Reactive oxygen and nitrogen species in pulmonary hypertension

Free Radical Biology and Medicine

Volumn 52, Issue 9, 2012, Pages 1970-1986

  Tabima, Diana M ^a   Frizzell, Sheila ^a   Gladwin, Mark T ^a  

^a UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

Mitochondria; Nox; Right ventricular failure; Uncoupled eNOS; Xanthine oxidase

Indexed keywords

4 AMINO 5 CYCLOPROPYL 2 [1 (2 FLUOROBENZYL) 1H PYRAZOLO[3,4 B]PYRIDIN 3 YL]PYRIMIDINE; AMBRISENTAN; AMLODIPINE; ATACIGUAT; BOSENTAN; CINACIGUAT; DILTIAZEM; ENDOTHELIN 1; ENDOTHELIN RECEPTOR ANTAGONIST; GLYCERYL TRINITRATE; GUANYLATE CYCLASE ACTIVATOR; ILOPROST; MANGANESE SUPEROXIDE DISMUTASE; N(G) NITROARGININE METHYL ESTER; NIFEDIPINE; NITRIC OXIDE; NITRIC OXIDE DONOR; NITRITE; PHOSPHODIESTERASE INHIBITOR; PROSTACYCLIN; PROSTACYCLIN DERIVATIVE; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; RIOCIGUAT; SILDENAFIL; SITAXSENTAN; SODIUM NITRITE; TADALAFIL; UNINDEXED DRUG; UNIPROST;

BLOOD VESSEL TONE; CELL PROLIFERATION; CHRONIC KIDNEY FAILURE; CHRONIC OBSTRUCTIVE LUNG DISEASE; CONGENITAL HEART DISEASE; DIASTOLIC DYSFUNCTION; ENDOTHELIAL DYSFUNCTION; EXERCISE; FLUSHING; HEADACHE; HEART FAILURE; HEART OUTPUT; HEART PALPITATION; HEART RIGHT VENTRICLE; HEART RIGHT VENTRICLE FAILURE; HEMATOLOGIC DISEASE; HEMOLYSIS; HUMAN; HYPOXEMIA; INTERSTITIAL LUNG DISEASE; LOW DRUG DOSE; LUNG ALVEOLUS HYPOVENTILATION; LUNG ARTERY PRESSURE; LUNG VASCULAR RESISTANCE; LUNG WEDGE PRESSURE; METABOLIC DISORDER; MITOCHONDRION; MYALGIA; NONHUMAN; OXIDATIVE STRESS; PERIPHERAL EDEMA; PRIORITY JOURNAL; PULMONARY HYPERTENSION; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SLEEP DISORDERED BREATHING; SYSTEMIC DISEASE; SYSTOLIC DYSFUNCTION; UNITED STATES; VALVULAR HEART DISEASE; VASODILATATION; WITHDRAWAL SYNDROME;

ANIMALS; HUMANS; HYPERTENSION, PULMONARY; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN SPECIES;

EID: 84859644104     PISSN: 08915849     EISSN: 18734596     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2012.02.041     Document Type: Review

References (247)

1. New developments in pulmonary hypertension/pulmonary arterial hypertension. Proceedings of Pulmonary Hypertension UP2DATE 2008 - post Dana Point. March 14-15, 2008. Munich, Germany Dtsch. Med. Wochenschr. 133 Suppl. 6 2008 S165 S218
2. M. Humbert, O. Sitbon, A. Chaouat, M. Bertocchi, G. Habib, V. Gressin, A. Yaici, E. Weitzenblum, J.F. Cordier, F. Chabot, C. Dromer, C. Pison, M. Reynaud-Gaubert, A. Haloun, M. Laurent, E. Hachulla, and G. Simonneau Pulmonary arterial hypertension in France: results from a national registry Am. J. Respir. Crit. Care Med. 173 2006 1023 1030
3. S. Rich, D.R. Dantzker, S.M. Ayres, E.H. Bergofsky, B.H. Brundage, K.M. Detre, A.P. Fishman, R.M. Goldring, B.M. Groves, and S.K. Koerner Primary pulmonary hypertension. A national prospective study Ann. Intern. Med. 107 1987 216 223
4. C.C. Sullivan, L. Du, D. Chu, A.J. Cho, M. Kido, P.L. Wolf, S.W. Jamieson, and P.A. Thistlethwaite Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway Proc. Natl. Acad. Sci. U. S. A. 100 2003 12331 12336
5. J.R. Thomson, R.D. Machado, M.W. Pauciulo, N.V. Morgan, M. Humbert, G.C. Elliott, K. Ward, M. Yacoub, G. Mikhail, P. Rogers, J. Newman, L. Wheeler, T. Higenbottam, J.S. Gibbs, J. Egan, A. Crozier, A. Peacock, R. Allcock, P. Corris, J.E. Loyd, R.C. Trembath, and W.C. Nichols Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family J. Med. Genet. 37 2000 741 745
6. J.F. Gielis, J.Y. Lin, K. Wingler, P.E. Van Schil, H.H. Schmidt, and A.L. Moens Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders Free Radic. Biol. Med. 50 2011 765 776
7. S. Adnot, B. Raffestin, S. Eddahibi, P. Braquet, and P.E. Chabrier Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia J. Clin. Invest. 87 1991 155 162
8. S.A. Barman Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C Am. J. Physiol. Lung Cell. Mol. Physiol. 293 2007 L472 L479
9. S. Rich, E. Kaufmann, and P.S. Levy The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension N. Engl. J. Med. 327 1992 76 81
10. R.T. Schermuly, K.P. Kreisselmier, H.A. Ghofrani, A. Samidurai, S. Pullamsetti, N. Weissmann, C. Schudt, L. Ermert, W. Seeger, and F. Grimminger Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension Circ. Res. 94 2004 1101 1108
11. O. Hallioglu, E. Dilber, and A. Celiker Comparison of acute hemodynamic effects of aerosolized and intravenous iloprost in secondary pulmonary hypertension in children with congenital heart disease Am. J. Cardiol. 92 2003 1007 1009
12. H. Wang, M. Gong., B. Zhou, and A. Dai Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery Adv. Ther. 26 2009 462 468
13. Y.L. Lai, H.D. Wu, and C.F. Chen Antioxidants attenuate chronic hypoxic pulmonary hypertension J. Cardiovasc. Pharmacol. 32 1998 714 720
14. Y. Hoshikawa, S. Ono, S. Suzuki, T. Tanita, M. Chida, C. Song, M. Noda, T. Tabata, N.F. Voelkel, and S. Fujimura Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia J. Appl. Physiol. 90 2001 1299 1306
15. B. Elmedal, M.Y. de Dam, M.J. Mulvany, and U. Simonsen The superoxide dismutase mimetic, tempol, blunts right ventricular hypertrophy in chronic hypoxic rats Br. J. Pharmacol. 141 2004 105 113
16. J.C. Wanstall, J.A. Kaye, and A. Gambino The in vitro pulmonary vascular effects of FK409 (nitric oxide donor): a study in normotensive and pulmonary hypertensive rats Br. J. Pharmacol. 121 1997 280 286
17. L.A. Brennan, R.H. Steinhorn, S. Wedgwood, E. Mata-Greenwood, E.A. Roark, J.A. Russell, and S.M. Black Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase Circ. Res. 92 2003 683 691
18. N.L. Jernigan, B.R. Walker, and T.C. Resta Endothelium-derived reactive oxygen species and endothelin-1 attenuate NO-dependent pulmonary vasodilation following chronic hypoxia Am. J. Physiol. Lung Cell. Mol. Physiol. 287 2004 L801 L808
19. H. Cai, and D.G. Harrison Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress Circ. Res. 87 2000 840 844
20. H. Li, and U. Forstermann Nitric oxide in the pathogenesis of vascular disease J. Pathol. 190 2000 244 254
21. D. Li, N. Zhou, and R.A. Johns Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia Am. J. Physiol. 277 1999 L841 L847
22. N.L. Jernigan, B.R. Walker, and T.C. Resta Pulmonary PKG-1 is upregulated following chronic hypoxia Am. J. Physiol. Lung Cell. Mol. Physiol. 285 2003 L634 L642
