SH, McGee AW, Craven SE, Santillano DR, Wu Z, Huang F, Xia H, Peters MF, et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha–syntrophin mediated by PDZ domains. Cell 1996;84:75–767.

    Google Scholar 

  48. Silvagno F, Xia H, Bredt DS. Neuronal nitric-oxide synthase-mu, an alternatively spliced isoform expressed in differentiated skeletal muscle. J Biol Chem 1996;271:1120–11208.

    Google Scholar 

  49. Brenman JE, Chao DS, Xia H, Aldape K, Bredt DS. Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 1995;82:74–752.

    Google Scholar 

  50. Jumrussirikul P, Dinerman J, Dawson TM, Dawson VL, Ekelund U, Georgakopoulos D, Schramm LP, Calkins H, Snyder SH, Hare JM, et al. Interaction between neuronal nitric oxide synthase and inhibitory G protein activity in heart rate regulation in conscious mice. J Clin Invest 1998;102:127–1285.

    Google Scholar 

  51. Woo MA, Stevenson WG, Moser DK, Trelease RB, Harper RM. Patterns of beat-to-beat heart rate variability in advanced heart failure. Am Heart J 1992;123:70– 710.

    Google Scholar 

  52. Choate JK, Danson EJ, Morris JF, Paterson DJ. Peripheral vagal control of heart rate is impaired in neuronal NOS knockout mice. Am J Physiol Heart Circ Physiol 2001;281:H231–H2317.

    Google Scholar 

  53. Jones SP, Girod WG, Huang PL, Lefer DJ. Myocardial reperfusion injury in neuronal nitric oxide synthase deficient mice. Coron Artery Dis 2000;11:59–597.

    Google Scholar 

  54. Sumeray MS, Rees DD, Yellon DM. Infarct size and nitric oxide synthase in murine myocardium. JMol Cell Cardiol 2000;32:3–42.

    Google Scholar 

  55. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994;265:188–1885.

    Google Scholar 

  56. Kelly RA, Balligand JL, Smith TW. Nitric oxide and cardiac function. Circ Res 1996;79:36–380.

    Google Scholar 

  57. Shaul PW. Regulation of endothelial nitric oxide synthase: Location, Location, Location. Annu Rev Physiol 2002;64:74–774.

    Google Scholar 

  58. Fleming I, Busse R. Signal transduction of eNOS activation. Cardiovasc Res 1999;43:53–541.

    Google Scholar 

  59. Robinson LJ, Busconi L, Michel T. Agonist-modulated palmitoylation of endothelial nitric oxide synthase. J Biol Chem 1995;270:99–998.

    Google Scholar 

  60. Robinson LJ, Michel T. Mutagenesis of palmitoylation sites in endothelial nitric oxide synthase identifies a novel motif for dual acylation and subcellular targeting. Proc Natl Acad Sci USA 1995;92:1177–11780.

    Google Scholar 

  61. Godecke A, Decking UK, Ding Z, Hirchenhain J, Bidmon HJ, Godecke S, Schrader J. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ Res 1998;82:18–194.

    Google Scholar 

  62. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995;377:23–242.

    Google Scholar 

  63. Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE, Sherman PA, Sessa WC, Smithies O. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci USA 1996;93:1317– 13181.

    Google Scholar 

  64. Stauss HM, Godecke A, Mrowka R, Schrader J, Persson PB. Enhanced blood pressure variability in eNOS knockout mice. Hypertension 1999;33:135–1363.

    Google Scholar 

  65. Gyurko R, Kuhlencordt P, Fishman MC, Huang PL. Modulation of mouse cardiac function in vivo by eNOS and ANP. Am J Physiol Heart Circ Physiol 2000;278:H97– H981.

    Google Scholar 

  66. Lee PC, Salyapongse AN, Bragdon GA, Shears LL II, Watkins SC, Edington HD, Billiar TR. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol 1999;277:H160–H1608.

    Google Scholar 

  67. Demas GE, Kriegsfeld LJ, Blackshaw S, Huang P, Gammie SC, Nelson RJ, Snyder SH. Elimination of aggressive behavior in male mice lacking endothelial nitric oxide synthase. J Neurosci 1999;19:RC30.

