Skip to main content
SpringerLink
Log in

Therapeutics Targeting of Dysregulated Redox Equilibrium and Endothelial Dysfunction

  • Chapter
  • First Online:
Pharmacotherapy of Pulmonary Hypertension

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

All forms of WHO Group 1 PAH share a progressive and complex vasculopathy. At the center of this derangement lies the pulmonary vascular endothelium, which plays a crucial role in maintaining a delicate and precise balance of opposing vasoconstricting and vasodilating forces. In PAH, endothelial cell damage and dysfunction alter vascular homeostasis in favor of vasoconstriction. There is evidence of increased expression and activity in the vasoconstrictor and mitogen endothelin-1 signaling system and a decreased production of the potent vasodilator prostacyclin. These pathways have been a major focus of FDA approved PAH-specific therapies. Beyond these pathways, there is the dysfunction within the endothelial nitric oxide (NO) synthase signaling pathway and dysregulation of reactive oxygen and nitrogen species (ROS) that contribute to the pathogenesis of PAH. The dysregulation of vasodilator systems in PAH in large part involves the NO pathway, with almost every step subject to impairments. This includes a reduction in endothelial NO synthase function (eNOS), the enzymatic “uncoupling” of eNOS, increased scavenging of NO by superoxide and cell-free hemoglobin, the elaboration of endogenous competitive inhibitors of eNOS (ADMA), and the oxidation of the NO target, soluble guanylyl cyclase. The dysregulation of NO signaling pathways occurs in the setting of parallel upregulation of vascular oxidases that generate ROS. Enzymatic sources of ROS in PH that have been identified include the NAPDPH oxidases 1, 2, and 4, xanthine oxidase, uncoupled eNOS, and complex III of the mitochondrial electron transport chain. Superoxide produced from these sources reacts with NO to form the reactive nitrogen species peroxynitrate, further diverting bioavailable NO to more injuries species. In PAH, this upstream dysregulation of ROS/NO redox homeostasis severely impairs vascular tone and contributes to the pathological activation of mitogenic pathways, leading to cellular proliferation and obliteration of the pulmonary vasculature. Therapeutic strategies are being evaluated that target the associated dysregulated redox equilibrium and endothelial dysfunction in PAH. Therapeutic interventions reviewed in this chapter include NO donor or NO generating drugs, therapies that recouple eNOS or directly increase cGMP levels via inhibition of phosphodiesterase 5 or stimulation of soluble guanylyl cyclase, and therapies that inhibit vascular oxidases or scavenge ROS.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

eNOS:

Endothelial nitric oxide synthase

PAH:

Pulmonary arterial hypertension

PH:

Pulmonary hypertension

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

References

  • Agbani EO, Coats P et al (2011) Peroxynitrite stimulates pulmonary artery endothelial and smooth muscle cell proliferation: involvement of ERK and PKC. Pulm Pharmacol Ther 24(1):100–109

    Article  PubMed  CAS  Google Scholar 

  • Amaya Y, Yamazaki K et al (1990) Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-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(24):14170–14175

    PubMed  CAS  Google Scholar 

  • Ameshima S, Golpon H et al (2003) Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 92(10):1162–1169

    Article  PubMed  CAS  Google Scholar 

  • Archer SL, Marsboom G et al (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121(24):2661–2671

    Article  PubMed  CAS  Google Scholar 

  • Arnold WP, Mittal CK et al (1977) Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA 74(8):3203–3207

    Article  PubMed  CAS  Google Scholar 

  • Artz JD, Schmidt B et al (2002) Effects of nitroglycerin on soluble guanylate cyclase: implications for nitrate tolerance. J Biol Chem 277(21):18253–18256

    Article  PubMed  CAS  Google Scholar 

  • Aslan M, Ryan TM et al (2001) Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci USA 98(26):15215–15220

    Article  PubMed  CAS  Google Scholar 

  • Ataga KI, Moore CG et al (2006) Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol 134(1):109–115

    Article  PubMed  Google Scholar 

  • Atz AM, Wessel DL (1997) Inhaled nitric oxide in the neonate with cardiac disease. Semin Perinatol 21(5):441–455

    Article  PubMed  CAS  Google Scholar 

  • Atz AM, Adatia I et al (1996) Rebound pulmonary hypertension after inhalation of nitric oxide. Ann Thorac Surg 62(6):1759–1764

    Article  PubMed  CAS  Google Scholar 

  • Baliga RS, Milsom AB et al (2012) Dietary nitrate ameliorates pulmonary hypertension: cytoprotective role for endothelial nitric oxide synthase and xanthine oxidoreductase. Circulation 125(23):2922–2932

    Article  PubMed  CAS  Google Scholar 

  • Barst RJ, McGoon M et al (2004) Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43(12 Suppl S):40S–47S

    Article  PubMed  Google Scholar 

  • Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271(5 Pt 1):C1424–C1437

    PubMed  CAS  Google Scholar 

  • Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87(1):245–313

    Article  PubMed  CAS  Google Scholar 

  • Benhar M, Stamler JS (2005) A central role for S-nitrosylation in apoptosis. Nat Cell Biol 7(7):645–646

    Article  PubMed  CAS  Google Scholar 

  • Bernatchez PN, Bauer PM et al (2005) Dissecting the molecular control of endothelial NO synthase by caveolin-1 using cell-permeable peptides. Proc Natl Acad Sci USA 102(3):761–766