23. J.Q. Liu, I.N. Zelko, E.M. Erbynn, J.S. Sham, and R.J. Folz Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox) Am. J. Physiol. Lung Cell. Mol. Physiol. 290 2006 L2 L10
24. S. Li, S.S. Tabar, V. Malec, B.G. Eul, W. Klepetko, N. Weissmann, F. Grimminger, W. Seeger, F. Rose, and J. Hanze NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts Antioxid. Redox Signal. 10 2008 1687 1698
25. M. Mittal, M. Roth, P. Konig, S. Hofmann, E. Dony, P. Goyal, A.C. Selbitz, R.T. Schermuly, H.A. Ghofrani, G. Kwapiszewska, W. Kummer, W. Klepetko, M.A. Hoda, L. Fink, J. Hanze, W. Seeger, F. Grimminger, H.H. Schmidt, and N. Weissmann Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature Circ. Res. 101 2007 258 267
26. A. Sturrock, B. Cahill, K. Norman, T.P. Huecksteadt, K. Hill, K. Sanders, S.V. Karwande, J.C. Stringham, D.A. Bull, M. Gleich, T.P. Kennedy, and J.R. Hoidal Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells Am. J. Physiol. Lung Cell. Mol. Physiol. 290 2006 L661 L673
27. S. Ismail, A. Sturrock, P. Wu, B. Cahill, K. Norman, T. Huecksteadt, K. Sanders, T. Kennedy, and J. Hoidal NOX4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-{beta}1 and insulin-like growth factor binding protein-3 Am. J. Physiol. Lung Cell. Mol. Physiol. 296 2009 L489 L499
28. A. Chatterjee, S.M. Black, and J.D. Catravas Endothelial nitric oxide (NO) and its pathophysiologic regulation Vascul. Pharmacol. 49 2008 134 140
29. M. Mandegar, Y.C. Fung, W. Huang, C.V. Remillard, L.J. Rubin, and J.X. Yuan Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension Microvasc. Res. 68 2004 75 103
30. M. Rabinovitch Molecular pathogenesis of pulmonary arterial hypertension J. Clin. Invest. 118 2008 2372 2379
31. S. Wedgwood, D.M. McMullan, J.M. Bekker, J.R. Fineman, and S.M. Black Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy Circ. Res. 89 2001 357 364
32. A.C. Grobe, S.M. Wells, E. Benavidez, P. Oishi, A. Azakie, J.R. Fineman, and S.M. Black Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase Am. J. Physiol. Lung Cell. Mol. Physiol. 290 2006 L1069 L1077
33. K. Karuppiah, L. Druhan, C.A. Chen, T. Smith, J.L. Zweier, W.C. Sessa, and A.J. Cardounel Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism Am. J. Physiol. Heart Circ. Physiol. 301 2011 H903 H911
34. S. Moncada, and A. Higgs The l-arginine-nitric oxide pathway N. Engl. J. Med. 329 1993 2002 2012
35. S. Moncada, and E.A. Higgs Molecular mechanisms and therapeutic strategies related to nitric oxide FASEB J. 9 1995 1319 1330
36. S. Moncada, and E.A. Higgs The discovery of nitric oxide and its role in vascular biology Br. J. Pharmacol. 147 Suppl. 1 2006 S193 S201
37. M.R. Kibbe, J. Li, S. Nie, S.C. Watkins, A. Lizonova, I. Kovesdi, R.L. Simmons, T.R. Billiar, and E. Tzeng Inducible nitric oxide synthase (iNOS) expression upregulates p21 and inhibits vascular smooth muscle cell proliferation through p42/44 mitogen-activated protein kinase activation and independent of p53 and cyclic guanosine monophosphate J. Vasc. Surg. 31 2000 1214 1228
38. B.S. Zuckerbraun, D.A. Stoyanovsky, R. Sengupta, R.A. Shapiro, B.A. Ozanich, J. Rao, J.E. Barbato, and E. Tzeng Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA Am. J. Physiol. Cell Physiol. 292 2007 C824 C831
39. S. Sharma, N. Sud, D.A. Wiseman, A.L. Carter, S. Kumar, Y. Hou, T. Rau, J. Wilham, C. Harmon, P. Oishi, J.R. Fineman, and S.M. Black Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension Am. J. Physiol. Lung Cell. Mol. Physiol. 294 2008 L46 L56
40. C. Xue, and R.A. Johns Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension N. Engl. J. Med. 333 1995 1642 1644
41. A. Giaid, and D. Saleh Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension N. Engl. J. Med. 333 1995 214 221
42. R.M. Tuder, C.D. Cool, M.W. Geraci, J. Wang, S.H. Abman, L. Wright, D. Badesch, and N.F. Voelkel Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension Am. J. Respir. Crit. Care Med. 159 1999 1925 1932
43. L.L. Hsu, H.C. Champion, S.A. Campbell-Lee, T.J. Bivalacqua, E.A. Manci, B.A. Diwan, D.M. Schimel, A.E. Cochard, X. Wang, A.N. Schechter, C.T. Noguchi, and M.T. Gladwin Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability Blood 109 2007 3088 3098
44. W. Hu, R. Jin, J. Zhang, T. You, Z. Peng, X. Ge, R.T. Bronson, J.A. Halperin, J. Loscalzo, and X. Qin The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model Blood 116 2010 1613 1622
45. J.P. Khoo, L. Zhao, N.J. Alp, J.K. Bendall, T. Nicoli, K. Rockett, M.R. Wilkins, and K.M. Channon Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension Circulation 111 2005 2126 2133
46. B.W. Christman, C.D. McPherson, J.H. Newman, G.A. King, G.R. Bernard, B.M. Groves, and J.E. Loyd An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension N. Engl. J. Med. 327 1992 70 75
47. A.M. Atz, I. Adatia, and D.L. Wessel Rebound pulmonary hypertension after inhalation of nitric oxide Ann. Thorac. Surg. 62 1996 1759 1764
48. S.M. Black, R.S. Heidersbach, D.M. McMullan, J.M. Bekker, M.J. Johengen, and J.R. Fineman Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension Am. J. Physiol. 277 1999 H1849 H1856
49. N. Benjamin, F. O'Driscoll, H. Dougall, C. Duncan, L. Smith, M. Golden, and H. McKenzie Stomach NO synthesis Nature 368 1994 502
50. J.L. Zweier, P. Wang, A. Samouilov, and P. Kuppusamy Enzyme-independent formation of nitric oxide in biological tissues Nat. Med. 1 1995 804 809
51. C.J. Hunter, A. Dejam, A.B. Blood, H. Shields, D.B. Kim-Shapiro, R.F. Machado, S. Tarekegn, N. Mulla, A.O. Hopper, A.N. Schechter, G.G. Power, and M.T. Gladwin Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator Nat. Med. 10 2004 1122 1127
52. J.O. Lundberg, E. Weitzberg, and M.T. Gladwin The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics Nat. Rev. Drug Discov. 7 2008 156 167
53. J.B. Snow, V. Kitzis, C.E. Norton, S.N. Torres, K.D. Johnson, N.L. Kanagy, B.R. Walker, and T.C. Resta Differential effects of chronic hypoxia and intermittent hypocapnic and eucapnic hypoxia on pulmonary vasoreactivity J. Appl. Physiol. 104 2008 110 118
54. T.C. Resta, T.L. O'Donaughy, S. Earley, L.G. Chicoine, and B.R. Walker Unaltered vasoconstrictor responsiveness after iNOS inhibition in lungs from chronically hypoxic rats Am. J. Physiol. 276 1999 L122 L130
55. E.A. Demoncheaux, T.W. Higenbottam, D.G. Kiely, J.M. Wong, S. Wharton, R. Varcoe, T. Siddons, A.C. Spivey, K. Hall, and A.P. Gize Decreased whole body endogenous nitric oxide production in patients with primary pulmonary hypertension J. Vasc. Res. 42 2005 133 136
