Genetic Disruption of Nitric Oxide Synthases and Cardiovascular Disease: Lessons from a Candidate Gene

  • P. L. Huang
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 160)


The nitric oxide (NO) system is vitally important to the function of the cardiovascular system. Abnormalities in NO signaling have been linked to a wide variety of cardiovascular diseases, including atherosclerosis, hypertension, congestive heart failure, thrombosis, stroke, and diabetes mellitus. This chapter will review the roles that NO synthases play in normal vascular function and in the molecular mechanisms of disease processes, focusing on information gained from the study of mutant mice in which the NO synthase genes have been disrupted or modified. Specifically, we wil review the various genetic polymorphisms that have been described in the NO synthase genes, their association with disease processes and their functional effects on NO synthase function or expression levels. The cellular pathways that involve NO are complex and offer not only insights into how abnormalities in NO signaling can lead to disease but also opportunities and targets on which to intervene to prevent or treat disease.


Nitric oxide Enzyme Knockout Endothelial Neuronal Inducible 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alderton WK, Cooper CE, Knowles RG (2001) Nitric oxide synthases: structure, function and inhibition. Biochem J 357: 593–615PubMedCrossRefGoogle Scholar
  2. Arnold WP, Mittal CK, Katsuki S et al (1977) Nitric oxide activates guanylate cyclase and increases guanosine 3’:5’-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA 74: 3203–7PubMedCrossRefGoogle Scholar
  3. Bath PM (1993). The effect of nitric oxide-donating vasodilators on monocyte chemotaxis and intracellular cGMP concentrations in vitro. Eur J Clin Pharmacol 45: 53–8PubMedCrossRefGoogle Scholar
  4. Beckman JS, Chen J, Ischiropoulos H et al (1994) Oxidative chemistry of peroxynitrite. Methods Enzymol 233: 229–240PubMedCrossRefGoogle Scholar
  5. Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271: C1424–37PubMedGoogle Scholar
  6. Bonnardeaux A, Nadaud S, Charru A et al (1995) Lack of evidence for linkage of the endothelial cell nitric oxide synthase gene to essential hypertension. Circulation 91: 96–102PubMedCrossRefGoogle Scholar
  7. Brenman JE, Christopherson KS, Craven SE et al (1996) Cloning and characterization of postsynaptic density 93, a nitric oxide synthase interacting protein. J Neurosci 16: 7407–15PubMedGoogle Scholar
  8. Brenman JE, Xia H, Chao DS et al (1997) Regulation of neuronal nitric oxide synthase through alternative transcripts. Dev Neurosci 19: 224–31PubMedCrossRefGoogle Scholar
  9. Brouet A, Sonveaux P, Dessy C et al (2001) Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins. Circ Res 89: 866–73PubMedCrossRefGoogle Scholar
  10. Brown GC (1995) Nitric oxide regulates mitochondrial respiration and cell functions by inhibiting cytochrome oxidase. FEBS Lett 369: 136–9PubMedCrossRefGoogle Scholar
  11. Busconi L, Michel T (1993) Endothelial nitric oxide synthase. N-terminal myristoylation determines subcellular localization. J Biol Chem 268: 8410–3Google Scholar
  12. Cai H, Harrison DG (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 87: 840–4PubMedCrossRefGoogle Scholar
  13. Chen J, Kuhlencordt P, Urano F et al (2003) Effects of chronic treatment with L-arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double-knockout mice. Arterioscler Thromb Vasc Biol 23: 97–103PubMedCrossRefGoogle Scholar