    Article  PubMed  CAS  Google Scholar 

  • Beyer J, Kolditz M et al (2008) L-arginine plasma levels and severity of idiopathic pulmonary arterial hypertension. Vasa 37(1):61–67

    Article  PubMed  CAS  Google Scholar 

  • Biswas G, Anandatheerthavarada HK et al (2003) Mitochondria to nucleus stress signaling: a distinctive mechanism of NFkappaB/Rel activation through calcineurin-mediated inactivation of IkappaBbeta. J Cell Biol 161(3):507–519

    Article  PubMed  CAS  Google Scholar 

  • Black SM, Heidersbach RS et al (1999) Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension. Am J Physiol 277(5 Pt 2):H1849–H1856

    PubMed  CAS  Google Scholar 

  • Boveris A, Oshino N et al (1972) The cellular production of hydrogen peroxide. Biochem J 128(3):617–630

    PubMed  CAS  Google Scholar 

  • Brennan LA, Steinhorn RH et al (2003) Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase. Circ Res 92(6):683–691

    Article  PubMed  CAS  Google Scholar 

  • Brown GC, Borutaite V (2006) Interactions between nitric oxide, oxygen, reactive oxygen species and reactive nitrogen species. Biochem Soc Trans 34(Pt 5):953–956

    PubMed  CAS  Google Scholar 

  • Burwell LS, Nadtochiy SM et al (2006) Direct evidence for S-nitrosation of mitochondrial complex I. Biochem J 394(Pt 3):627–634

    PubMed  CAS  Google Scholar 

  • Cannon RO 3rd, Schechter AN et al (2001) Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 108(2):279–287

    PubMed  CAS  Google Scholar 

  • Chatterjee A, Black SM et al (2008) Endothelial nitric oxide (NO) and its pathophysiologic regulation. Vascul Pharmacol 49(4–6):134–140

    Article  PubMed  CAS  Google Scholar 

  • Chen B, Calvert AE et al (2009) Hypoxia promotes human pulmonary artery smooth muscle cell proliferation through induction of arginase. Am J Physiol Lung Cell Mol Physiol 297(6):L1151–L1159

    Article  PubMed  CAS  Google Scholar 

  • Christman BW, McPherson CD et al (1992) An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327(2):70–75

    Article  PubMed  CAS  Google Scholar 

  • Coggins MP, Bloch KD (2007) Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol 27(9):1877–1885

    Article  PubMed  CAS  Google Scholar 

  • Cosby K, Partovi KS et al (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9(12):1498–1505

    Article  PubMed  CAS  Google Scholar 

  • Cote CG, Yu FS et al (1996) Regulation of intracellular xanthine oxidase by endothelial-derived nitric oxide. Am J Physiol 271(5 Pt 1):L869–L874

    PubMed  CAS  Google Scholar 

  • Crabtree MJ, Tatham AL et al (2009) 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(2):1136–1144

    Article  PubMed  CAS  Google Scholar 

  • Cross AR, Segal AW (2004) The NADPH oxidase of professional phagocytes – prototype of the NOX electron transport chain systems. Biochim Biophys Acta 1657(1):1–22

    Article  PubMed  CAS  Google Scholar 

  • Cueto E, Lopez-Herce J et al (1997) Life-threatening effects of discontinuing inhaled nitric oxide in children. Acta Paediatr 86(12):1337–1339

    Article  PubMed  CAS  Google Scholar 

  • Cunnington C, Channon KM (2010) Tetrahydrobiopterin: pleiotropic roles in cardiovascular pathophysiology. Heart 96(23):1872–1877

    Article  PubMed  CAS  Google Scholar 

  • D’Alecy LG, Billecke SS (2010) Massive quantities of asymmetric dimethylarginine (ADMA) are incorporated in red blood cell proteins and may be released by proteolysis following hemolytic stress. Blood Cells Mol Dis 45(1):40

    Article  PubMed  CAS  Google Scholar 

  • Dahm CC, Moore K et al (2006) 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(15):10056–10065

    Article  PubMed  CAS  Google Scholar 

  • Dasgupta T, Fabry ME et al (2010) Antisickling property of fetal hemoglobin enhances nitric oxide bioavailability and ameliorates organ oxidative stress in transgenic-knockout sickle mice. Am J Physiol Regul Integr Comp Physiol 298(2):R394–R402

    Article  PubMed  CAS  Google Scholar 

  • De Castro LM, Jonassaint JC et al (2008) Pulmonary hypertension associated with sickle cell disease: clinical and laboratory endpoints and disease outcomes. Am J Hematol 83(1):19–25

    Article  PubMed  CAS  Google Scholar 

  • de Man FS, Tu L et al (2012) Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension. Am J Respir Crit Care Med 186(8):780–789

    Article  PubMed  CAS  Google Scholar 

  • Dejam A, Hunter CJ et al (2004) Emerging role of nitrite in human biology. Blood Cells Mol Dis 32(3):423–429

    Article  PubMed  CAS  Google Scholar 

  • DeMarco VG, Habibi J et al (2008) Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 294(6):H2659–H2668

    Article  PubMed  CAS  Google Scholar 

  • DeMarco VG, Habibi J et al (2009) Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 297(3):H1128–H1139

    Article  PubMed  CAS  Google Scholar 

  • Demoncheaux EA, Higenbottam TW et al (2005) Decreased whole body endogenous nitric oxide production in patients with primary pulmonary hypertension. J Vasc Res 42(2):133–136

    Article  PubMed  CAS  Google Scholar 

  • Deruelle P, Grover TR et al (2005) 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(5):L798–L806