56. R.P. Weerackody, D.J. Welsh, R.M. Wadsworth, and A.J. Peacock Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction Am. J. Physiol. Heart Circ. Physiol. 296 2009 H1312 H1320
57. J.S. Beckman, and W.H. Koppenol Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly Am. J. Physiol. 271 1996 C1424 C1437
58. S.P. Kunuthur, P.H. Milliken, C.L. Gibson, C.J. Suckling, and R.M. Wadsworth Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties Eur. J. Pharmacol. 650 2011 6
59. C. Cunnington, and K.M. Channon Tetrahydrobiopterin: pleiotropic roles in cardiovascular pathophysiology Heart 96 2010 1872 1877
60. M.J. Crabtree, A.L. Tatham, Y. Al-Wakeel, N. Warrick, A.B. Hale, S. Cai, K.M. Channon, and N.J. Alp Quantitative regulation of intracellular endothelial nitric-oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: insights from cells with tet-regulated GTP cyclohydrolase I expression J. Biol. Chem. 284 2009 1136 1144
61. B.N. Francis, M.R. Wilkins, and L. Zhao Tetrahydrobiopterin and the regulation of hypoxic pulmonary vasoconstriction Eur. Respir. J. 36 2010 323 330
62. P.N. Bernatchez, P.M. Bauer, J. Yu, J.S. Prendergast, P. He, and W.C. Sessa Dissecting the molecular control of endothelial NO synthase by caveolin-1 using cell-permeable peptides Proc. Natl. Acad. Sci. U. S. A. 102 2005 761 766
63. G. Garcia-Cardena, P. Martasek, B.S. Masters, P.M. Skidd, J. Couet, S. Li, M.P. Lisanti, and W.C. Sessa Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo J. Biol. Chem. 272 1997 25437 25440
64. N.A. Maniatis, V. Shinin, D.E. Schraufnagel, S. Okada, S.M. Vogel, A.B. Malik, and R.D. Minshall Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1-/- mice Am. J. Physiol. Lung Cell. Mol. Physiol. 294 2008 L865 L873
65. C. Wunderlich, K. Schober, A. Schmeisser, C. Heerwagen, A.K. Tausche, N. Steinbronn, A. Brandt, M. Kasper, C. Schwencke, R.C. Braun-Dullaeus, and R.H. Strasser The adverse cardiopulmonary phenotype of caveolin-1 deficient mice is mediated by a dysfunctional endothelium J. Mol. Cell. Cardiol. 44 2008 938 947
66. C. Wunderlich, A. Schmeisser, C. Heerwagen, B. Ebner, K. Schober, R.C. Braun-Dullaeus, C. Schwencke, M. Kasper, H. Morawietz, and R.H. Strasser Chronic NOS inhibition prevents adverse lung remodeling and pulmonary arterial hypertension in caveolin-1 knockout mice Pulm. Pharmacol. Ther. 21 2008 507 515
67. T. Murata, M.I. Lin, Y. Huang, J. Yu, P.M. Bauer, F.J. Giordano, and W.C. Sessa Reexpression of caveolin-1 in endothelium rescues the vascular, cardiac, and pulmonary defects in global caveolin-1 knockout mice J. Exp. Med. 204 2007 2373 2382
68. M. Ozaki, S. Kawashima, T. Yamashita, Y. Ohashi, Y. Rikitake, N. Inoue, K.I. Hirata, Y. Hayashi, H. Itoh, and M. Yokoyama Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium Hypertension 37 2001 322 327
69. M. Ozaki, S. Kawashima, T. Yamashita, T. Hirase, M. Namiki, N. Inoue, K. Hirata, H. Yasui, H. Sakurai, Y. Yoshida, M. Masada, and M. Yokoyama Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice J. Clin. Invest. 110 2002 331 340
70. Y.Y. Zhao, Y.D. Zhao, M.K. Mirza, J.H. Huang, H.H. Potula, S.M. Vogel, V. Brovkovych, J.X. Yuan, J. Wharton, and A.B. Malik Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration J. Clin. Invest. 119 2009 2009 2018
71. M. Knorr, M. Hausding, S. Kröller-Schuhmacher, S. Steven, M. Oelze, T. Heeren, A. Scholz, T. Gori, P. Wenzel, E. Schulz, A. Daiber, and T. Münzel Nitroglycerin-induced endothelial dysfunction and tolerance involve adverse phosphorylation and S-Glutathionylation of endothelial nitric oxide synthase: beneficial effects of therapy with the AT1 receptor blocker telmisartan Arterioscler. Thromb. Vasc. Biol. 31 2011 2223 2231
72. C.A. Chen, T.Y. Wang, S. Varadharaj, L.A. Reyes, C. Hemann, M.A. Talukder, Y.R. Chen, L.J. Druhan, and J.L. Zweier S-Glutathionylation uncouples eNOS and regulates its cellular and vascular function Nature 468 2010 1115 1118
73. A.M. Sheehy, M.A. Burson, and S.M. Black Nitric oxide exposure inhibits endothelial NOS activity but not gene expression: a role for superoxide Am. J. Physiol. 274 1998 L833 L841
74. P. Deruelle, T.R. Grover, and S.H. Abman Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep Am. J. Physiol. Lung Cell. Mol. Physiol. 289 2005 L798 L806
75. E.J. Tsai, and D.A. Kass Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics Pharmacol. Ther. 122 2009 216 238
76. R.T. Schermuly, J.P. Stasch, S.S. Pullamsetti, R. Middendorff, D. Muller, K.D. Schluter, A. Dingendorf, S. Hackemack, E. Kolosionek, C. Kaulen, R. Dumitrascu, N. Weissmann, J. Mittendorf, W. Klepetko, W. Seeger, H.A. Ghofrani, and F. Grimminger Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension Eur. Respir. J. 32 2008 881 891
77. M. Kirsch, B. Kemp-Harper, N. Weissmann, F. Grimminger, and H.H. Schmidt Sildenafil in hypoxic pulmonary hypertension potentiates a compensatory up-regulation of NO-cGMP signaling FASEB J. 22 2008 30 40
78. A. Sebkhi, J.W. Strange, S.C. Phillips, J. Wharton, and M.R. Wilkins Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension Circulation 107 2003 3230 3235
79. L. Zhao, N.A. Mason, N.W. Morrell, B. Kojonazarov, A. Sadykov, A. Maripov, M.M. Mirrakhimov, A. Aldashev, and M.R. Wilkins Sildenafil inhibits hypoxia-induced pulmonary hypertension Circulation 104 2001 424 428
80. M.T. Gladwin, V. Sachdev, M.L. Jison, Y. Shizukuda, J.F. Plehn, K. Minter, B. Brown, W.A. Coles, J.S. Nichols, I. Ernst, L.A. Hunter, W.C. Blackwelder, A.N. Schechter, G.P. Rodgers, O. Castro, and F.P. Ognibene Pulmonary hypertension as a risk factor for death in patients with sickle cell disease N. Engl. J. Med. 350 2004 886 895
81. M.T. Gladwin, and E. Vichinsky Pulmonary complications of sickle cell disease N. Engl. J. Med. 359 2008 2254 2265
82. C.D. Reiter, X. Wang, J.E. Tanus-Santos, N. Hogg, R.O. Cannon III, A.N. Schechter, and M.T. Gladwin Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease Nat. Med. 8 2002 1383 1389
83. R.P. Rother, L. Bell, P. Hillmen, and M.T. Gladwin The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease JAMA 293 2005 1653 1662
84. C.R. Morris, G.J. Kato, M. Poljakovic, X. Wang, W.C. Blackwelder, V. Sachdev, S.L. Hazen, E.P. Vichinsky, S.M. Morris Jr., and M.T. Gladwin Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease JAMA 294 2005 81 90
