Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2014 (2014), Article ID 501612, 11 pages
http://dx.doi.org/10.1155/2014/501612
Review Article

The Endothelial ADMA/NO Pathway in Hypoxia-Related Chronic Respiratory Diseases

1University Medical Center Hamburg-Eppendorf, Department of Clinical Pharmacology and Toxicology, Martinistraße 52, 20246 Hamburg, Germany
2University Medical Center Hamburg-Eppendorf, II Department of Medicine-Oncology, Hematology, Stem Cell Transplantation, Section of Pneumology, Hamburg, Germany
3The Vera Moulton Wall Center for Pulmonary Vascular Disease and Cardiovascular Institute, Stanford University - School of Medicine, Stanford, USA

Received 14 November 2013; Accepted 18 January 2014; Published 25 February 2014

Academic Editor: Silvia M. Arribas

Copyright © 2014 Nicole Lüneburg et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. S. Moncada and A. Higgs, “The L-arginine-nitric oxide pathway,” The New England Journal of Medicine, vol. 329, no. 27, pp. 2002–2012, 1993. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Michel and O. Feron, “Nitric oxide synthases: which, where, how, and why?” The Journal of Clinical Investigation, vol. 100, no. 9, pp. 2146–2152, 1997. View at Google Scholar · View at Scopus
  3. D. S. Bredt, C. E. Glatt, P. M. Hwang, M. Fotuhi, T. M. Dawson, and S. H. Snyder, “Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase,” Neuron, vol. 7, no. 4, pp. 615–624, 1991. View at Publisher · View at Google Scholar · View at Scopus
  4. C. J. Lowenstein, C. S. Glatt, D. S. Bredt, and S. H. Snyder, “Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 15, pp. 6711–6715, 1992. View at Publisher · View at Google Scholar · View at Scopus
  5. K. Sase and T. Michel, “Expression and regulation of endothelial nitric oxide synthase,” Trends in Cardiovascular Medicine, vol. 7, no. 1, pp. 28–37, 1997. View at Publisher · View at Google Scholar · View at Scopus
  6. J. N. Wilcox, R. R. Subramanian, C. L. Sundell et al., “Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, no. 11, pp. 2479–2488, 1997. View at Google Scholar · View at Scopus
  7. S. Moncada, R. M. J. Palmer, and E. A. Higgs, “Nitric oxide: physiology, pathophysiology, and pharmacology,” Pharmacological Reviews, vol. 43, no. 2, pp. 109–142, 1991. View at Google Scholar · View at Scopus
  8. G. L. Semenza, “Mechanisms of disease: oxygen sensing, homeostasis, and disease,” The New England Journal of Medicine, vol. 365, no. 6, pp. 537–547, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. J. J. Ho, H. S. Man, and P. A. Marsden, “Nitric oxide signaling in hypoxia,” Journal of Molecular Medicine, vol. 90, pp. 217–231, 2012. View at Google Scholar
  10. K. Howell, C. M. Costello, M. Sands, I. Dooley, and P. McLoughlin, “L-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 296, no. 6, pp. L1042–L1050, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. C. T. L. Tran, J. M. Leiper, and P. Vallance, “The DDAH/ADMA/NOS pathway,” Atherosclerosis Supplements, vol. 4, no. 4, pp. 33–40, 2003. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Leiper and P. Vallance, “Biological significance of endogenous methylarginines that inhibit nitric oxide synthases,” Cardiovascular Research, vol. 43, no. 3, pp. 542–548, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. L. J. Druhan, S. P. Forbes, A. J. Pope, C.-A. Chen, J. L. Zweier, and A. J. Cardounel, “Regulation of eNOS-derived superoxide by endogenous methylarginines,” Biochemistry, vol. 47, no. 27, pp. 7256–7263, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. J. Strobel, M. Mieth, B. Endreß et al., “Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1),” Journal of Molecular and Cellular Cardiology, vol. 53, pp. 392–400, 2012. View at Google Scholar