    Article  PubMed  CAS  Google Scholar 

  • Doherty DH, Doyle MP et al (1998) Rate of reaction with nitric oxide determines the hypertensive effect of cell-free hemoglobin. Nat Biotechnol 16(7):672–676

    Article  PubMed  CAS  Google Scholar 

  • Dou Y, Maillett DH et al (2002) Myoglobin as a model system for designing heme protein based blood substitutes. Biophys Chem 98(1–2):127–148

    Article  PubMed  CAS  Google Scholar 

  • Eddahibi S, Adnot S et al (1992) L-arginine restores endothelium-dependent relaxation in pulmonary circulation of chronically hypoxic rats. Am J Physiol 263(2 Pt 1):L194–L200

    PubMed  CAS  Google Scholar 

  • Elkayam U (1991) Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med 114(8):667–677

    Article  PubMed  CAS  Google Scholar 

  • Erusalimsky JD, Moncada S (2007) Nitric oxide and mitochondrial signaling: from physiology to pathophysiology. Arterioscler Thromb Vasc Biol 27(12):2524–2531

    Article  PubMed  CAS  Google Scholar 

  • Evgenov OV, Pacher P et al (2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5(9):755–768

    Article  PubMed  CAS  Google Scholar 

  • Farrow KN, Groh BS et al (2008a) Hyperoxia increases phosphodiesterase 5 expression and activity in ovine fetal pulmonary artery smooth muscle cells. Circ Res 102(2):226–233

    Article  PubMed  CAS  Google Scholar 

  • Farrow KN, Lakshminrusimha S et al (2008b) 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(6):L979–L987

    Article  PubMed  CAS  Google Scholar 

  • Fialkow L, Wang Y et al (2007) Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med 42(2):153–164

    Article  PubMed  CAS  Google Scholar 

  • Fike CD, Slaughter JC et al (2008) 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(5):L881–L888

    Article  PubMed  CAS  Google Scholar 

  • Flogel U, Godecke A et al (2004) Role of myoglobin in the antioxidant defense of the heart. FASEB J 18(10):1156–1158

    PubMed  Google Scholar 

  • Fonseca GH, Souza R et al (2012) Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J 39(1):112–118

    Article  PubMed  CAS  Google Scholar 

  • Forstermann U, Munzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113(13):1708–1714

    Article  PubMed  CAS  Google Scholar 

  • Foster MW, McMahon TJ et al (2003) S-nitrosylation in health and disease. Trends Mol Med 9(4):160–168

    Article  PubMed  CAS  Google Scholar 

  • Francis BN, Wilkins MR et al (2010) Tetrahydrobiopterin and the regulation of hypoxic pulmonary vasoconstriction. Eur Respir J 36(2):323–330

    Article  PubMed  CAS  Google Scholar 

  • Frei AC, Guo Y et al (2008) Vascular dysfunction in a murine model of severe hemolysis. Blood 112(2):398–405

    Article  PubMed  CAS  Google Scholar 

  • Fresquet F, Pourageaud F et al (2006) Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia. Br J Pharmacol 148(5):714–723

    Article  PubMed  CAS  Google Scholar 

  • Friebe A, Koesling D (2003) Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 93(2):96–105

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Ghofrani HA et al (2005) Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353(20):2148–2157

    Article  PubMed  CAS  Google Scholar 

  • Galie N, Brundage BH et al (2009) Tadalafil therapy for pulmonary arterial hypertension. Circulation 119(22):2894–2903

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Cardena G, Martasek P et al (1997) Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 272(41):25437–25440

    Article  PubMed  CAS  Google Scholar 

  • Gaston B, Reilly J et al (1993) Endogenous nitrogen oxides and bronchodilator S-nitrosothiols in human airways. Proc Natl Acad Sci USA 90(23):10957–10961

    Article  PubMed  CAS  Google Scholar 

  • Gaston B, Fry E et al (1998) Umbilical arterial S-nitrosothiols in stressed newborns: role in perinatal circulatory transition. Biochem Biophys Res Commun 253(3):899–901

    Article  PubMed  CAS  Google Scholar 

  • Gaston B, Singel D et al (2006) S-nitrosothiol signaling in respiratory biology. Am J Respir Crit Care Med 173(11):1186–1193

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Wiedemann R et al (2002) Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet 360(9337):895–900

    Article  PubMed  CAS  Google Scholar 

  • Ghofrani HA, Hoeper MM et al (2010) Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 36(4):792–799

    Article  PubMed  CAS  Google Scholar 

  • Giaid A, Yanagisawa M et al (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328(24):1732–1739

    Article  PubMed  CAS  Google Scholar 

  • Gielis JF, Lin JY et al (2011) Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders. Free Radic Biol Med 50(7):765–776

    Article  PubMed  CAS  Google Scholar 

  • Gladwin MT (2006) Deconstructing endothelial dysfunction: soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 116(9):2330–2332

    Article  PubMed  CAS  Google Scholar 

  • Gladwin MT, Vichinsky E (2008) Pulmonary complications of sickle cell disease. N Engl J Med 359(21):2254–2265

    Article  PubMed  CAS  Google Scholar 

  • Gladwin MT, Shelhamer JH et al (2000) Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. Proc Natl Acad Sci USA 97(21):11482–11487

    Article  PubMed  CAS  Google Scholar 

  • Gladwin MT, Sachdev V et al (2004) Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350(9):886–895

    Article  PubMed  CAS  Google Scholar 

  • Grimminger F, Weimann G et al (2009) First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 33(4):785–792