85. D.D. Ivy, T.A. Parker, J.W. Ziegler, H.L. Galan, J.P. Kinsella, R.M. Tuder, and S.H. Abman Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus J. Clin. Invest. 99 1997 1179 1186
86. M.P. Coggins, and K.D. Bloch Nitric oxide in the pulmonary vasculature Arterioscler. Thromb. Vasc. Biol. 27 2007 1877 1885
87. A.M. Atz, and D.L. Wessel Inhaled nitric oxide in the neonate with cardiac disease Semin. Perinatol. 21 1997 441 455
88. B.A. Markewitz, and J.R. Michael Inhaled nitric oxide in adults with the acute respiratory distress syndrome Respir. Med. 94 2000 1023 1028
89. J.D. Roberts Jr., J.R. Fineman, F.C. Morin III, P.W. Shaul, S. Rimar, M.D. Schreiber, R.A. Polin, M.S. Zwass, M.M. Zayek, I. Gross, M.A. Heymann, and W.M. Zapol Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group N. Engl. J. Med. 336 1997 605 610
90. R. Rossaint, K.J. Falke, F. Lopez, K. Slama, U. Pison, and W.M. Zapol Inhaled nitric oxide for the adult respiratory distress syndrome N. Engl. J. Med. 328 1993 399 405
91. E. Cueto, J. Lopez-Herce, A. Sanchez, and A. Carrillo Life-threatening effects of discontinuing inhaled nitric oxide in children Acta Paediatr. 86 1997 1337 1339
92. A. Lavoie, J.B. Hall, D.M. Olson, and M.E. Wylam Life-threatening effects of discontinuing inhaled nitric oxide in severe respiratory failure Am. J. Respir. Crit. Care Med. 153 1996 1985 1987
93. O.I. Miller, S.F. Tang, A. Keech, and D.S. Celermajer Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide Lancet 346 1995 51 52
94. P. Namachivayam, U. Theilen, W.W. Butt, S.M. Cooper, D.J. Penny, and L.S. Shekerdemian Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children Am. J. Respir. Crit. Care Med. 174 2006 1042 1047
95. U. Elkayam Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention Ann. Intern. Med. 114 1991 667 677
96. T. Munzel, H. Sayegh, B.A. Freeman, M.M. Tarpey, and D.G. Harrison Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance J. Clin. Invest. 95 1995 187 194
97. T. Munzel, S. Kurz, S. Rajagopalan, M. Thoenes, W.R. Berrington, J.A. Thompson, B.A. Freeman, and D.G. Harrison Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug J. Clin. Invest. 98 1996 1465 1470
98. S. Kurz, U. Hink, G. Nickenig, A.B. Borthayre, D.G. Harrison, and T. Munzel Evidence for a causal role of the renin-angiotensin system in nitrate tolerance Circulation 99 1999 3181 3187
99. T. Munzel, A. Giaid, S. Kurz, D.J. Stewart, and D.G. Harrison Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance Proc. Natl. Acad. Sci. U. S. A. 92 1995 5244 5248
100. K. Sydow, A. Daiber, M. Oelze, Z. Chen, M. August, M. Wendt, V. Ullrich, A. Mulsch, E. Schulz, J.F. Keaney Jr., J.S. Stamler, and T. Munzel Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance J. Clin. Invest. 113 2004 482 489
101. A. Modin, H. Bjorne, M. Herulf, K. Alving, E. Weitzberg, and J.O. Lundberg Nitrite-derived nitric oxide: a possible mediator of 'acidic-metabolic' vasodilation Acta Physiol. Scand. 171 2001 9 16
102. K. Cosby, K. Cosby, K.S. Partovi, J.H. Crawford, R.P. Patel, C.D. Reiter, S. Martyr, B.K. Yang, M.A. Waclawiw, G. Zalos, X. Xu, K.T. Huang, H. Shields, D.B. Kim-Shapiro, A.N. Schechter, R.O. Cannon III, and M.T. Gladwin Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation Nat. Med. 9 2003 1498 1505
103. A. Dejam, C.J. Hunter, A.N. Schechter, and M.T. Gladwin Emerging role of nitrite in human biology Blood Cells Mol. Dis. 32 2004 423 429
104. M.T. Gladwin, J.H. Shelhamer, A.N. Schechter, M.E. Pease-Fye, M.A. Waclawiw, J.A. Panza, F.P. Ognibene, and R.O. Cannon III Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans Proc. Natl. Acad. Sci. U. S. A. 97 2000 11482 11487
105. B. Tota, A.M. Quintieri, and T. Angelone The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function Curr. Med. Chem. 17 2010 1915 1925
106. T. Rassaf, U. Flogel, C. Drexhage, U. Hendgen-Cotta, M. Kelm, and J. Schrader Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function Circ. Res. 100 2007 1749 1754
107. K.T. Huang, A. Keszler, N. Patel, R.P. Patel, M.T. Gladwin, D.B. Kim-Shapiro, and N. Hogg The reaction between nitrite and deoxyhemoglobin. Reassessment of reaction kinetics and stoichiometry J. Biol. Chem. 280 2005 31126 31131
108. U. Flogel, A. Godecke, L.O. Klotz, and J. Schrader Role of myoglobin in the antioxidant defense of the heart FASEB J. 18 2004 1156 1158
109. M. Tiso, J. Tejero, S. Basu, I. Azarov, X. Wang, V. Simplaceanu, S. Frizzell, T. Jayaraman, L. Geary, C. Shapiro, C. Ho, S. Shiva, D.B. Kim-Shapiro, and M.T. Gladwin Human neuroglobin functions as a redox-regulated nitrite reductase J. Biol. Chem. 286 2011 18277 18289
110. S. Shiva, and M.T. Gladwin Shining a light on tissue NO stores: near infrared release of NO from nitrite and nitrosylated hemes J. Mol. Cell. Cardiol. 46 2009 1 3
111. U.B. Hendgen-Cotta, M.W. Merx, S. Shiva, J. Schmitz, S. Becher, J.P. Klare, H.J. Steinhoff, A. Goedecke, J. Schrader, M.T. Gladwin, M. Kelm, and T. Rassaf Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury Proc. Natl. Acad. Sci. U. S. A. 105 2008 10256 10261
112. S. Shiva, Z. Huang, R. Grubina, J. Sun, L.A. Ringwood, P.H. MacArthur, X. Xu, E. Murphy, V.M. Darley-Usmar, and M.T. Gladwin Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration Circ. Res. 100 2007 654 661
113. B.S. Zuckerbraun, S. Shiva, E. Ifedigbo, M.A. Mathier, K.P. Mollen, J. Rao, P.M. Bauer, J.J. Choi, E. Curtis, A.M. Choi, and M.T. Gladwin Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation Circulation 121 2010 98 109
114. A. Friebe, and D. Koesling Regulation of nitric oxide-sensitive guanylyl cyclase Circ. Res. 93 2003 96 105
115. N. Galie, H.A. Ghofrani, A. Torbicki, R.J. Barst, L.J. Rubin, D. Badesch, T. Fleming, T. Parpia, G. Burgess, A. Branzi, F. Grimminger, M. Kurzyna, and G. Simonneau Sildenafil use in pulmonary arterial hypertension study, G. Sildenafil citrate therapy for pulmonary arterial hypertension N. Engl. J. Med. 353 2005 2148 2157
116. J. Pepke-Zaba, C. Gilbert, L. Collings, and M.C. Brown Sildenafil improves health-related quality of life in patients with pulmonary arterial hypertension Chest 133 2008 183 189
117. E.A. Palmieri, F. Affuso, S. Fazio, and D. Lembo Tadalafil in primary pulmonary arterial hypertension Ann. Intern. Med. 141 2004 743 744
118. N. Galie, B.H. Brundage, H.A. Ghofrani, R.J. Oudiz, G. Simonneau, Z. Safdar, S. Shapiro, R.J. White, M. Chan, A. Beardsworth, L. Frumkin, and R.J. Barst Pulmonary arterial, H.; response to tadalafil study, G. Tadalafil therapy for pulmonary arterial hypertension Circulation 119 2009 2894 2903