  15. R. H. Böger, H. G. Endres, E. Schwedhelm et al., “Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease,” Journal of Internal Medicine, vol. 269, no. 3, pp. 349–361, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. R. H. Böger, R. Maas, F. Schulze, and E. Schwedhelm, “Asymmetric dimethylarginine (ADMA) as a prospective marker of cardiovascular disease and mortality-An update on patient populations with a wide range of cardiovascular risk,” Pharmacological Research, vol. 60, no. 6, pp. 481–487, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. M. O. Gore, N. Lüneburg, E. Schwedhelm et al., “Symmetrical dimethylarginine predicts mortality in the general population: observations from the dallas heart study,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, pp. 2682–2688, 2013. View at Google Scholar
  18. S. Kiechl, T. Lee, P. Santer et al., “Asymmetric and symmetric dimethylarginines are of similar predictive value for cardiovascular risk in the general population,” Atherosclerosis, vol. 205, no. 1, pp. 261–265, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. N. Lüneburg, R.-A. von Holten, R. F. Töpper, E. Schwedhelm, R. Maas, and R. H. Böger, “Symmetric dimethylarginine is a marker of detrimental outcome in the acute phase after ischaemic stroke: role of renal function,” Clinical Science, vol. 122, no. 3, pp. 105–111, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. F. Schulze, A. M. Carter, E. Schwedhelm et al., “Symmetric dimethylarginine predicts all-cause mortality following ischemic stroke,” Atherosclerosis, vol. 208, no. 2, pp. 518–523, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. X. Hu, X. Xu, G. Zhu et al., “Vascular endothelial-specific dimethylarginine dimethylaminohydrolase-1- deficient mice reveal that vascular endothelium plays an important role in removing asymmetric dimethylarginine,” Circulation, vol. 120, no. 22, pp. 2222–2229, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. D. Wang, P. S. Gill, T. Chabrashvili et al., “Isoform-specific regulation by NG,NG-dimethylarginine dimethylaminohydrolase of rat serum asymmetric dimethylarginine and vascular endothelium-derived relaxing factor/NO,” Circulation Research, vol. 101, no. 6, pp. 627–635, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. H. Dayoub, V. Achan, S. Adimoolam et al., “Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence,” Circulation, vol. 108, no. 24, pp. 3042–3047, 2003. View at Publisher · View at Google Scholar · View at Scopus
  24. H. Dayoub, R. Rodionov, J. P. Cooke, S. R. Lentz, and F. M. Faraci, “Human DDAH-I transgenic mice exhibit increased basal vascular NO and are protected against ADMA-induced endothelial dysfunction,” The Faseb Journal, vol. 19, pp. A1238–A1238, 2005. View at Google Scholar
  25. K. Hasegawa, S. Wakino, S. Tatematsu et al., “Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2,” Circulation Research, vol. 101, no. 2, pp. e2–e10, 2007. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Jacobi, K. Sydow, G. von Degenfeld et al., “Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis,” Circulation, vol. 111, no. 11, pp. 1431–1438, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. H. Konishi, K. Sydow, and J. P. Cooke, “Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury,” Journal of the American College of Cardiology, vol. 49, no. 10, pp. 1099–1105, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. M. Tanaka, K. Sydow, F. Gunawan et al., “Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease,” Circulation, vol. 112, no. 11, pp. 1549–1556, 2005. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Bełtowski and A. Kedra, “Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy,” Pharmacological Reports, vol. 58, no. 2, pp. 159–178, 2006. View at Google Scholar · View at Scopus
  30. M. Yoshimatsu, G. Toyokawa, S. Hayami et al., “Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers,” International Journal of Cancer, vol. 128, no. 3, pp. 562–573, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Zakrzewicz and O. Eickelberg, “From arginine methylation to ADMA: a novel mechanism with therapeutic potential in chronic lung diseases,” BMC Pulmonary Medicine, vol. 9, article 5, 2009. View at Publisher · View at Google Scholar · View at Scopus