  14. Chen J, Kuhlencordt PJ, Astern J et al (2001) Hypertension does not account for the accelerated atherosclerosis and development of aneurysms in male apolipoprotein e/endothelial nitric oxide synthase double knockout mice. Circulation 104: 2391–4PubMedCrossRefGoogle Scholar
  15. Chen ZP, Mitchelhill KI, Michell BJ et al (1999) AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 443: 285–9PubMedCrossRefGoogle Scholar
  16. Crosby G, Marota JJ, Huang PL (1995) Intact nociception-induced neuroplasticity in transgenic mice deficient in neuronal nitric oxide synthase. Neuroscience 69: 1013–1017PubMedCrossRefGoogle Scholar
  17. Darius S, Wolf G, Huang PL et al (1995) Localization of NADPH-diaphorase/nitric oxide synthase in the rat retina: an electron microscopic study. Brain Res 690: 231–5PubMedCrossRefGoogle Scholar
  18. Dawson E, Abecasis GR, Bumpstead S et al (2002) A first-generation linkage disequilibrium map of human chromosome 22. Nature 418: 544–8PubMedCrossRefGoogle Scholar
  19. Dawson TM, Dawson VL, Snyder SH (1993) Nitric oxide as a mediator of neurotoxicity. NIDA Res Monogr 136: 258–71PubMedGoogle Scholar
  20. Dawson TM, Dawson VL, Snyder SH (1994) Molecular mechanisms of nitric oxide actions in the brain. Ann N YAcad Sci 738: 76–85CrossRefGoogle Scholar
  21. Dawson VL, Kizushi VM, Huang PL et al (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J Neurosci 16: 2479–87PubMedGoogle Scholar
  22. Dimmeler S, Fleming L, Fisslthaler B et al (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399: 601–5PubMedCrossRefGoogle Scholar
  23. Du XL, Edelstein D, Dimmeler S et al (2001) Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 108: 1341–8PubMedGoogle Scholar
  24. Endres M, Laufs U, Huang Z et al (1998) Stroke protection by 3-hydroxy-3-methylglutaryl ( HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci USA 95: 8880–5Google Scholar
  25. Endres M, Scott G, Namura S et al (1998) Role of peroxynitrite and neuronal nitric oxide synthase in the activation of poly(ADP-ribose) synthetase in a murine model of cerebral ischemia-reperfusion. Neurosci Lett 248: 41–4PubMedCrossRefGoogle Scholar
  26. Feron O, Michel JB, Sase K et al (1998) Dynamic regulation of endothelial nitric oxide synthase: complementary roles of dual acylation and caveolin interactions. Biochemistry 37: 193–200PubMedCrossRefGoogle Scholar
  27. Feron O, Saldana F, Michel JB et al (1998) The endothelial nitric-oxide synthase-caveolin regulatory cycle. J Biol Chem 273: 3125–8PubMedCrossRefGoogle Scholar
  28. Freedman JE, Sauter R, Battinelli EM et al (1999) Deficient platelet-derived nitric oxide and enhanced hemostasis in mice lacking the NOSIII gene. Circ Res 84: 1416–21PubMedCrossRefGoogle Scholar
  29. Fulton D, Gratton JP, McCabe TJ et al (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399: 597–601PubMedCrossRefGoogle Scholar
  30. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288: 373–6PubMedCrossRefGoogle Scholar
  31. Garcia-Cardena G, Fan R, Shah V et al (1998) Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392: 821–4PubMedCrossRefGoogle Scholar
  32. Garcia-Cardena G, Martasek P, Masters BS et al (1997) Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 272: 25437–40Google Scholar
  33. Garcia-Cardena G, Oh P, Liu J et al (1996) Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: implications for nitric oxide signaling. Proc Natl Acad Sci USA 93: 6448–53PubMedCrossRefGoogle Scholar
  34. Gerlai R (2001) Gene targeting: technical confounds and potential solutions in behavioral brain research. Behav Brain Res 125: 13–21PubMedCrossRefGoogle Scholar
  35. Gimbrone MA Jr. (1989) Endothelial dysfunction and atherosclerosis. J Card Surg 4: 1803CrossRefGoogle Scholar