119. O.V. Evgenov, P. Pacher, P.M. Schmidt, G. Hasko, H.H. Schmidt, and J.P. Stasch NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential Nat. Rev. Drug Discov. 5 2006 755 768
120. J.P. Stasch, E.M. Becker, C. Alonso-Alija, H. Apeler, K. Dembowsky, A. Feurer, R. Gerzer, T. Minuth, E. Perzborn, U. Pleiss, H. Schroder, W. Schroeder, E. Stahl, W. Steinke, A. Straub, and M. Schramm NO-independent regulatory site on soluble guanylate cyclase Nature 410 2001 212 215
121. J. Mittendorf, S. Weigand, C. Alonso-Alija, E. Bischoff, A. Feurer, M. Gerisch, A. Kern, A. Knorr, D. Lang, K. Muenter, M. Radtke, H. Schirok, K.H. Schlemmer, E. Stahl, A. Straub, F. Wunder, and J.P. Stasch Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension ChemMedChem 4 2009 853 865
122. H.A. Ghofrani, M.M. Hoeper, M. Halank, F.J. Meyer, G. Staehler, J. Behr, R. Ewert, G. Weimann, and F. Grimminger Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study Eur. Respir. J. 36 2010 792 799
123. W.G. Haynes, and D.J. Webb Endothelin as a regulator of cardiovascular function in health and disease J. Hypertens. 16 1998 1081 1098
124. C. Staniloae, J. Dupuis, M. White, G. Gosselin, I. Dyrda, M. Bois, J. Crepeau, R. Bonan, A. Caron, and J. Lavoie Reduced pulmonary clearance of endothelin in congestive heart failure: a marker of secondary pulmonary hypertension J. Card. Fail. 10 2004 427 432
125. J.Y. Duffy, S.M. Schwartz, J.M. Lyons, J.H. Bell, C.J. Wagner, B. Zingarelli, and J.M. Pearl Calpain inhibition decreases endothelin-1 levels and pulmonary hypertension after cardiopulmonary bypass with deep hypothermic circulatory arrest Crit. Care Med. 33 2005 623 628
126. G.A. Ross, P. Oishi, A. Azakie, S. Fratz, R.K. Fitzgerald, M.J. Johengen, C. Harmon, K. Hendricks-Munoz, J. Xu, S.M. Black, and J.R. Fineman Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension Am. J. Physiol. Lung Cell. Mol. Physiol. 288 2005 L27 L35
127. T. Sakurai, M. Yanagisawa, Y. Takuwa, H. Miyazaki, S. Kimura, K. Goto, and T. Masaki Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor Nature 348 1990 732 735
128. H. Arai, S. Hori, I. Aramori, H. Ohkubo, and S. Nakanishi Cloning and expression of a cDNA encoding an endothelin receptor Nature 348 1990 730 732
129. M.A. Zamora, E.C. Dempsey, S.J. Walchak, and T.J. Stelzner BQ123, an ETA receptor antagonist, inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells Am. J. Respir. Cell Mol. Biol. 9 1993 429 433
130. K. Sato, M. Oka, K. Hasunuma, M. Ohnishi, and S. Kira Effects of separate and combined ETA and ETB blockade on ET-1-induced constriction in perfused rat lungs Am. J. Physiol. 269 1995 L668 L672
131. M. Shichiri, H. Kato, F. Marumo, and Y. Hirata Endothelin-1 as an autocrine/paracrine apoptosis survival factor for endothelial cells Hypertension 30 1997 1198 1203
132. S. Soma, H. Takahashi, M. Muramatsu, M. Oka, and Y. Fukuchi Localization and distribution of endothelin receptor subtypes in pulmonary vasculature of normal and hypoxia-exposed rats Am. J. Respir. Cell Mol. Biol. 20 1999 620 630
133. H. Li, T.S. Elton, Y.F. Chen, and S. Oparil Increased endothelin receptor gene expression in hypoxic rat lung Am. J. Physiol. 266 1994 L553 L560
134. S. Wedgwood, and S.M. Black Endothelin-1 decreases endothelial NOS expression and activity through ETA receptor-mediated generation of hydrogen peroxide Am. J. Physiol. Lung Cell. Mol. Physiol. 288 2005 L480 L487
135. Z.K. Dai, M.S. Tan, C.Y. Chai, S.H. Chou, P.C. Lin, J.L. Yeh, A.Y. Jeng, C.I. Chang, I.J. Chen, and J.R. Wu Effects of sildenafil on pulmonary hypertension and levels of ET-1, eNOS, and cGMP in aorta-banded rats Exp. Biol. Med. (Maywood) 231 2006 942 947
136. E.M. Redmond, P.A. Cahill, R. Hodges, S. Zhang, and J.V. Sitzmann Regulation of endothelin receptors by nitric oxide in cultured rat vascular smooth muscle cells J. Cell. Physiol. 166 1996 469 479
137. C. Boulanger, and T.F. Luscher Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide J. Clin. Invest. 85 1990 587 590
138. S. Wedgwood, R.W. Dettman, and S.M. Black ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species Am. J. Physiol. Lung Cell. Mol. Physiol. 281 2001 L1058 L1067
139. T.H. Cheng, N.L. Shih, S.Y. Chen, S.H. Loh, P.Y. Cheng, C.S. Tsai, S.H. Liu, D.L. Wang, and J.J. Chen Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells J. Mol. Cell. Cardiol. 33 2001 1805 1814
140. M. Kyaw, M. Yoshizumi, K. Tsuchiya, K. Kirima, Y. Suzaki, S. Abe, T. Hasegawa, and T. Tamaki Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1) Biochem. Pharmacol. 64 2002 1521 1531
141. J. Fei, C. Viedt, U. Soto, C. Elsing, L. Jahn, and J. Kreuzer Endothelin-1 and smooth muscle cells: induction of jun amino-terminal kinase through an oxygen radical-sensitive mechanism Arterioscler. Thromb. Vasc. Biol. 20 2000 1244 1249
142. L.J. Rubin, D.B. Badesch, R.J. Barst, N. Galie, C.M. Black, A. Keogh, T. Pulido, A. Frost, S. Roux, I. Leconte, M. Landzberg, and G. Simonneau Bosentan therapy for pulmonary arterial hypertension N. Engl. J. Med. 346 2002 896 903
143. R.J. Barst, D. Ivy, J. Dingemanse, A. Widlitz, K. Schmitt, A. Doran, D. Bingaman, N. Nguyen, M. Gaitonde, and P.L. van Giersbergen Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension Clin. Pharmacol. Ther. 73 2003 372 382
144. H. Hardy, E.S. Backman, and H.W. Farber Successful bosentan and nonnucleoside reverse transcriptase inhibitor-based therapy in a patient with acquired immunodeficiency syndrome and pulmonary arterial hypertension Pharmacotherapy 30 2010 139e 144e
145. M.M. Hoeper, H.J. Seyfarth, G. Hoeffken, H. Wirtz, E. Spiekerkoetter, M.W. Pletz, T. Welte, and M. Halank Experience with inhaled iloprost and bosentan in portopulmonary hypertension Eur. Respir. J. 30 2007 1096 1102
146. R.N. Channick, G. Simonneau, O. Sitbon, I.M. Robbins, A. Frost, V.F. Tapson, D.B. Badesch, S. Roux, M. Rainisio, F. Bodin, and L.J. Rubin Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study Lancet 358 2001 1119 1123
147. N. Galie, H. Olschewski, R.J. Oudiz, F. Torres, A. Frost, H.A. Ghofrani, D.B. Badesch, M.D. McGoon, V.V. McLaughlin, E.B. Roecker, M.J. Gerber, C. Dufton, B.L. Wiens, and L.J. Rubin Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 Circulation 117 2008 3010 3019