  32. Y. T. Ghebremariam, D. A. Erlanson, and J. P. Cooke, “A novel and potent inhibitor of dimethylarginine dimethylaminohydrolase: a modulator of cardiovascular nitric oxide,” Journal of Pharmacology and Experimental Therapeutics, vol. 348, pp. 69–76, 2014. View at Google Scholar
  33. M. Anderssohn, E. Schwedhelm, N. Lüneburg, R. S. Vasan, and R. H. Böger, “Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus,” Diabetes and Vascular Disease Research, vol. 7, no. 2, pp. 105–118, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. R. H. Böger, A. Diemert, E. Schwedhelm, N. Lüneburg, R. Maas, and K. Hecher, “The role of nitric oxide synthase inhibition by asymmetric dimethylarginine in the pathophysiology of preeclampsia,” Gynecologic and Obstetric Investigation, vol. 69, no. 1, pp. 1–13, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. E. Schwedhelm and R. H. Böger, “The role of asymmetric and symmetric dimethylarginines in renal disease,” Nature Reviews Nephrology, vol. 7, no. 5, pp. 275–285, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. A. Giaid and D. Saleh, “Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension,” The New England Journal of Medicine, vol. 333, no. 4, pp. 214–221, 1995. View at Publisher · View at Google Scholar · View at Scopus
  37. J. T. Kielstein, S. M. Bode-Böger, G. Hesse et al., “Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 7, pp. 1414–1418, 2005. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Pullamsetti, L. Kiss, H. A. Ghofrani et al., “Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension,” The FASEB Journal, vol. 19, no. 9, pp. 1175–1177, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. S. Rich and B. H. Brundage, “Pulmonary hypertension: a cellular basis for understanding the pathophysiology and treatment,” Journal of the American College of Cardiology, vol. 14, no. 3, pp. 545–550, 1989. View at Google Scholar · View at Scopus
  40. M. Rabinovitch, “Molecular pathogenesis of pulmonary arterial hypertension,” The Journal of Clinical Investigation, vol. 122, pp. 4306–4313, 2012. View at Google Scholar
  41. R. M. Tuder, B. Groves, D. B. Badesch, and N. F. Voelkel, “Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension,” The American Journal of Pathology, vol. 144, no. 2, pp. 275–285, 1994. View at Google Scholar · View at Scopus
  42. J. P. Cooke, “A novel mechanism for pulmonary arterial hypertension?” Circulation, vol. 108, no. 12, pp. 1420–1421, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. S. S. Pullamsetti, R. Savai, M. B. Schaefer et al., “CAMP phosphodiesterase inhibitors increases nitric oxide production by modulating dimethylarginine dimethylaminohydrolases,” Circulation, vol. 123, no. 11, pp. 1194–1204, 2011. View at Publisher · View at Google Scholar · View at Scopus
  44. S. Namkoong, C.-K. Kim, Y.-L. Cho et al., “Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling,” Cellular Signalling, vol. 21, no. 6, pp. 906–915, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. N. Galiè, H. A. Ghofrani, A. Torbicki et al., “Sildenafil citrate therapy for pulmonary arterial hypertension,” The New England Journal of Medicine, vol. 353, no. 20, pp. 2148–2157, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. H. A. Ghofrani, R. Wiedemann, F. Rose et al., “Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial,” The Lancet, vol. 360, no. 9337, pp. 895–900, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. M. R. Wilkins, J. Wharton, F. Grimminger, and H. A. Ghofrani, “Phosphodiesterase inhibitors for the treatment of pulmonary hypertension,” European Respiratory Journal, vol. 32, no. 1, pp. 198–209, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. H. A. Ghofrani and F. Grimminger, “Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy,” European Respiratory Review, vol. 18, no. 111, pp. 35–41, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. H. A. Ghofrani, M. M. Hoeper, M. Halank et al., “Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study,” European Respiratory Journal, vol. 36, no. 4, pp. 792–799, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. H. A. Ghofrani, N. Galie, F. Grimminger et al., “Riociguat for the treatment of pulmonary arterial hypertension,” The New England Journal of Medicine, vol. 369, pp. 330–340, 2013. View at Google Scholar