    Google Scholar 

  68. Gregg AR, Schauer A, Shi O, Liu Z, Lee CG, O'Brien WE. Limb reduction defects in endothelial nitric oxide synthase-deficient mice. Am J Physiol 1998;275:H231– H2324.

    Google Scholar 

  69. Lee TC, Zhao YD, Courtman DW, Stewart DJ. Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. Circulation 2000;101:234–2348.

    Google Scholar 

  70. Huang A, Sun D, Shesely EG, Levee EM, Koller A, Kaley G. Neuronal NOS-dependent dilation to flow in coronary arteries of male eNOS-KO mice. Am J Physiol Heart Circ Physiol 2002;282:H42–H436.

    Google Scholar 

  71. Meng W, Ayata C, Waeber C, Huang PL, Moskowitz MA. Neuronal NOS-cGMP-dependent ACh-induced relaxation in pial arterioles of endothelial NOS knockout mice. Am J Physiol 1998;274:H41–H415.

    Google Scholar 

  72. Chataigneau T, Feletou M, Huang PL, Fishman MC, Duhault J, Vanhoutte PM. Acetylcholine-induced relaxation in blood vessels from endothelial nitric oxide synthase knockout mice. Br J Pharmacol 1999;126:21–226.

    Google Scholar 

  73. Sanz MJ, Hickey MJ, Johnston B, McCafferty DM, Raharjo E, Huang PL, Kubes P. Neuronal nitric oxide synthase (NOS) regulates leukocyte-endothelial cell interactions in endothelial NOS deficient mice. Br J Pharmacol 2001;134:30–312.

    Google Scholar 

  74. Knowles JW, Reddick RL, Jennette JC, Shesely EG, Smithies O, Maeda N. Enhanced atherosclerosis and kidney dysfunction in eNOS(-/-)Apoe(-/-) mice are ameliorated by enalapril treatment. J Clin Invest 2000;105:45–458.

    Google Scholar 

  75. Kuhlencordt PJ, Gyurko R, Han F, Scherrer-Crosbie M, Aretz TH, Hajjar R, Picard MH, Huang PL. Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 2001;104:44–454.

    Google Scholar 

  76. Lee PC, Wang ZL, Qian S, Watkins SC, Lizonova A, Kovesdi I, Tzeng E, Simmons RL, Billiar TR, Shears LL, II. Endothelial nitric oxide synthase protects aortic allografts from the development of transplant arteriosclerosis. Transplantation 2000;69:118–1192.

    Google Scholar 

  77. Yang XP, Liu YH, Shesely EG, Bulagannawar M, Liu F, Carretero OA. Endothelial nitric oxide gene knockout mice: Cardiac phenotypes and the effect of angiotensinconverting enzyme inhibitor on myocardial ischemia/ reperfusion injury. Hypertension 1999;34:2–30.

    Google Scholar 

  78. Bell RM, Yellon DM. The contribution of endothelial nitric oxide synthase to early ischaemic preconditioning: The lowering of the preconditioning threshold. An investigation in eNOS knockout mice. Cardiovasc Res 2001;52:27–280.

    Google Scholar 

  79. Flogel U, Decking UK, Godecke A, Schrader J. Contribution of NO to ischemia-reperfusion injury in the saline-perfused heart: A study in endothelial NO synthase knockout mice. J Mol Cell Cardiol 1999;31:82– 836.

    Google Scholar 

  80. Ohashi Y, Kawashima S, Hirata K, Yamashita T, Ishida T, Inoue N, Sakoda T, Kurihara H, Yazaki Y, Yokoyama M. Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. J Clin Invest 1998;102:206–2071.

    Google Scholar 

  81. Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Rikitake Y, Inoue N, Hirata K, Akita H, Yokoyama M. Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. Hypertension 2000;36:9–102.

    Google Scholar 

  82. Yamashita T, Kawashima S, Ohashi Y, Ozaki M, Ueyama T, Ishida T, Inoue N, Hirata K, Akita H, Yokoyama M. Resistance to endotoxin shock in transgenic mice overexpressing endothelial nitric oxide synthase. Circulation 2000;101:93–937.