    Article  PubMed  CAS  Google Scholar 

  • Grobe AC, Wells SM et al (2006) 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(6):L1069–L1077

    Article  PubMed  CAS  Google Scholar 

  • Hansmann G, Zamanian RT (2009) PPARgamma activation: a potential treatment for pulmonary hypertension. Sci Transl Med 1(12):12ps14

    Article  PubMed  CAS  Google Scholar 

  • Harris CM, Massey V (1997) The oxidative half-reaction of xanthine dehydrogenase with NAD; reaction kinetics and steady-state mechanism. J Biol Chem 272(45):28335–28341

    Article  PubMed  CAS  Google Scholar 

  • Hassoun PM, Mouthon L et al (2009) Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54(1 Suppl):S10–S19

    Article  PubMed  CAS  Google Scholar 

  • Hattori Y, Nakanishi N et al (2003) HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells. Arterioscler Thromb Vasc Biol 23(2):176–182

    Article  PubMed  CAS  Google Scholar 

  • He W, Barak Y et al (2003) Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 100(26):15712–15717

    Article  PubMed  CAS  Google Scholar 

  • Hemnes AR, Zaiman A et al (2008) 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(1):L24–L33

    Article  PubMed  CAS  Google Scholar 

  • Hendgen-Cotta UB, Merx MW et al (2008) Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci USA 105(29):10256–10261

    Article  PubMed  CAS  Google Scholar 

  • Hill A, Rother RP et al (2010) Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 149(3):414–425

    Article  PubMed  CAS  Google Scholar 

  • Hoshikawa Y, Ono S et al (2001) Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol 90(4):1299–1306

    PubMed  CAS  Google Scholar 

  • Houston M, Estevez A et al (1999) Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem 274(8):4985–4994

    Article  PubMed  CAS  Google Scholar 

  • Howell K, Costello CM et al (2009) L-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 296(6):L1042–L1050

    Article  PubMed  CAS  Google Scholar 

  • Hsu LL, Champion HC et al (2007) Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 109(7):3088–3098

    PubMed  CAS  Google Scholar 

  • Huang KT, Keszler A et al (2005) The reaction between nitrite and deoxyhemoglobin. Reassessment of reaction kinetics and stoichiometry. J Biol Chem 280(35):31126–31131

    Article  PubMed  CAS  Google Scholar 

  • Humbert M, Sitbon O et al (2006) Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 173(9):1023–1030

    Article  PubMed  Google Scholar 

  • Humbert M, Sitbon O, Yaïci A, Montani D, O'Callaghan DS, Jaïs X, Parent F, Savale L, Natali D, Günther S, Chaouat A, Chabot F, Cordier JF, Habib G, Gressin V, Jing ZC, Souza R, Simonneau G, French Pulmonary Arterial Hypertension Network (2010) Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 36(3):549–55. doi:10.1183/09031936.00057010, Epub 2010 Jun 18

    Google Scholar 

  • Hunter CJ, Dejam A et al (2004) Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator. Nat Med 10(10):1122–1127

    Article  PubMed  CAS  Google Scholar 

  • Ignarro LJ, Degnan JN et al (1982) Activation of purified guanylate cyclase by nitric oxide requires heme. Comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung. Biochim Biophys Acta 718(1):49–59

    Article  PubMed  CAS  Google Scholar 

  • Ignarro LJ, Buga GM et al (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84(24):9265–9269

    Article  PubMed  CAS  Google Scholar 

  • Ignarro LJ, Napoli C et al (2002) Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circ Res 90(1):21–28

    Article  PubMed  CAS  Google Scholar 

  • Imanishi T, Ikejima H et al (2008) Addition of eplerenone to an angiotensin-converting enzyme inhibitor effectively improves nitric oxide bioavailability. Hypertension 51(3):734–741

    Article  PubMed  CAS  Google Scholar 

  • Ishii M, Shimizu S et al (2001) Stimulation of tetrahydrobiopterin synthesis induced by insulin: possible involvement of phosphatidylinositol 3-kinase. Int J Biochem Cell Biol 33(1):65–73

    Article  PubMed  CAS  Google Scholar 

  • Ivy DD, Parker TA et al (1997) Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus. J Clin Invest 99(6):1179–1186

    Article  PubMed  CAS  Google Scholar 

  • Jankov RP, Kantores C et al (2008) Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats. Am J Physiol Lung Cell Mol Physiol 294(2):L233–L245

    Article  PubMed  CAS  Google Scholar 

  • Joppa P, Petrasova D et al (2007) Oxidative stress in patients with COPD and pulmonary hypertension. Wien Klin Wochenschr 119(13–14):428–434

    Article  PubMed  CAS  Google Scholar 

  • Kanno S, Wu YJ et al (2001) Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats. Circulation 104(8):945–950

    Article  PubMed  CAS  Google Scholar 

  • Karuppiah K, Druhan LJ et al (2011) Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism. Am J Physiol Heart Circ Physiol 301(3):H903–H911

    Article  PubMed  CAS  Google Scholar 

  • Kato GJ, McGowan V et al (2006) Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 107(6):2279–2285

    Article  PubMed  CAS  Google Scholar 

  • Kato GJ, Wang Z et al (2009) Endogenous nitric oxide synthase inhibitors in sickle cell disease: abnormal levels and correlations with pulmonary hypertension, desaturation, haemolysis, organ dysfunction and death. Br J Haematol 145(4):506–513