  51. F. L. M. Ricciardolo, P. J. Sterk, B. Gaston, and G. Folkerts, “Nitric oxide in health and disease of the respiratory system,” Physiological Reviews, vol. 84, no. 3, pp. 731–765, 2004. View at Publisher · View at Google Scholar · View at Scopus
  52. R. A. Robbins, P. J. Barnes, D. R. Springall et al., “Expression of inducible nitric oxide in human lung epithelial cells,” Biochemical and Biophysical Research Communications, vol. 203, no. 1, pp. 209–218, 1994. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Lane, D. Knight, S. Burgess et al., “Epithelial inducible nitric oxide synthase activity is the major determinant of nitric oxide concentration in exhaled breath,” Thorax, vol. 59, no. 9, pp. 757–760, 2004. View at Publisher · View at Google Scholar · View at Scopus
  54. H. Maarsingh, B. E. Bossenga, I. S. T. Bos, H. H. Volders, J. Zaagsma, and H. Meurs, “L-Arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction,” European Respiratory Journal, vol. 34, no. 1, pp. 191–199, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. C. R. Morris, M. Poljakovic, L. Lavrisha, L. Machado, F. A. Kuypers, and S. M. Morris Jr., “Decreased arginine bioavailability and increased serum arginase activity in asthma,” The American Journal of Respiratory and Critical Care Medicine, vol. 170, no. 2, pp. 148–153, 2004. View at Google Scholar · View at Scopus
  56. A. Lara, S. B. Khatri, Z. Wang et al., “Alterations of the arginine metabolome in asthma,” The American Journal of Respiratory and Critical Care Medicine, vol. 178, no. 7, pp. 673–681, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. J. A. Scott, M. L. North, M. Rafii et al., “Asymmetric dimethylarginine is increased in asthma,” The American Journal of Respiratory and Critical Care Medicine, vol. 184, no. 7, pp. 779–785, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. S. M. Bode-Böger, F. Scalera, and L. J. Ignarro, “The l-arginine paradox: importance of the l-arginine/asymmetrical dimethylarginine ratio,” Pharmacology and Therapeutics, vol. 114, no. 3, pp. 295–306, 2007. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Klein, J. Weigel, M. C. Buford, A. Holian, and S. M. Wells, “Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 299, no. 6, pp. L816–L825, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. T. Ahmad, U. Mabalirajan, B. Ghosh, and A. Agrawal, “Altered asymmetric dimethyl arginine metabolism in allergically inflamed mouse lungs,” The American Journal of Respiratory Cell and Molecular Biology, vol. 42, no. 1, pp. 3–8, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. P. N. Black, P. S. T. Ching, B. Beaumont, S. Ranasinghe, G. Taylor, and M. J. Merrilees, “Changes in elastic fibres in the small airways and alveoli in COPD,” European Respiratory Journal, vol. 31, no. 5, pp. 998–1004, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. O. A. Minai, A. Chaouat, and S. Adnot, “Pulmonary hypertension in COPD: epidemiology, significance, and management: pulmonary vascular disease: the global perspective,” CHEST Journal, vol. 137, no. 6, pp. 39S–51S, 2010. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Tsoumakidou, N. Tzanakis, G. Chrysofakis, and N. M. Siafakas, “Nitrosative stress, heme oxygenase-1 expression and airway inflammation during severe exacerbations of COPD,” CHEST Journal, vol. 127, no. 6, pp. 1911–1918, 2005. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Seimetz, N. Parajuli, A. Pichl et al., “Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice,” Cell, vol. 147, no. 2, pp. 293–305, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. I. M. di Gangi, P. Pirillo, S. Carraro et al., “Online trapping and enrichment ultra performance liquid chromatography-tandem mass spectrometry method for sensitive measurement of, “arginine-asymmetric dimethylarginine cycle” biomarkers in human exhaled breath condensate,” Analytica Chimica Acta, vol. 754, pp. 67–74, 2012. View at Google Scholar