    Google Scholar 

  83. Kawashima S, Yamashita T, Ozaki M, Ohashi Y, Azumi H, Inoue N, Hirata K, Hayashi Y, Itoh H, Yokoyama M. Endothelial NO synthase overexpression inhibits lesion formation in mouse model of vascular remodeling. Arterioscler Thromb Vasc Biol 2001;21:20–207.

    Google Scholar 

  84. Brunner F, Andrew P, Wolkart G, Zechner R, Mayer B. Myocardial contractile function and heart rate in mice with myocyte-specific overexpression of endothelial nitric oxide synthase. Circulation 2001;104:309–3102.

    Google Scholar 

  85. Kamijo R, Harada H, Matsuyama T, Bosland M, Gerecitano J, Shapiro D, Le J, Koh SI, Kimura T, Green SJ, et al. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science 1994;263:161–1615.

    Google Scholar 

  86. Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 1994;269:470–4708.

    Google Scholar 

  87. Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in macrophages. Proc Natl Acad Sci USA 1997;94:695–6958.

    Google Scholar 

  88. Vasquez-Vivar J, Kalyanaraman B, Martasek P, Hogg N, Masters BS, Karoui H, Tordo P, Pritchard KA Jr. Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors. Proc Natl Acad Sci USA 1998;95:922–9225.

    Google Scholar 

  89. Xia Y, Dawson VL, Dawson TM, Snyder SH, Zweier JL. Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitritemediated cellular injury. Proc Natl Acad Sci USA 1996;93:677–6774.

    Google Scholar 

  90. Thoenes M, Forstermann U, Tracey WR, Bleese NM, Nussler AK, Scholz H, Stein B. Expression of inducible nitric oxide synthase in failing and non-failing human heart. J Mol Cell Cardiol 1996;28:16–169.

    Google Scholar 

  91. Yang X, Chowdhury N, Cai B, Brett J, Marboe C, Sciacca RR, Michler RE, Cannon PJ. Induction of myocardial nitric oxide synthase by cardiac allograft rejection. J Clin Invest 1994;94:71–721.

    Google Scholar 

  92. Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub MH, Polak JM. Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy. Lancet 1996;347:115–1155.

    Google Scholar 

  93. Haywood GA, Tsao PS, von der Leyen HE, Mann MJ, Keeling PJ, Trindade PT, Lewis NP, Byrne CD, Rickenbacher PR, Bishopric NH, et al. Expression of inducible nitric oxide synthase in human heart failure. Circulation 1996;93:108–1094.

    Google Scholar 

  94. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie QW, Sokol K, Hutchinson N, et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995;81:64–650.

    Google Scholar 

  95. Wei XQ, Charles IG, Smith A, Ure J, Feng GJ, Huang FP, Xu D, Muller W, Moncada S, Liew FY. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 1995;375:40–411.

    Google Scholar 

  96. Laubach VE, Shesely EG, Smithies O, Sherman PA. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA 1995;92:1068–10692.

    Google Scholar 

  97. Lee JK, Borhani M, Ennis TL, Upchurch GR Jr, Thompson RW. Experimental abdominal aortic aneurysms in mice lacking expression of inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 2001;21:139–1401.

    Google Scholar 

  98. Cobb JP, Hotchkiss RS, Swanson PE, Chang K, Qiu Y, Laubach VE, Karl IE, Buchman TG. Inducible nitric oxide synthase (iNOS) gene deficiency increases the mortality of sepsis in mice. Surgery 1999;126:43–442.

    Google Scholar 

  99. Boyle WA III, Parvathaneni LS, Bourlier V, Sauter C, Laubach VE, Cobb JP. iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice. Circ Res 2000;87:E1–E24.

    Google Scholar 

  100. Hollenberg SM, Broussard M, Osman J, Parrillo JE. Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res 2000;86:77–778.

    Google Scholar 

  101. Suzuki Y, Deitch EA, Mishima S, Duran WN, Xu DZ. Endotoxin-induced mesenteric microvascular changes involve iNOS-derived nitric oxide: Results from a study using iNOS knock out mice. Shock 2000;13:39–403.