    Article  PubMed  CAS  Google Scholar 

  • Kaul DK, Liu XD et al (2000) Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse. Am J Physiol Heart Circ Physiol 278(6):H1799–H1806

    PubMed  CAS  Google Scholar 

  • Kaul DK, Liu XD et al (2004) Effect of fetal hemoglobin on microvascular regulation in sickle transgenic-knockout mice. J Clin Invest 114(8):1136–1145

    PubMed  CAS  Google Scholar 

  • Kelleher ZT, Matsumoto A et al (2007) NOS2 regulation of NF-kappaB by S-nitrosylation of p65. J Biol Chem 282(42):30667–30672

    Article  PubMed  CAS  Google Scholar 

  • Kelley EE, Hock T et al (2006) Moderate hypoxia induces xanthine oxidoreductase activity in arterial endothelial cells. Free Radic Biol Med 40(6):952–959

    Article  PubMed  CAS  Google Scholar 

  • Kelley EE, Khoo NK et al (2010) Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic Biol Med 48(4):493–498

    Article  PubMed  CAS  Google Scholar 

  • Khoo JP, Zhao L et al (2005) Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension. Circulation 111(16):2126–2133

    Article  PubMed  CAS  Google Scholar 

  • Kibbe MR, Li J et al (2000) 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(6):1214–1228

    PubMed  CAS  Google Scholar 

  • Krasuski RA, Devendra GP et al (2011) Response to inhaled nitric oxide predicts survival in patients with pulmonary hypertension. J Card Fail 17(4):265–271

    Article  PubMed  CAS  Google Scholar 

  • Kunuthur SP, Milliken PH et al (2011) Tetrahydrobiopterin analogues with NO-dependent pulmonary vasodilator properties. Eur J Pharmacol 650(1):371–377

    Article  PubMed  CAS  Google Scholar 

  • Kurz S, Hink U et al (1999) Evidence for a causal role of the renin-angiotensin system in nitrate tolerance. Circulation 99(24):3181–3187

    Article  PubMed  CAS  Google Scholar 

  • Landburg PP, Teerlink T et al (2008) Plasma concentrations of asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell patients but do not increase further during painful crisis. Am J Hematol 83(7):577–579

    Article  PubMed  CAS  Google Scholar 

  • Landburg PP, Teerlink T et al (2010) Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype. Blood Cells Mol Dis 44(4):229–232

    Article  PubMed  CAS  Google Scholar 

  • Langle F, Roth E et al (1995) Arginase release following liver reperfusion. Evidence of hemodynamic action of arginase infusions. Transplantation 59(11):1542–1549

    PubMed  CAS  Google Scholar 

  • Lavoie A, Hall JB et al (1996) Life-threatening effects of discontinuing inhaled nitric oxide in severe respiratory failure. Am J Respir Crit Care Med 153(6 Pt 1):1985–1987

    Article  PubMed  CAS  Google Scholar 

  • Li H, Forstermann U (2000) Nitric oxide in the pathogenesis of vascular disease. J Pathol 190(3):244–254

    Article  PubMed  CAS  Google Scholar 

  • Li D, Zhou N et al (1999) Soluble guanylate cyclase gene expression and localization in rat lung after exposure to hypoxia. Am J Physiol 277(4 Pt 1):L841–L847

    PubMed  CAS  Google Scholar 

  • List BM, Klosch B et al (1997) Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization. Biochem J 323(Pt 1):159–165

    PubMed  CAS  Google Scholar 

  • Liu L, Hausladen A et al (2001) A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410(6827):490–494

    Article  PubMed  CAS  Google Scholar 

  • Liu L, Yan Y et al (2004) Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell 116(4):617–628

    Article  PubMed  CAS  Google Scholar 

  • Liu JQ, Zelko IN et al (2006) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290(1):L2–L10

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Gai Y et al (2010) Trimetazidine inhibits pressure overload-induced cardiac fibrosis through NADPH oxidase-ROS-CTGF pathway. Cardiovasc Res 88(1):150–158

    Article  PubMed  CAS  Google Scholar 

  • Lu X, Murphy TC et al (2010) 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(4):L559–L566

    Article  PubMed  CAS  Google Scholar 

  • Lundberg JO, Weitzberg E et al (2008) The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 7(2):156–167

    Article  PubMed  CAS  Google Scholar 

  • Lundberg JO, Gladwin MT et al (2009) Nitrate and nitrite in biology, nutrition and therapeutics. Nat Chem Biol 5(12):865–869

    Article  PubMed  CAS  Google Scholar 

  • Machado RF, Anthi A et al (2006) N-terminal pro-brain natriuretic peptide levels and risk of death in sickle cell disease. JAMA 296(3):310–318

    Article  PubMed  CAS  Google Scholar 

  • Machado RF, Hildescheim M et al (2009) NT-pro brain natriuretic peptide levels and the risk of stroke and death in the cooperative study of sickle cell disease. Blood 114:1541

    Google Scholar 

  • Malhotra R, Hess D et al (2011) Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension. Pulm Circ 1(2):250–258

    Article  PubMed  CAS  Google Scholar 

  • Markewitz BA, Michael JR (2000) Inhaled nitric oxide in adults with the acute respiratory distress syndrome. Respir Med 94(11):1023–1028

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin VV, Archer SL et al (2009a) ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 53(17):1573–1619

    Article  PubMed  Google Scholar 

  • McLaughlin VV, Archer SL et al (2009b) ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 119(16):2250–2294