  66. T. E. King Jr., A. Pardo, and M. Selman, “Idiopathic pulmonary fibrosis,” The Lancet, vol. 378, no. 9807, pp. 1949–1961, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. S. S. Pullamsetti, R. Savai, R. Dumitrascu et al., “The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis,” Science Translational Medicine, vol. 3, no. 87, Article ID 87ra53, 2011. View at Publisher · View at Google Scholar · View at Scopus
  68. A. J. Burke, F. J. Sullivan, F. J. Giles, and S. A. Glynn, “The yin and yang of nitric oxide in cancer progression,” Carcinogenesis, vol. 34, pp. 503–512, 2013. View at Google Scholar
  69. C.-Y. Liu, C.-H. Wang, T.-C. Chen, H.-C. Lin, C.-T. Yu, and H.-P. Kuo, “Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer,” British Journal of Cancer, vol. 78, no. 4, pp. 534–541, 1998. View at Google Scholar · View at Scopus
  70. L. R. Kisley, B. S. Barrett, A. K. Bauer et al., “Genetic ablation of inducible nitric oxide synthase decreases mouse lung tumorigenesis,” Cancer Research, vol. 62, no. 23, pp. 6850–6856, 2002. View at Google Scholar · View at Scopus
  71. H. Okayama, M. Saito, N. Oue et al., “NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA-21 expression,” International Journal of Cancer, vol. 132, pp. 9–18, 2013. View at Google Scholar
  72. D. E. B. Swinson, J. L. Jones, D. Richardson, G. Cox, J. G. Edwards, and K. J. O'Byrne, “Tumour necrosis is an independent prognostic marker in non-small cell lung cancer: correlation with biological variables,” Lung Cancer, vol. 37, no. 3, pp. 235–240, 2002. View at Publisher · View at Google Scholar · View at Scopus
  73. M. J. Pollheimer, P. Kornprat, R. A. Lindtner et al., “Tumor necrosis is a new promising prognostic factor in colorectal cancer,” Human Pathology, vol. 41, no. 12, pp. 1749–1757, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. D. Fukumura, S. Kashiwagi, and R. K. Jain, “The role of nitric oxide in tumour progression,” Nature Reviews Cancer, vol. 6, no. 7, pp. 521–534, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. Q.-S. Ng, V. Goh, J. Milner et al., “Effect of nitric-oxide synthesis on tumour blood volume and vascular activity: a phase I study,” The Lancet Oncology, vol. 8, no. 2, pp. 111–118, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. G. M. Tozer, V. E. Prise, and D. J. Chaplin, “Inhibition of nitric oxide synthase induces a selective reduction in tumor blood flow that is reversible with L-arginine,” Cancer Research, vol. 57, no. 5, pp. 948–955, 1997. View at Google Scholar · View at Scopus
  77. P. Lévy, J.-L. Pépin, C. Arnaud et al., “Intermittent hypoxia and sleep-disordered breathing: current concepts and perspectives,” European Respiratory Journal, vol. 32, no. 4, pp. 1082–1095, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. D. Gozal and L. Kheirandish-Gozal, “Cardiovascular morbidity in obstructive sleep apnea: oxidative stress, inflammation, and much more,” The American Journal of Respiratory and Critical Care Medicine, vol. 177, no. 4, pp. 369–375, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. L. Dyugovskaya, P. Lavie, and L. Lavie, “Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients,” The American Journal of Respiratory and Critical Care Medicine, vol. 165, no. 7, pp. 934–939, 2002. View at Google Scholar · View at Scopus