  36. Goligorsky MS, Noiri E, Tsukahara H et al (2000) A pivotal role of nitric oxide in endothelial cell dysfunction. Acta Physiol Scand 168: 33–40PubMedCrossRefGoogle Scholar
  37. Guzik TJ, Black E, West NE et al (2001) Relationship between the G894T polymorphism (G1u298Asp variant) in endothelial nitric oxide synthase and nitric oxide-mediated endothelial function in human atherosclerosis. Am J Med Genet 100: 130–7PubMedCrossRefGoogle Scholar
  38. 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: H971–81PubMedGoogle Scholar
  39. 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: 2767–74PubMedCrossRefGoogle Scholar
  40. Hara H, Huang PL, Panahian N et al (1996) Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. J Cereb Blood Flow Metab 16: 605–11PubMedCrossRefGoogle Scholar
  41. Harris MB, Ju H, Venema VJ et al (2001) Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 276: 16587–91PubMedCrossRefGoogle Scholar
  42. Hibi K, Ishigami T, Tamura K et al (1998) Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction. Hypertension 32: 521–6PubMedCrossRefGoogle Scholar
  43. Hingorani AD (2003) Endothelial nitric oxide synthase polymorphisms and hypertension. Curr Hypertens Rep 5: 19–25PubMedCrossRefGoogle Scholar
  44. Hisamoto K, Ohmichi M, Kurachi H et al (2001) Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 276: 3459–67PubMedCrossRefGoogle Scholar
  45. Huang PL, Dawson TM, Bredt DS et al (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75: 1273–86PubMedCrossRefGoogle Scholar
  46. Huang PL, Huang Z, Mashimo H et al (1995) Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377: 239–42PubMedCrossRefGoogle Scholar
  47. Huang Z, Huang PL, Ma J et al (1996) Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 16: 981–987PubMedCrossRefGoogle Scholar
  48. Huang Z, Huang PL, Panahian N et al (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265: 1883–5PubMedCrossRefGoogle Scholar
  49. Iadecola C, Pelligrino DA, Moskowitz MA et al (1994) Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab 14: 175–92PubMedCrossRefGoogle Scholar
  50. Iadecola C, Zhang F, Casey R et al (1997) Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 17: 9157–9164PubMedGoogle Scholar
  51. Iadecola C, Zhang F, Xu X (1995) Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Physiol 268: R286–92PubMedGoogle Scholar
  52. Ichinose F, Huang PL, Zapol WM (1995) Effects of targeted neuronal nitric oxide synthase gene disruption and nitroG-L-arginine methylester on the threshold for isoflurane anesthesia. Anesthesiology 83: 101–8PubMedCrossRefGoogle Scholar
  53. Ignarro LJ, Buga GM, Wood KS et al (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84: 9265–9PubMedCrossRefGoogle Scholar
  54. Irikura K, Huang PL, Ma J et al (1995) Cerebrovascular alterations in mice lacking neuronal nitric oxide synthase gene expression. Proc Natl Acad Sci USA 92: 6823–7PubMedCrossRefGoogle Scholar
  55. Jachymova M, Horky K, Bultas J et al (2001) Association of the Glu298Asp polymorphism in the endothelial nitric oxide synthase gene with essential hypertension resistant to conventional therapy. Biochem Biophys Res Commun 284: 426–30PubMedCrossRefGoogle Scholar
  56. Janssens SP, Shimouchi A, Quertermous T et al (1992) Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 267: 14519–22PubMedGoogle Scholar
  57. Katsuki S, Arnold W, Mittal C et al (1977) Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 3: 23–35PubMedGoogle Scholar
  58. Kojda G, Cheng YC, Burchfield J et al (2001) Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103: 2839–44PubMedCrossRefGoogle Scholar