148. J.C. Hartman, K. Brouwer, A. Mandagere, L. Melvin, and R. Gorczynski Evaluation of the endothelin receptor antagonists ambrisentan, darusentan, bosentan, and sitaxsentan as substrates and inhibitors of hepatobiliary transporters in sandwich-cultured human hepatocytes Can. J. Physiol. Pharmacol. 88 2010 682 691
149. S. Wedgwood, J.M. Bekker, and S.M. Black Shear stress regulation of endothelial NOS in fetal pulmonary arterial endothelial cells involves PKC Am. J. Physiol. Lung Cell. Mol. Physiol. 281 2001 L490 498
150. V.G. DeMarco, J. Habibi, A.T. Whaley-Connell, R.I. Schneider, R.L. Heller, J.P. Bosanquet, M.R. Hayden, K. Delcour, S.A. Cooper, B.T. Andresen, J.R. Sowers, and K.C. Dellsperger Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat Am. J. Physiol. Heart Circ. Physiol. 294 2008 H2659 H2668
151. R.P. Jankov, C. Kantores, J. Pan, and J. Belik Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats Am. J. Physiol. Lung Cell. Mol. Physiol. 294 2008 L233 L245
152. P. Joppa, D. Petrasova, B. Stancak, Z. Dorkova, and R. Tkacova Oxidative stress in patients with COPD and pulmonary hypertension Wien. Klin. Wochenschr. 119 2007 428 434
153. 2+]i through the mitochondrial ROS-PKCepsilon signaling axis in pulmonary artery smooth muscle cells Free Radic. Biol. Med. 45 2008 1223 1231
154. 2- in vascular smooth muscle cells Circ. Res. 77 1995 29 36
155. G.N. Rao, and B.C. Berk Active oxygen species stimulate vascular smooth muscle cell growth and proto-oncogene expression Circ. Res. 70 1992 593 599
156. G.N. Rao, B. Lassegue, K.K. Griendling, and R.W. Alexander Hydrogen peroxide stimulates transcription of c-jun in vascular smooth muscle cells: role of arachidonic acid Oncogene 8 1993 2759 2764
157. 2 for platelet-derived growth factor signal transduction Science 270 1995 296 299
158. C. Madjdpour, U.R. Jewell, S. Kneller, U. Ziegler, R. Schwendener, C. Booy, L. Klausli, T. Pasch, R.C. Schimmer, and B. Beck-Schimmer Decreased alveolar oxygen induces lung inflammation Am. J. Physiol. Lung Cell. Mol. Physiol. 284 2003 L360 L367
159. K.R. Stenmark, N.J. Davie, J.T. Reeves, and M.G. Frid Hypoxia, leukocytes, and the pulmonary circulation J. Appl. Physiol. 98 2005 715 721
160. D.A. Linseman, C.W. Benjamin, and D.A. Jones Convergence of angiotensin II and platelet-derived growth factor receptor signaling cascades in vascular smooth muscle cells J. Biol. Chem. 270 1995 12563 12568
161. M. Sausbier, R. Schubert, V. Voigt, C. Hirneiss, A. Pfeifer, M. Korth, T. Kleppisch, P. Ruth, and F. Hofmann Mechanisms of NO/cGMP-dependent vasorelaxation Circ. Res. 87 2000 825 830
162. S. Negash, Y. Gao, W. Zhou, J. Liu, S. Chinta, and J.U. Raj Regulation of cGMP-dependent protein kinase-mediated vasodilation by hypoxia-induced reactive species in ovine fetal pulmonary veins Am. J. Physiol. Lung Cell. Mol. Physiol. 293 2007 L1012 L1020
163. S. Aggarwal, C.M. Gross, S. Kumar, S. Datar, P. Oishi, G. Kalka, C. Schreiber, S. Fratz, J.R. Fineman, and S.M. Black Attenuated vasodilatation in lambs with endogenous and exogenous activation of cGMP signaling: role of protein kinase G nitration J. Cell. Physiol. 226 2011 3104 3113
164. E.O. Agbani, P. Coats, A. Mills, and R.M. Wadsworth Peroxynitrite stimulates pulmonary artery endothelial and smooth muscle cell proliferation: involvement of ERK and PKC Pulm. Pharmacol. Ther. 24 2011 100 109
165. M.H. Zou, R. Cohen, and V. Ullrich Peroxynitrite and vascular endothelial dysfunction in diabetes mellitus Endothelium 11 2004 89 97
166. H. Nie, J.L. Wu, M. Zhang, J. Xu, and M.H. Zou Endothelial nitric oxide synthase-dependent tyrosine nitration of prostacyclin synthase in diabetes in vivo Diabetes 55 2006 3133 3141
167. K.M. Mohazzab, and M.S. Wolin Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle Am. J. Physiol. 267 1994 L815 L822
168. S.A. Jones, V.B. O'Donnell, J.D. Wood, J.P. Broughton, E.J. Hughes, and O.T. Jones Expression of phagocyte NADPH oxidase components in human endothelial cells Am. J. Physiol. 271 1996 H1626 H1634
169. K.K. Griendling, C.A. Minieri, J.D. Ollerenshaw, and R.W. Alexander Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells Circ. Res. 74 1994 1141 1148
170. P.J. Pagano, Y. Ito, K. Tornheim, P.M. Gallop, A.I. Tauber, and R.A. Cohen An NADPH oxidase superoxide-generating system in the rabbit aorta Am. J. Physiol. 268 1995 H2274 H2280
171. P.J. Pagano, J.K. Clark, M.E. Cifuentes-Pagano, S.M. Clark, G.M. Callis, and M.T. Quinn Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II Proc. Natl. Acad. Sci. U. S. A. 94 1997 14483 14488
172. K.E. Dennis, J.L. Aschner, D. Milatovic, J.W. Schmidt, M. Aschner, M.R. Kaplowitz, Y. Zhang, and C.D. Fike NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets Am. J. Physiol. Lung Cell. Mol. Physiol. 297 2009 L596 L607
173. F. Fresquet, F. Pourageaud, V. Leblais, R.P. Brandes, J.P. Savineau, R. Marthan, and B. Muller Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia Br. J. Pharmacol. 148 2006 714 723
174. C.D. Fike, J.C. Slaughter, M.R. Kaplowitz, Y. Zhang, and J.L. Aschner Reactive oxygen species from NADPH oxidase contribute to altered pulmonary vascular responses in piglets with chronic hypoxia-induced pulmonary hypertension Am. J. Physiol. Lung Cell. Mol. Physiol. 295 2008 L881 L888
175. S.L. Lee, W.W. Wang, G.A. Finlay, and B.L. Fanburg Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion Am. J. Physiol. 277 1999 L282 L291
176. S.L. Lee, A.R. Simon, W.W. Wang, and B.L. Fanburg H(2)O(2) signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells Am. J. Physiol. Lung Cell. Mol. Physiol. 281 2001 L646 L652
177. V.G. DeMarco, J. Habibi, A.T. Whaley-Connell, R.I. Schneider, J.R. Sowers, B.T. Andresen, A.A. Gutweiler, L. Ma, M.S. Johnson, C.M. Ferrario, and K.C. Dellsperger Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat Am. J. Physiol. Heart Circ. Physiol. 297 2009 H1128 H1139
178. A.J. Ferreira, V. Shenoy, Y. Yamazato, S. Sriramula, J. Francis, L. Yuan, R.K. Castellano, D.A. Ostrov, S.P. Oh, M.J. Katovich, and M.K. Raizada Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension Am. J. Respir. Crit. Care Med. 179 2009 1048 1054
179. Y. Yamazato, A.J. Ferreira, K.H. Hong, S. Sriramula, J. Francis, M. Yamazato, L. Yuan, C.N. Bradford, V. Shenoy, S.P. Oh, M.J. Katovich, and M.K. Raizada Prevention of pulmonary hypertension by Angiotensin-converting enzyme 2 gene transfer Hypertension 54 2009 365 371
180. S. Kanno, Y.J. Wu, P.C. Lee, T.R. Billiar, and C. Ho Angiotensin- converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats Circulation 104 2001 945 950