    Article  PubMed  Google Scholar 

  • Mehari A, Gladwin MT et al (2012) Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 307(12):1254–1256

    Article  PubMed  CAS  Google Scholar 

  • Mehta S, Stewart DJ et al (1995) Short-term pulmonary vasodilation with L-arginine in pulmonary hypertension. Circulation 92(6):1539–1545

    Article  PubMed  CAS  Google Scholar 

  • Meyer C, Heiss C et al (2010) Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function. J Am Coll Cardiol 55(5):454–459

    Article  PubMed  CAS  Google Scholar 

  • Miller OI, Tang SF et al (1995) Rebound pulmonary hypertension on withdrawal from inhaled nitric oxide. Lancet 346(8966):51–52

    Article  PubMed  CAS  Google Scholar 

  • Minneci PC, Deans KJ et al (2005) Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin. J Clin Invest 115(12):3409–3417

    Article  PubMed  CAS  Google Scholar 

  • Minniti CP, Sable C et al (2009) Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation. Haematologica 94(3):340–347

    Article  PubMed  CAS  Google Scholar 

  • Mittal M, Roth M et al (2007) Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 101(3):258–267

    Article  PubMed  CAS  Google Scholar 

  • Mittendorf J, Weigand S et al (2009) Discovery of riociguat (BAY 63-2521): a potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 4(5):853–865

    Article  PubMed  CAS  Google Scholar 

  • Modin A, Bjorne H et al (2001) Nitrite-derived nitric oxide: a possible mediator of ‘acidic-metabolic’ vasodilation. Acta Physiol Scand 171(1):9–16

    PubMed  CAS  Google Scholar 

  • Morris CR, Morris SM Jr et al (2003) Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 168(1):63–69

    Article  PubMed  Google Scholar 

  • Morris CR, Kato GJ et al (2005) Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 294(1):81–90

    Article  PubMed  CAS  Google Scholar 

  • Morris CR, Gladwin MT et al (2008) Nitric oxide and arginine dysregulation: a novel pathway to pulmonary hypertension in hemolytic disorders. Curr Mol Med 8(7):620–632

    Article  PubMed  CAS  Google Scholar 

  • Moya MP, Gow AJ et al (2002) Inhaled ethyl nitrite gas for persistent pulmonary hypertension of the newborn. Lancet 360(9327):141–143

    Article  PubMed  CAS  Google Scholar 

  • Munzel T, Giaid A et al (1995a) Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance. Proc Natl Acad Sci USA 92(11):5244–5248

    Article  PubMed  CAS  Google Scholar 

  • Munzel T, Sayegh H et al (1995b) Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest 95(1):187–194

    Article  PubMed  CAS  Google Scholar 

  • Munzel T, Kurz S et al (1996) Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest 98(6):1465–1470

    Article  PubMed  CAS  Google Scholar 

  • Nagaya N, Uematsu M et al (2001) Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med 163(4):887–891

    Article  PubMed  CAS  Google Scholar 

  • Namachivayam P, Theilen U et al (2006) Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric oxide in children. Am J Respir Crit Care Med 174(9):1042–1047

    Article  PubMed  CAS  Google Scholar 

  • Nandi M, Miller A et al (2005) Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse. Circulation 111(16):2086–2090

    Article  PubMed  CAS  Google Scholar 

  • Naoman SG, Nouraie M et al (2010) Echocardiographic findings in patients with sickle cell disease. Ann Hematol 89(1):61–66

    Article  PubMed  Google Scholar 

  • Nisbet RE, Bland JM et al (2010) Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 42(4):482–490

    Article  PubMed  CAS  Google Scholar 

  • Nisimoto Y, Motalebi S et al (1999) The p67(phox) activation domain regulates electron flow from NADPH to flavin in flavocytochrome b(558). J Biol Chem 274(33):22999–23005

    Article  PubMed  CAS  Google Scholar 

  • Nolan VG, Wyszynski DF et al (2005) Hemolysis associated priapism in sickle cell disease. Blood 106(9):3264–3267

    Article  PubMed  CAS  Google Scholar 

  • Nolan VG, Adewoye A et al (2006) Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol 133(5):570–578

    Article  PubMed  CAS  Google Scholar 

  • Nong Z, Stassen JM et al (1996) Inhibition of tissue angiotensin-converting enzyme with quinapril reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Circulation 94(8):1941–1947

    Article  PubMed  CAS  Google Scholar 

  • Nozik-Grayck E, Suliman HB et al (2008) Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 295(3):L422–L430

    Article  PubMed  CAS  Google Scholar 

  • Oak JH, Cai H (2007) Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice. Diabetes 56(1):118–126

    Article  PubMed  CAS  Google Scholar 

  • Onyekwere OC, Campbell A et al (2008) Pulmonary hypertension in children and adolescents with sickle cell disease. Pediatr Cardiol 29(2):309–312

    Article  PubMed  CAS  Google Scholar 

  • Oudiz RJ, Brundage BH et al (2012) Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study. J Am Coll Cardiol 60(8):768–774

    Article  PubMed  CAS  Google Scholar 

  • Ozaki M, Kawashima S et al (2002) Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 110(3):331–340

    PubMed  CAS  Google Scholar 

  • Pagano PJ, Clark JK et al (1997) Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc Natl Acad Sci USA 94(26):14483–14488

    Article  PubMed  CAS  Google Scholar 

  • Palmer RM, Ferrige AG et al (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327(6122):524–526

    Article  PubMed  CAS  Google Scholar 

  • Palmer RM, Ashton DS et al (1988) Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333(6174):664–666