  59. Kuhlencordt PJ, Gyurko R, Han F et al (2001) Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 104: 448–54PubMedCrossRefGoogle Scholar
  60. Kureishi Y, Luo Z, Shiojima I et al (2000) The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 6: 1004–10PubMedCrossRefGoogle Scholar
  61. Lacolley P, Gautier S, Poirier O et al (1998) Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects. J Hypertens 16: 31–5PubMedCrossRefGoogle Scholar
  62. Lamas S, Marsden PA, Li GK et al (1992) Endothelial nitric oxide synthase: molecular cloning and characterization of a distinct constitutive enzyme isoform. Proc Natl Acad Sci USA 89: 6348–52PubMedCrossRefGoogle Scholar
  63. Laubach VE, Shesely EG, Smithies O et al (1995) Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc Natl Acad Sci USA 92: 10688–10692PubMedCrossRefGoogle Scholar
  64. Laufs U, Endres M, Stagliano N et al (2000) Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest 106: 15–24PubMedCrossRefGoogle Scholar
  65. Lea RA, Curtain RP, Shepherd AG et al (2001) No evidence for involvement of the human inducible nitric oxide synthase (iNOS) gene in susceptibility to typical migraine. Am J Med Genet 105: 110–3PubMedCrossRefGoogle Scholar
  66. Leeson CP, Hingorani AD, Mullen MJ et al (2002) Glu298Asp endothelial nitric oxide synthase gene polymorphism interacts with environmental and dietary factors to influence endothelial function. Circ Res 90: 1153–8PubMedCrossRefGoogle Scholar
  67. Lefer DJ, Jones SP, Girod WG et al (1999) Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am J Physiol 276: H1943–50PubMedGoogle Scholar
  68. Liou YJ, Hong CJ, Liu HC et al (2002) No association between the neuronal nitric oxide synthase gene polymorphism and Alzheimer Disease. Am J Med Genet 114: 687–8PubMedCrossRefGoogle Scholar
  69. Liu J, Sessa WC (1994) Identification of covalently bound amino-terminal myristic acid in endothelial nitric oxide synthase. J Biol Chem 269: 11691–4PubMedGoogle Scholar
  70. Lo E, Hara H, Rogowska J et al (1996) Temporal correlation mapping analysis of the hemodynamic penumbra in mutant mice deficient in endothelial nitric oxide synthase gene expression. Stroke 27: 1381–1385PubMedCrossRefGoogle Scholar
  71. Lo HS, Hogan EL, Soong BW (2002) 5’-flanking region polymorphism of the neuronal nitric oxide synthase gene with Parkinson’s disease in Taiwan. J Neurol Sci 194: 11–3Google Scholar
  72. Loscalzo J (2003) Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism? Arterioscler Thromb Vasc Biol 23: 3–5PubMedCrossRefGoogle Scholar
  73. Ma J, Ayata C, Huang PL et al (1996) Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression. Am J Physiol 270: H1085–90PubMedGoogle Scholar
  74. MacMicking JD, Nathan C, Hom G et al (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81: 641–50PubMedCrossRefGoogle Scholar
  75. Malinski T, Bailey F, Zhang ZG et al (1993) Nitric oxide measured by a porphyrinic microsensor in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 13: 355–8PubMedCrossRefGoogle Scholar
  76. Marsden PA, Schappert KT, Chen HS et al (1992) Molecular cloning and characterization of human endothelial nitric oxide synthase. FEBS Lett 307: 287–93PubMedCrossRefGoogle Scholar
  77. Michel JB, Feron O, Sacks D et al (1997) Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem 272: 15583–6PubMedCrossRefGoogle Scholar
  78. Michel JB, Feron O, Sase K et al (1997) Caveolin versus calmodulin. Counterbalancing al- losteric modulators of endothelial nitric oxide synthase. J Biol Chem 272: 25907–12Google Scholar
  79. Michell BJ, Chen Z, Tiganis T et al (2001) Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem 276: 17625–8PubMedCrossRefGoogle Scholar