  80. F. J. Nieto, D. M. Herrington, S. Redline, E. J. Benjamin, and J. A. Robbins, “Sleep apnea and markers of vascular endothelial function in a large community sample of older adults,” The American Journal of Respiratory and Critical Care Medicine, vol. 169, no. 3, pp. 354–360, 2004. View at Google Scholar · View at Scopus
  81. V. A. Imadojemu, K. Gleeson, S. A. Quraishi, A. R. Kunselman, L. I. Sinoway, and U. A. Leuenberger, “Impaired vasodilator responses in obstructive sleep apnea are improved with continuous positive airway pressure therapy,” The American Journal of Respiratory and Critical Care Medicine, vol. 165, no. 7, pp. 950–953, 2002. View at Google Scholar · View at Scopus
  82. M. S. M. Ip, B. Lam, L.-Y. Chan et al., “Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure,” The American Journal of Respiratory and Critical Care Medicine, vol. 162, no. 6, pp. 2166–2171, 2000. View at Google Scholar · View at Scopus
  83. A. Barceló, M. de la Peña, O. Ayllón et al., “Increased plasma levels of asymmetric dimethylarginine and soluble CD40 ligand in patients with sleep apnea,” Respiration, vol. 77, pp. 85–90, 2009. View at Google Scholar
  84. Y. Ohike, K. Kozaki, K. Iijima et al., “Amelioration of vascular endothelial dysfunction in obstructive sleep apnea syndrome by nasal continuous positive airway pressure: possible involvement of nitric oxide and asymmetric NG, NG-dimethylarginine,” Circulation Journal, vol. 69, no. 2, pp. 221–226, 2005. View at Publisher · View at Google Scholar · View at Scopus
  85. C. H. Orchard, R. Sanchea De Leon, and M. K. Sykes, “The relationship between hypoxic pulmonary vasoconstriction and arterial oxygen tension in the intact dog,” The Journal of Physiology, vol. 338, pp. 61–74, 1983. View at Google Scholar · View at Scopus
  86. H. L. Motley, A. Cournand, L. Werko, A. Himmelstein, and D. Dresdale, “The influence of short periods of induced acute anoxia upon pulmonary artery pressures in man,” The American Journal of Physiology, vol. 150, pp. 315–320, 1947. View at Google Scholar
  87. N. Sommer, A. Dietrich, R. T. Schermuly et al., “Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms,” European Respiratory Journal, vol. 32, no. 6, pp. 1639–1651, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. Q. Liu, J. S. K. Sham, L. A. Shimoda, and J. T. Sylvester, “Hypoxic constriction of porcine distal pulmonary arteries: endothelium and endothelin dependence,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 280, no. 5, pp. L856–L865, 2001. View at Google Scholar · View at Scopus
  89. P. I. Aaronson, T. P. Robertson, and J. P. T. Ward, “Endothelium-derived mediators and hypoxic pulmonary vasoconstriction,” Respiratory Physiology & Neurobiology, vol. 132, no. 1, pp. 107–120, 2002. View at Publisher · View at Google Scholar · View at Scopus
  90. O. Pak, A. Aldashev, D. Welsh, and A. Peacock, “The effects of hypoxia on-the cells of the pulmonary vasculature,” European Respiratory Journal, vol. 30, no. 2, pp. 364–372, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. M. Tucci, S. I. Hammerman, S. Furfaro, J. J. Saukonnen, T. J. Conca, and H. W. Farber, “Distinct effect of hypoxia on endothelial cell proliferation and cycling,” The American Journal of Physiology—Cell Physiology, vol. 272, no. 5, pp. C1700–C1708, 1997. View at Google Scholar · View at Scopus
  92. K. R. Stenmark, K. A. Fagan, and M. G. Frid, “Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms,” Circulation Research, vol. 99, no. 7, pp. 675–691, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. D. Penaloza and J. Arias-Stella, “The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness,” Circulation, vol. 115, no. 9, pp. 1132–1146, 2007. View at Publisher · View at Google Scholar · View at Scopus
  94. A. Chaouat, A.-S. Bugnet, N. Kadaoui et al., “Severe pulmonary hypertension and chronic obstructive pulmonary disease,” The American Journal of Respiratory and Critical Care Medicine, vol. 172, no. 2, pp. 189–194, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. S. van Eeden, J. Leipsic, S. F. Paul Man, and D. D. Sin, “The relationship between lung inflammation and cardiovascular disease,” The American Journal of Respiratory and Critical Care Medicine, vol. 186, pp. 11–16, 2012. View at Google Scholar