181. Z. Nong, J.M. Stassen, L. Moons, D. Collen, and S. Janssens Inhibition of tissue angiotensin-converting enzyme with quinapril reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling Circulation 94 1996 1941 1947
182. K.N. Farrow, S. Lakshminrusimha, W.J. Reda, S. Wedgwood, L. Czech, S.F. Gugino, J.M. Davis, J.A. Russell, and R.H. Steinhorn Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension Am. J. Physiol. Lung Cell. Mol. Physiol. 295 2008 L979 L987
183. S. Wedgwood, R.H. Steinhorn, M. Bunderson, J. Wilham, S. Lakshminrusimha, L.A. Brennan, and S.M. Black Increased hydrogen peroxide downregulates soluble guanylate cyclase in the lungs of lambs with persistent pulmonary hypertension of the newborn Am. J. Physiol. Lung Cell. Mol. Physiol. 289 2005 L660 L666
184. K.N. Farrow, B.S. Groh, P.T. Schumacker, S. Lakshminrusimha, L. Czech, S.F. Gugino, J.A. Russell, and R.H. Steinhorn Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells Circ. Res. 102 2008 226 233
185. S. Wedgwood, and S.M. Black Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension Antioxid. Redox Signal. 5 2003 759 769
186. R.E. Nisbet, J.M. Bland, D.J. Kleinhenz, P.O. Mitchell, E.R. Walp, R.L. Sutliff, and C.M. Hart Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model Am. J. Respir. Cell Mol. Biol. 42 2010 482 490
187. M.S. Wolin, M. Ahmad, and S.A. Gupte The sources of oxidative stress in the vessel wall Kidney Int. 67 2005 1659 1661
188. K. Bedard, and K.H. Krause The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology Physiol. Rev. 87 2007 245 313
189. 2-dependent type. Amino acid sequence of rat liver xanthine dehydrogenase and identification of the cleavage sites of the enzyme protein during irreversible conversion by trypsin J. Biol. Chem. 265 1990 14170 14175
190. 2-dependent form (type O) Arch. Biochem. Biophys. 172 1976 365 379
191. C.M. Harris, and V. Massey The oxidative half-reaction of xanthine dehydrogenase with NAD; reaction kinetics and steady-state mechanism J. Biol. Chem. 272 1997 28335 28341
192. J.R. Williamson, K. Chang, M. Frangos, K.S. Hasan, Y. Ido, T. Kawamura, J.R. Nyengaard, M. van den Enden, C. Kilo, and R.G. Tilton Hyperglycemic pseudohypoxia and diabetic complications Diabetes 42 1993 801 813
193. E.E. Kelley, N.K. Khoo, N.J. Hundley, U.Z. Malik, B.A. Freeman, and M.M. Tarpey Hydrogen peroxide is the major oxidant product of xanthine oxidase Free Radic. Biol. Med. 48 2010 493 498
194. E.E. Kelley, T. Hock, N.K. Khoo, G.R. Richardson, K.K. Johnson, P.C. Powell, G.I. Giles, A. Agarwal, J.R. Lancaster Jr., and M.M. Tarpey Moderate hypoxia induces xanthine oxidoreductase activity in arterial endothelial cells Free Radic. Biol. Med. 40 2006 952 959
195. S. Spiekermann, K. Schenk, and M.M. Hoeper Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension Eur. Respir. J. 34 2009 276
196. M.S. Lewis, R.E. Whatley, P. Cain, T.M. McIntyre, S.M. Prescott, and G.A. Zimmerman Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion J. Clin. Invest. 82 1988 2045 2055
197. L.S. Terada, D.M. Guidot, J.A. Leff, I.R. Willingham, M.E. Hanley, D. Piermattei, and J.E. Repine Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity Proc. Natl. Acad. Sci. U. S. A. 89 1992 3362 3366
198. C.G. Cote, F.S. Yu, J.J. Zulueta, R.J. Vosatka, and P.M. Hassoun Regulation of intracellular xanthine oxidase by endothelial-derived nitric oxide Am. J. Physiol. 271 1996 L869 874
199. M. Houston, A. Estevez, P. Chumley, M. Aslan, S. Marklund, D.A. Parks, and B.A. Freeman Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling J. Biol. Chem. 274 1999 4985 4994
200. J.J. Zulueta, R. Sawhney, U. Kayyali, M. Fogel, C. Donaldson, H. Huang, J.J. Lanzillo, and P.M. Hassoun Modulation of inducible nitric oxide synthase by hypoxia in pulmonary artery endothelial cells Am. J. Respir. Cell Mol. Biol. 26 2002 22 30
201. P.C. Hinkle, R.A. Butow, E. Racker, and B. Chance Partial resolution of the enzymes catalyzing oxidative phosphorylation. XV. Reverse electron transfer in the flavin-cytochrome beta region of the respiratory chain of beef heart submitochondrial particles J. Biol. Chem. 242 1967 5169 5173
202. A. Boveris, and B. Chance The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen Biochem. J. 134 1973 707 716
203. G. Loschen, A. Azzi, C. Richter, and L. Flohe Superoxide radicals as precursors of mitochondrial hydrogen peroxide FEBS Lett. 42 1974 68 72
204. A. Boveris, E. Cadenas, and A.O. Stoppani Role of ubiquinone in the mitochondrial generation of hydrogen peroxide Biochem. J. 156 1976 435 444
205. J.F. Turrens, and A. Boveris Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria Biochem. J. 191 1980 421 427
206. 2-sensing pathway at the intersection of pulmonary hypertension and cancer Am. J. Physiol. Heart Circ. Physiol. 294 2008 H570 H578
207. M.S. Wolin Reactive oxygen species and the control of vascular function Am. J. Physiol. Heart Circ. Physiol. 296 2009 H539 H549
208. L.L. Hilenski, R.E. Clempus, M.T. Quinn, J.D. Lambeth, and K.K. Griendling Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells Arterioscler. Thromb. Vasc. Biol. 24 2004 677 683
209. J.D. Erusalimsky, and S. Moncada Nitric oxide and mitochondrial signaling: from physiology to pathophysiology Arterioscler. Thromb. Vasc. Biol. 27 2007 2524 2531
210. G. Biswas, H.K. Anandatheerthavarada, M. Zaidi, and N.G. Avadhani Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta J. Cell Biol. 161 2003 507 519
211. M. Palacios-Callender, M. Quintero, V.S. Hollis, R.J. Springett, and S. Moncada Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase Proc. Natl. Acad. Sci. U. S. A. 101 2004 7630 7635
212. A. Cogolludo, G. Frazziano, L. Cobeno, L. Moreno, F. Lodi, E. Villamor, J. Tamargo, and F. Perez-Vizcaino Role of reactive oxygen species in Kv channel inhibition and vasoconstriction induced by TP receptor activation in rat pulmonary arteries Ann. N. Y. Acad. Sci. 1091 2006 41 51
213. E. Nozik-Grayck, H.B. Suliman, S. Majka, J. Albietz, Z. Van Rheen, K. Roush, and K.R. Stenmark Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling Am. J. Physiol. Lung Cell. Mol. Physiol. 295 2008 L422 L430
214. L.S. Burwell, S.M. Nadtochiy, A.J. Tompkins, S. Young, and P.S. Brookes Direct evidence for S-nitrosation of mitochondrial complex I Biochem. J. 394 2006 627 634