  80. Miyamoto Y, Saito Y, Kajiyama N et al (1998) Endothelial nitric oxide synthase gene is positively associated with essential hypertension. Hypertension 32: 3–8PubMedCrossRefGoogle Scholar
  81. Montagnani M, Chen H, Barr VA et al (2001) Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem 276: 30392–8PubMedCrossRefGoogle Scholar
  82. Mooradian DL, Hutsell TC, Keefer LK (1995) Nitric oxide (NO) donor molecules: effect of NO release rate on vascular smooth muscle cell proliferation in vitro. J Cardiovasc Pharmacol 25: 674–8PubMedCrossRefGoogle Scholar
  83. Moroi M, Zhang L, Yasuda T 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: 1225–32PubMedCrossRefGoogle Scholar
  84. Nakayama M, Yasue H, Yoshimura M et al (1999) T-786->C mutation in the 5’-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation 99: 2864–70PubMedCrossRefGoogle Scholar
  85. Nakayama T, Soma M, Takahashi Y et al (1997) Association analysis of CA repeat polymorphism of the endothelial nitric oxide synthase gene with essential hypertension in Japanese. Clin Genet 51: 26–30PubMedCrossRefGoogle Scholar
  86. Nishida K, Harrison DG, Navas JP et al (1992) Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthase. J Clin Invest 90: 2092–6PubMedCrossRefGoogle Scholar
  87. Okada S, Takehara Y, Yabuki Met al (1996) Nitric oxide, a physiological modulator of mitochondrial function. Physiol Chem Phys Med NMR 28: 69–82PubMedGoogle Scholar
  88. Panahian N, Yoshida T, Huang PL et al (1996) Attenuated hippocampal damage after global cerebral ischemia in mice mutant in neuronal nitric oxide synthase. Neuroscience 72: 343–354PubMedCrossRefGoogle Scholar
  89. Pollock JS, Klinghofer V, Forstermann U et al (1992) Endothelial nitric oxide synthase is myristylated. FEBS Lett 309: 402–4PubMedCrossRefGoogle Scholar
  90. Radomski MW, Palmer RM, Moncada S (1991) Modulation of platelet aggregation by an L-arginine-nitric oxide pathway. Trends Pharmacol Sci 12: 87–88PubMedCrossRefGoogle Scholar
  91. Ringertz N (2001) Alfred Nobel-his life and work. Nat Rev Mol Cell Biol 2: 925–8PubMedCrossRefGoogle Scholar
  92. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990 s. Nature 362: 801–9PubMedCrossRefGoogle Scholar
  93. Schneider MP, Erdmann J, Delles C et al (2000) Functional gene testing of the Glu298Asp polymorphism of the endothelial NO synthase. J Hypertens 18: 1767–73PubMedCrossRefGoogle Scholar
  94. Sessa WC, Harrison JK, Barber CM et al (1992) Molecular cloning and expression of a cDNA encoding endothelial cell nitric oxide synthase. J Biol Chem 267: 15274–6PubMedGoogle Scholar
  95. Shaul PW (2002) Regulation of endothelial nitric oxide synthase: Location, location, location. Annu Rev Physiol 64: 749–774PubMedCrossRefGoogle Scholar
  96. Shesely EG, Maeda N, Kim HS et al (1996) Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci USA 93: 13176–81PubMedCrossRefGoogle Scholar
  97. Shimasaki Y, Yasue H, Yoshimura M et al (1998) Association of the missense Glu298Asp variant of the endothelial nitric oxide synthase gene with myocardial infarction. J Am Coll Cardiol 31: 1506–10PubMedCrossRefGoogle Scholar
  98. Singleton AB, Gibson AM, McKeith IG et al (2001) Nitric oxide synthase gene polymorphisms in Alzheimer’s disease and dementia with Lewy bodies. Neurosci Lett 303: 336CrossRefGoogle Scholar
  99. Stamler JS (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78: 931–6PubMedCrossRefGoogle Scholar
  100. Stamler JS, Jia L, Eu JP et al (1997) Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 276: 2034–7PubMedCrossRefGoogle Scholar