  96. G. L. Semenza, “Hypoxia-inducible factors in physiology and medicine,” Cell, vol. 148, no. 3, pp. 399–408, 2012. View at Publisher · View at Google Scholar · View at Scopus
  97. M. Ivan, K. Kondo, H. Yang et al., “HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing,” Science, vol. 292, no. 5516, pp. 464–468, 2001. View at Google Scholar · View at Scopus
  98. A. C. R. Epstein, J. M. Gleadle, L. A. McNeill et al., “C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation,” Cell, vol. 107, no. 1, pp. 43–54, 2001. View at Publisher · View at Google Scholar · View at Scopus
  99. W. G. Kaelin Jr. and P. J. Ratcliffe, “Oxygen sensing by metazoans: the central role of the hif hydroxylase pathway,” Molecular Cell, vol. 30, no. 4, pp. 393–402, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. V. H. Haase, “Regulation of erythropoiesis by hypoxia-inducible factors,” Blood Reviews, vol. 27, pp. 41–53, 2013. View at Google Scholar
  101. L. Gao, Q. Chen, X. Zhou, and L. Fan, “The role of hypoxia-inducible factor 1 in atherosclerosis,” Journal of Clinical Pathology, vol. 65, pp. 872–876, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Germani, C. di Campli, G. Pompilio, P. Biglioli, and M. C. Capogrossi, “Regenerative therapy in peripheral artery disease,” Cardiovascular Therapeutics, vol. 27, no. 4, pp. 289–304, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. A. Robinson, S. Keely, J. Karhausen, M. E. Gerich, G. T. Furuta, and S. P. Colgan, “Mucosal protection by hypoxia-inducible factor prolyl hydroxylase inhibition,” Gastroenterology, vol. 134, no. 1, pp. 145–155, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. D. S. Wilkes, “Chronic lung allograft rejection and airway microvasculature: is HIF-1 the missing link?” The Journal of Clinical Investigation, vol. 121, no. 6, pp. 2155–2157, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. Y.-P. Tsai and K.-J. Wu, “Hypoxia-regulated target genes implicated in tumor metastasis,” Journal of Biomedical Science, vol. 19, article 102, 2012. View at Google Scholar
  106. J. Bond, D. P. Gale, T. Connor et al., “Dysregulation of the HIF pathway due to VHL mutation causing severe erythrocytosis and pulmonary arterial hypertension,” Blood, vol. 117, no. 13, pp. 3699–3701, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. J. F. Garvey, C. T. Taylor, and W. T. McNicholas, “Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation,” European Respiratory Journal, vol. 33, no. 5, pp. 1195–1205, 2009. View at Publisher · View at Google Scholar · View at Scopus
  108. M. W. Foster, T. J. McMahon, and J. S. Stamler, “S-nitrosylation in health and disease,” Trends in Molecular Medicine, vol. 9, no. 4, pp. 160–168, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. L. A. Palmer, A. Doctor, P. Chhabra et al., “S-Nitrosothiols signal hypoxia-mimetic vascular pathology,” The Journal of Clinical Investigation, vol. 117, no. 9, pp. 2592–2601, 2007. View at Publisher · View at Google Scholar · View at Scopus
  110. F. Li, P. Sonveaux, Z. N. Rabbani et al., “Regulation of HIF-1α stability through S-nitrosylation,” Molecular Cell, vol. 26, no. 1, pp. 63–74, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. J. Mateo, M. García-Lecea, S. Cadenas, C. Hernández, and S. Moncada, “Regulation of hypoxia-inducible factor-1α by nitric oxide through mitochondria-dependent and -independent pathways,” Biochemical Journal, vol. 376, no. 2, pp. 537–544, 2003. View at Publisher · View at Google Scholar · View at Scopus
  112. T. Hagen, C. T. Taylor, F. Lam, and S. Moncada, “Redistribution of intracellular oxygen in hypoxia by nitric oxide: effect on HIF1α,” Science, vol. 302, no. 5652, pp. 1975–1978, 2003. View at Publisher · View at Google Scholar · View at Scopus