    Google Scholar 

  102. Ihrig M, Dangler CA, Fox JG. Mice lacking inducible nitric oxide synthase develop spontaneous hypercholesterolaemia and aortic atheromas. Atherosclerosis 2001;156:10–107.

    Google Scholar 

  103. Niu XL, Yang X, Hoshiai K, Tanaka K, Sawamura S, Koga Y, Nakazawa H. Inducible nitric oxide synthase deficiency does not affect the susceptibility of mice to atherosclerosis but increases collagen content in lesions. Circulation 2001;103:111–1120.

    Google Scholar 

  104. Kuhlencordt PJ, Chen J, Han F, Astern J, Huang PL. Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Circulation 2001;103:309–3104.

    Google Scholar 

  105. Detmers PA, Hernandez M, Mudgett J, Hassing H, Burton C, Mundt S, Chun S, Fletcher D, Card DJ, Lisnock J, et al. Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein Edeficient mice. J Immunol 2000;165:343–3435.

    Google Scholar 

  106. Koglin J, Glysing-Jensen T, Mudgett JS, Russell ME. Exacerbated transplant arteriosclerosis in inducible nitric oxide-deficient mice. Circulation 1998;97:205–2065.

    Google Scholar 

  107. Gray GA, Sharif I, Webb DJ, Seckl JR. Oestrogen and the cardiovascular system: The good, the bad and the puzzling. Trends Pharmacol Sci 2001;22:15–156.

    Google Scholar 

  108. Miller VM. Gender, vascular reactivity. Lupus 1999;8:40–415.

    Google Scholar 

  109. Chyu KY, Dimayuga P, Zhu J, Nilsson J, Kaul S, Shah PK, Cercek B. Decreased neointimal thickening after arterial wall injury in inducible nitric oxide synthase knockout mice. Circ Res 1999;85:119–1198.

    Google Scholar 

  110. Tolbert T, Thompson JA, Bouchard P, Oparil S. Estrogeninduced vasoprotection is independent of inducible nitric oxide synthase expression: Evidence from the mouse carotid artery ligation model. Circulation 2001;104:274– 2745.

    Google Scholar 

  111. Koglin J, Glysing-Jensen T, Mudgett JS, Russell ME. NOS2 mediates opposing effects in models of acute and chronic cardiac rejection: Insights from NOS–knockout mice. Am J Pathol 1998;153:137– 1376.

    Google Scholar 

  112. Koglin J, Granville DJ, Glysing-Jensen T, Mudgett JS, Carthy CM, McManus BM, Russell ME. Attenuated acute cardiac rejection in NOS2-/- recipients correlates with reduced apoptosis. Circulation 1999;99:83–842.

    Google Scholar 

  113. Xi L, Jarrett NC, Hess ML, Kukreja RC. Myocardial ischemia/reperfusion injury in the inducible nitric oxide synthase knockout mice. Life Sci 1999;65:93– 945.

    Google Scholar 

  114. Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, Schulz R, Butany J, Stewart DJ, Husain M. Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. J Clin Invest 2002;109:73–743.

    Google Scholar 

  115. Heger J, Godecke A, Flogel U, Merx MW, Molojavyi A, Kuhn-Velten WN, Schrader J. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction. Circ Res 2002;90:9– 99.

    Google Scholar 

  116. Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, Tonegawa S. Subregion-and cell type-restricted gene knockout in mouse brain. Cell 1996;87:131–1326.

    Google Scholar 

  117. Lipardi C, Wei Q, Paterson BM. RNAi as random degradative PCR: siRNA primers convert mRNA into dsRNAs that are degraded to generate new siRNAs. Cell 2001;107:29–307.

    Google Scholar 

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  1. Imran N. Mungrue
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  2. Mansoor Husain
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  3. Duncan J. Stewart
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Mungrue, I.N., Husain, M. & Stewart, D.J. The Role of NOS in Heart Failure: Lessons from Murine Genetic Models. Heart Fail Rev 7, 407–422 (2002). https://doi.org/10.1023/A:1020762401408

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