    Article  PubMed  CAS  Google Scholar 

  • Parent F, Bachir D et al (2011) A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med 365(1):44–53

    Article  PubMed  CAS  Google Scholar 

  • Pearson DL, Dawling S et al (2001) Neonatal pulmonary hypertension – urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med 344(24):1832–1838

    Article  PubMed  CAS  Google Scholar 

  • Quyyumi AA, Dakak N et al (1995) Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis. J Clin Invest 95(4):1747–1755

    Article  PubMed  CAS  Google Scholar 

  • Rabinovitch M (2008) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 118(7):2372–2379

    Article  PubMed  CAS  Google Scholar 

  • Rassaf T, Flogel U et al (2007) Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function. Circ Res 100(12):1749–1754

    Article  PubMed  CAS  Google Scholar 

  • Reiter CD, Wang X et al (2002) Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8(12):1383–1389

    Article  PubMed  CAS  Google Scholar 

  • Robbins IM, Hemnes AR et al (2011) Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension. Exp Lung Res 37(1):26–34

    Article  PubMed  CAS  Google Scholar 

  • Roberts JD Jr, Fineman JR et al (1997) Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med 336(9):605–610

    Article  PubMed  CAS  Google Scholar 

  • Rossaint R, Falke KJ et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328(6):399–405

    Article  PubMed  CAS  Google Scholar 

  • Rother RP, Bell L et al (2005) The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293(13):1653–1662

    Article  PubMed  CAS  Google Scholar 

  • Sachdev V, Kato GJ et al (2011) Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom. Circulation 124(13):1452–1460

    Article  PubMed  CAS  Google Scholar 

  • Sanders KA, Hoidal JR (2007) The NOX on pulmonary hypertension. Circ Res 101(3):224–226

    Article  PubMed  CAS  Google Scholar 

  • Sanghani PC, Davis WI et al (2009) Kinetic and cellular characterization of novel inhibitors of S-nitrosoglutathione reductase. J Biol Chem 284(36):24354–24362

    Article  PubMed  CAS  Google Scholar 

  • Schnog JB, Teerlink T et al (2005) Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease. Ann Hematol 84(5):282–286

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Kumar S et al (2009) Alterations in lung arginine metabolism in lambs with pulmonary hypertension associated with increased pulmonary blood flow. Vascul Pharmacol 51(5–6):359–364

    Article  PubMed  CAS  Google Scholar 

  • Shiva S, Gladwin MT (2009) Shining a light on tissue NO stores: near infrared release of NO from nitrite and nitrosylated hemes. J Mol Cell Cardiol 46(1):1–3

    Article  PubMed  CAS  Google Scholar 

  • Shiva S, Huang Z et al (2007) Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration. Circ Res 100(5):654–661

    Article  PubMed  CAS  Google Scholar 

  • Sitbon O, Humbert M et al (1998) Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J 12(2):265–270

    Article  PubMed  CAS  Google Scholar 

  • Sitbon O, Humbert M et al (2005) Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111(23):3105–3111

    Article  PubMed  CAS  Google Scholar 

  • Spiekermann S, Schenk K et al (2009) Increased xanthine oxidase activity in idiopathic pulmonary arterial hypertension. Eur Respir J 34(1):276

    Article  PubMed  CAS  Google Scholar 

  • Stasch JP, Becker EM et al (2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410(6825):212–215

    Article  PubMed  CAS  Google Scholar 

  • Stewart DJ, Levy RD et al (1991) Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 114(6):464–469

    Article  PubMed  CAS  Google Scholar 

  • Sturrock A, Cahill B et al (2006) 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(4):L661–L673

    Article  PubMed  CAS  Google Scholar 

  • Sutendra G, Bonnet S et al (2010) Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med 2(44):44ra58

    Article  PubMed  CAS  Google Scholar 

  • Sutliff RL, Kang BY et al (2010) PPARgamma as a potential therapeutic target in pulmonary hypertension. Ther Adv Respir Dis 4(3):143–160

    Article  PubMed  CAS  Google Scholar 

  • Sydow K, Daiber A et al (2004) Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J Clin Invest 113(3):482–489

    PubMed  CAS  Google Scholar 

  • Tabima DM, Frizzell S et al (2012) Reactive oxygen and nitrogen species in pulmonary hypertension. Free Radic Biol Med 52(9):1970–1986

    Article  PubMed  CAS  Google Scholar 

  • Takeya R, Sumimoto H (2003) Molecular mechanism for activation of superoxide-producing NADPH oxidases. Mol Cells 16(3):271–277

    PubMed  CAS  Google Scholar 

  • Teng RJ, Du J et al (2011) Sepiapterin improves angiogenesis of pulmonary artery endothelial cells with in utero pulmonary hypertension by recoupling endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 301(3):L334–L345

    Article  PubMed  CAS  Google Scholar 

  • Tian J, Smith A et al (2009) Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: gene profiling in pulmonary hypertension. Physiol Genomics 40(1):48–60

    Article  PubMed  CAS  Google Scholar 

  • Tiso M, Tejero J et al (2011) Human neuroglobin functions as a redox-regulated nitrite reductase. J Biol Chem 286(20):18277–18289

    Article  PubMed  CAS  Google Scholar 

  • Tofovic SP, Jackson EK et al (2009) Adenosine deaminase-adenosine pathway in hemolysis-associated pulmonary hypertension. Med Hypotheses 72(6):713–719