215. C.C. Dahm, K. Moore, and M.P. Murphy Persistent S-nitrosation of complex I and other mitochondrial membrane proteins by S-nitrosothiols but not nitric oxide or peroxynitrite: implications for the interaction of nitric oxide with mitochondria J. Biol. Chem. 281 2006 10056 10065
216. R.M. Leach, H.M. Hill, V.A. Snetkov, T.P. Robertson, and J.P. Ward Divergent roles of glycolysis and the mitochondrial electron transport chain in hypoxic pulmonary vasoconstriction of the rat: identity of the hypoxic sensor J. Physiol. 536 2001 211 224
217. N. Weissmann, N. Ebert, M. Ahrens, H.A. Ghofrani, R.T. Schermuly, J. Hanze, L. Fink, F. Rose, J. Conzen, W. Seeger, and F. Grimminger Effects of mitochondrial inhibitors and uncouplers on hypoxic vasoconstriction in rabbit lungs Am. J. Respir. Cell Mol. Biol. 29 2003 721 732
218. G.L. Semenza Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1 Biochem. J. 405 2007 1 9
219. 2 sensing J. Biol. Chem. 275 2000 25130 25138
220. R.D. Guzy, B. Hoyos, E. Robin, H. Chen, L. Liu, K.D. Mansfield, M.C. Simon, U. Hammerling, and P.T. Schumacker Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing Cell Metab. 1 2005 401 408
221. E. Delannoy, A. Courtois, V. Freund-Michel, V. Leblais, R. Marthan, and B. Muller Hypoxia-induced hyperreactivity of pulmonary arteries: role of cyclooxygenase-2, isoprostanes, and thromboxane receptors Cardiovasc. Res. 85 2010 582 592
222. S.L. Archer, G. Marsboom, G.H. Kim, H.J. Zhang, P.T. Toth, E.C. Svensson, J.R. Dyck, M. Gomberg-Maitland, B. Thebaud, A.N. Husain, N. Cipriani, and J. Rehman Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target Circulation 121 2010 2661 2671
223. M.S. McMurtry, S. Bonnet, X. Wu, J.R. Dyck, A. Haromy, K. Hashimoto, and E.D. Michelakis Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis Circ. Res. 95 2004 830 840
224. S. Bonnet, E.D. Michelakis, C.J. Porter, M.A. Andrade-Navarro, B. Thebaud, A. Haromy, G. Harry, R. Moudgil, M.S. McMurtry, E.K. Weir, and S.L. Archer An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension Circulation 113 2006 2630 2641
225. S. Bonnet, and S.L. Archer Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension Pharmacol. Ther. 115 2007 56 69
226. E.D. Michelakis, V. Hampl, A. Nsair, X. Wu, G. Harry, A. Haromy, R. Gurtu, and S.L. Archer Diversity in mitochondrial function explains differences in vascular oxygen sensing Circ. Res. 90 2002 1307 1315
227. T. Dohi, E. Beltrami, N.R. Wall, J. Plescia, and D.C. Altieri Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis J. Clin. Invest. 114 2004 1117 1127
228. M.S. McMurtry, S.L. Archer, D.C. Altieri, S. Bonnet, A. Haromy, G. Harry, L. Puttagunta, and E.D. Michelakis Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension J. Clin. Invest. 115 2005 1479 1491
229. I. Fijalkowska, W. Xu, S.A. Comhair, A.J. Janocha, L.A. Mavrakis, B. Krishnamachary, L. Zhen, T. Mao, A. Richter, S.C. Erzurum, and R.M. Tuder Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells Am. J. Pathol. 176 2010 1130 1138
230. W. Xu, T. Koeck, A.R. Lara, D. Neumann, F.P. DiFilippo, M. Koo, A.J. Janocha, F.A. Masri, A.C. Arroliga, C. Jennings, R.A. Dweik, R.M. Tuder, D.J. Stuehr, and S.C. Erzurum Alterations of cellular bioenergetics in pulmonary artery endothelial cells Proc. Natl. Acad. Sci. U. S. A. 104 2007 1342 1347
231. J.W. Kim, and C.V. Dang Multifaceted roles of glycolytic enzymes Trends Biochem. Sci. 30 2005 142 150
232. S. Bonnet, S.L. Archer, J. Allalunis-Turner, A. Haromy, C. Beaulieu, R. Thompson, C.T. Lee, G.D. Lopaschuk, L. Puttagunta, G. Harry, K. Hashimoto, C.J. Porter, M.A. Andrade, B. Thebaud, and E.D. Michelakis A mitochondria-K+channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth Cancer Cell 11 2007 37 51
233. R.E. Girgis, D. Li, X. Zhan, J.G. Garcia, R.M. Tuder, P.M. Hassoun, and R.A. Johns Attenuation of chronic hypoxic pulmonary hypertension by simvastatin Am. J. Physiol. Heart Circ. Physiol. 285 2003 H938 H945
234. T. Murata, K. Kinoshita, M. Hori, M. Kuwahara, H. Tsubone, H. Karaki, and H. Ozaki Statin protects endothelial nitric oxide synthase activity in hypoxia-induced pulmonary hypertension Arterioscler. Thromb. Vasc. Biol. 25 2005 2335 2342
235. A.R. Hemnes, A. Zaiman, and H.C. Champion PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation Am. J. Physiol. Lung Cell. Mol. Physiol. 294 2008 L24 L33
236. D. Kentera, D. Susic, V. Veljkovic, G. Tucakovic, and V. Koko Pulmonary artery pressure in rats with hereditary platelet function defect Respiration 54 1988 110 114
237. M. Rabinovitch PPARgamma and the pathobiology of pulmonary arterial hypertension Adv. Exp. Med. Biol. 661 2010 447 458
238. G. Sutendra, S. Bonnet, G. Rochefort, A. Haromy, K.D. Folmes, G.D. Lopaschuk, J.R. Dyck, and E.D. Michelakis Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension Sci. Transl. Med. 2 2010 44ra58
239. X. Lu, T.C. Murphy, M.S. Nanes, and C.M. Hart PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B Am. J. Physiol. Lung Cell. Mol. Physiol. 299 2010 L559 L566
240. E.K. Kim, J.H. Lee, Y.M. Oh, Y.S. Lee, and S.D. Lee Rosiglitazone attenuates hypoxia-induced pulmonary arterial hypertension in rats Respirology 15 2010 659 668
241. R.L. Sutliff, B.Y. Kang, and C.M. Hart PPARgamma as a potential therapeutic target in pulmonary hypertension Ther. Adv. Respir. Dis. 4 2010 143 160
242. G. Hansmann, and R.T. Zamanian PPARgamma activation: a potential treatment for pulmonary hypertension Sci. Transl. Med. 1 2009 12 ps14
243. M. Li, Z. Li, X. Sun, L. Yang, P. Fang, Y. Liu, W. Li, J. Xu, J. Lu, M. Xie, and D. Zhang Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells FEBS J. 277 2010 1543 1550
244. J. Tian, A. Smith, J. Nechtman, R. Podolsky, S. Aggarwal, C. Snead, S. Kumar, M. Elgaish, P. Oishi, A. Goerlach, S. Fratz, J. Hess, J.D. Catravas, A.D. Verin, J.R. Fineman, J.X. She, and S.M. Black Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension Physiol. Genomics 40 2009 48 60
245. J.P. Stasch, P. Pacher, and O.V. Evgenov Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease Circulation 123 2011 2263 2273
246. M.T. Gladwin, S.A., D.B. Kim-Shapiro, R.P. Patel, N. Hogg, S. Shiva, R.O. Cannon III, M. Kelm, D.A. Wink, M.G. Espey, E.H. Oldfield, R.M. Pluta, B.A. Freeman, J.R. Lancaster Jr., M. Feelisch, and J.O. Lundberg The emerging biology of the nitrite anion Nat. Chem. Biol. 1 2005 308 314
247. J.W. Cheng Ambrisentan for the management of pulmonary arterial hypertension Clin. Ther. 30 2008 825 833