  101. Stangl K, Cascorbi I, Laule M et al (2000) High CA repeat numbers in intron 13 of the endothelial nitric oxide synthase gene and increased risk of coronary artery disease. Pharmacogenetics 10: 133–40PubMedCrossRefGoogle Scholar
  102. Sullivan KJ, Kissoon N, Duckworth LJ et al (2001) Low exhaled nitric oxide and a polymorphism in the NOS I gene is associated with acute chest syndrome. Am J Respir Crit Care Med 164: 2186–90PubMedGoogle Scholar
  103. Takehara Y, Kanno T, Yoshioka T et al (1995) Oxygen-dependent regulation of mitochondrial energy metabolism by nitric oxide. Arch Biochem Biophys 323: 27–32PubMedCrossRefGoogle Scholar
  104. Tanus-Santos JE, Desai M, Deak LR et al (2002) Effects of endothelial nitric oxide synthase gene polymorphisms on platelet function, nitric oxide release, and interactions with estradiol. Pharmacogenetics 12: 407–13PubMedCrossRefGoogle Scholar
  105. Tanus-Santos JE, Desai M, Flockhart DA (2001) Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 11: 719–25PubMedCrossRefGoogle Scholar
  106. Tesauro M, Thompson WC, Rogliani P et al (2000) Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA 97: 2832–5PubMedCrossRefGoogle Scholar
  107. Tsukada T, Yokoyama K, Arai T et al (1998) Evidence of association of the ecNOS gene polymorphism with plasma NO metabolite levels in humans. Biochem Biophys Res Commun 245: 190–3PubMedCrossRefGoogle Scholar
  108. Wade CM, Kulbokas EJ, 3rd, Kirby AW et al (2002) The mosaic structure of variation in the laboratory mouse genome. Nature 420: 574–8PubMedCrossRefGoogle Scholar
  109. Wang J, Dudley D, Wang XL (2002) Haplotype-specific effects of endothelial NO synthase promoter efficiency: modifiable by cigarette smoking. Arterioscler Thromb Vasc Biol 22: el-4Google Scholar
  110. Wang XL, Wang J (2000) Endothelial nitric oxide synthase gene sequence variations and vascular disease. Mol Genet Metab 70: 241–51PubMedCrossRefGoogle Scholar
  111. Wattanapitayakul SK, Mihm MJ, Young AP et al (2001) Therapeutic implications of human endothelial nitric oxide synthase gene polymorphism. Trends Pharmacol Sci 22: 361–8PubMedCrossRefGoogle Scholar
  112. Wei XQ, Charles IG, Smith A et al (1995) Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375: 408–11PubMedCrossRefGoogle Scholar
  113. Xu W, Liu L, Emson P et al (2000) The CCTTT polymorphism in the NOS2A gene is associated with dementia with Lewy bodies. Neuroreport 11: 297–9PubMedCrossRefGoogle Scholar
  114. Yogo K, Shimokawa H, Funakoshi H et al (2000) Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol 20: E96 - E100PubMedCrossRefGoogle Scholar
  115. Yoshimura M, Yasue H, Nakayama M (1998) A missense Glu298Asp variant in the endothelilal nitric oxide sythase gene is associated with coronary spasm in the Japanese. Hum Genet 103: 65–69PubMedCrossRefGoogle Scholar
  116. Yoshimura M, Yasue H, Nakayama M et al (2000) Genetic risk factors for coronary artery spasm: significance of endothelial nitric oxide synthase gene T-786->C and missense Glu298Asp variants. J Investig Med 48: 367–74PubMedGoogle Scholar
  117. Zaharchuk G, Hara H, Huang PL et al (1997) Neuronal nitric oxide synthase mutant mice show smaller infarcts and attenuated apparent diffusion coefficient changes in the peri-infarct zone during focal cerebral ischemia. Magn Reson Med 37: 170–5PubMedCrossRefGoogle Scholar
  118. Zhang L, Fishman MC, Huang PL (1999) Estrogen mediates the protective effects of pregnancy and chorionic gonadotropin in a mouse model of vascular injury. Arterioscler Thromb Vasc Biol 19: 2059–65PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • P. L. Huang
    • 1
  1. 1.Cardiovascular Research Center, Massachusetts General HospitalHarvard Medical SchoolBostonUSA

Personalised recommendations