  113. R. Chowdhury, E. Flashman, J. Mecinović et al., “Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1),” Journal of Molecular Biology, vol. 410, no. 2, pp. 268–279, 2011. View at Publisher · View at Google Scholar · View at Scopus
  114. E. R. Block, H. Herrera, and M. Couch, “Hypoxia inhibits L-arginine uptake by pulmonary artery endothelial cells,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 269, no. 5, pp. L574–L580, 1995. View at Google Scholar · View at Scopus
  115. R. Maas, “Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA),” Vascular Medicine, vol. 10, no. 2, supplement, pp. S49–S57, 2005. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Murray-Rust, J. Leiper, M. McAlister et al., “Structural insights into the hydrolysis of cellular nitric oxide synthase inhibitors by dimethylarginine dimethylaminohydrolase,” Nature Structural & Molecular Biology, vol. 8, pp. 679–683, 2001. View at Google Scholar
  117. J. Leiper, J. Murray-Rust, N. McDonald, and P. Vallance, “S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13527–13532, 2002. View at Publisher · View at Google Scholar · View at Scopus
  118. A. Bakr, O. Pak, A. Taye et al., “Effects of dimethylarginine dimethylaminohydrolase-1 overexpression on the response of the pulmonary vasculature to hypoxia,” The American Journal of Respiratory Cell and Molecular Biology, vol. 49, pp. 491–500, 2013. View at Google Scholar
  119. A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa, and J. P. Cooke, “Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase,” Circulation, vol. 99, no. 24, pp. 3092–3095, 1999. View at Google Scholar · View at Scopus
  120. K. Y. Lin, A. Ito, T. Asagami et al., “Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase,” Circulation, vol. 106, no. 8, pp. 987–992, 2002. View at Publisher · View at Google Scholar · View at Scopus
  121. K. Sydow and T. Münzel, “ADMA and oxidative stress,” Atherosclerosis Supplements, vol. 4, no. 4, pp. 41–51, 2003. View at Publisher · View at Google Scholar · View at Scopus
  122. C. Y. Ivashchenko, B. T. Bradley, Z. Ao, J. Leiper, P. Vallance, and D. G. Johns, “Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 298, no. 1, pp. H251–H258, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. K. Hasegawa, S. Wakino, T. Tanaka et al., “Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through Sp1 transcription factor in endothelial cells,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 7, pp. 1488–1494, 2006. View at Publisher · View at Google Scholar · View at Scopus
  124. C. H. Jung, W. J. Lee, J. Y. Hwang et al., “Vaspin increases nitric oxide bioavailability through the reduction of asymmetric dimethylarginine in vascular endothelial cells,” PLoS ONE, vol. 7, Article ID e52346, 2012. View at Google Scholar
  125. J. W. Eikelboom, E. Lonn, J. Genest Jr., G. Hankey, and S. Yusuf, “Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence,” Annals of Internal Medicine, vol. 131, no. 5, pp. 363–375, 1999. View at Google Scholar · View at Scopus
  126. J.-G. Zhang, J.-X. Liu, Z.-H. Li, L.-Z. Wang, Y.-D. Jiang, and S.-R. Wang, “Dysfunction of endothelial NO system originated from homocysteine-induced aberrant methylation pattern in promoter region of DDAH2 gene,” Chinese Medical Journal, vol. 120, no. 23, pp. 2132–2137, 2007. View at Google Scholar · View at Scopus
  127. W. Janssen, S. S. Pullamsetti, J. Cooke, N. Weissmann, A. Guenther, and R. T. Schermuly, “The role of dimethylarginine dimethylaminohydrolase (DDAH) in pulmonary fibrosis,” The Journal of Pathology, vol. 229, pp. 242–249, 2013. View at Google Scholar
  128. M. Nandi, P. Kelly, B. Torondel et al., “Genetic and pharmacological inhibition of dimethylarginine dimethylaminohydrolase 1 is protective in endotoxic shock,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, pp. 2589–2597, 2012. View at Google Scholar