    Article  PubMed  CAS  Google Scholar 

  • Tota B, Quintieri AM et al (2010) The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function. Curr Med Chem 17(18):1915–1925

    Article  PubMed  CAS  Google Scholar 

  • Tuder RM, Groves B et al (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 144(2):275–285

    PubMed  CAS  Google Scholar 

  • Vachiery JL, Huez S et al (2011) Safety, tolerability and pharmacokinetics of an intravenous bolus of sildenafil in patients with pulmonary arterial hypertension. Br J Clin Pharmacol 71(2):289–292

    Article  PubMed  CAS  Google Scholar 

  • Venema VJ, Zou R et al (1997) Caveolin-1 detergent solubility and association with endothelial nitric oxide synthase is modulated by tyrosine phosphorylation. Biochem Biophys Res Commun 236(1):155–161

    Article  PubMed  CAS  Google Scholar 

  • Vignais PV (2002) The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci 59(9):1428–1459

    Article  PubMed  CAS  Google Scholar 

  • Vosatka RJ, Kashyap S et al (1994) Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate 66(2–3):65–70

    PubMed  CAS  Google Scholar 

  • Voskaridou E, Christoulas D et al (2010) The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood 115(12):2354–2363

    Article  PubMed  CAS  Google Scholar 

  • Wedgwood S, Black SM (2003) Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension. Antioxid Redox Signal 5(6):759–769

    Article  PubMed  CAS  Google Scholar 

  • Wedgwood S, Bekker JM et al (2001) Shear stress regulation of endothelial NOS in fetal pulmonary arterial endothelial cells involves PKC. Am J Physiol Lung Cell Mol Physiol 281(2):L490–L498

    PubMed  CAS  Google Scholar 

  • Wedgwood S, Steinhorn RH et al (2005) 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(4):L660–L666

    Article  PubMed  CAS  Google Scholar 

  • Weerackody RP, Welsh DJ et al (2009) Inhibition of p38 MAPK reverses hypoxia-induced pulmonary artery endothelial dysfunction. Am J Physiol Heart Circ Physiol 296(5):H1312–H1320

    Article  PubMed  CAS  Google Scholar 

  • Weinberger B, Laskin DL et al (2001) The toxicology of inhaled nitric oxide. Toxicol Sci 59(1):5–16

    Article  PubMed  CAS  Google Scholar 

  • Wenzel P, Schulz E et al (2008) AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats. Free Radic Biol Med 45(5):619–626

    Article  PubMed  CAS  Google Scholar 

  • Whalen EJ, Foster MW et al (2007) Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129(3):511–522

    Article  PubMed  CAS  Google Scholar 

  • Williamson JR, Chang K et al (1993) Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42(6):801–813

    Article  PubMed  CAS  Google Scholar 

  • Wolin MS (2009) Reactive oxygen species and the control of vascular function. Am J Physiol Heart Circ Physiol 296(3):H539–H549

    Article  PubMed  CAS  Google Scholar 

  • Wolin MS, Ahmad M et al (2005) The sources of oxidative stress in the vessel wall. Kidney Int 67(5):1659–1661

    Article  PubMed  CAS  Google Scholar 

  • Wood KC, Hebbel RP et al (2005) Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. FASEB J 19(8):989–991

    PubMed  CAS  Google Scholar 

  • Wood KC, Hsu LL et al (2008) Sickle cell disease vasculopathy: a state of nitric oxide resistance. Free Radic Biol Med 44(8):1506–1528

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Du L et al (2010) Increased nitrosoglutathione reductase activity in hypoxic pulmonary hypertension in mice. J Pharmacol Sci 113(1):32–40

    Article  PubMed  CAS  Google Scholar 

  • Wunderlich C, Schober K et al (2008) The adverse cardiopulmonary phenotype of caveolin-1 deficient mice is mediated by a dysfunctional endothelium. J Mol Cell Cardiol 44(5):938–947

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Kaneko FT et al (2004) Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J 18(14):1746–1748

    PubMed  CAS  Google Scholar 

  • Yeo TW, Lampah DA et al (2007) Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med 204(11):2693–2704

    Article  PubMed  CAS  Google Scholar 

  • Yeo TW, Lampah DA et al (2009) Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria. J Infect Dis 200(10):1522–1529

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Chen Z et al (2004) Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels: an intact canine model. Circulation 110(6):750–755

    Article  PubMed  CAS  Google Scholar 

  • Zhao YY, Zhao YD et al (2009) Persistent eNOS activation secondary to caveolin-1 deficiency induces pulmonary hypertension in mice and humans through PKG nitration. J Clin Invest 119(7):2009–2018

    Article  PubMed  CAS  Google Scholar 

  • Zisman DA, Schwarz M et al (2010) A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 363(7):620–628

    Article  PubMed  Google Scholar 

  • Zuckerbraun BS, Stoyanovsky DA et al (2007) Nitric oxide-induced inhibition of smooth muscle cell proliferation involves S-nitrosation and inactivation of RhoA. Am J Physiol Cell Physiol 292(2):C824–C831

    Article  PubMed  CAS  Google Scholar 

  • Zuckerbraun BS, Shiva S et al (2010) Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation 121(1):98–109

    Article  PubMed  CAS  Google Scholar 

  • Zuckerbraun BS, George P et al (2011) Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling. Cardiovasc Res 89(3):542–552

    Article  PubMed  CAS  Google Scholar 

  • Zulueta JJ, Sawhney R et al (2002) Modulation of inducible nitric oxide synthase by hypoxia in pulmonary artery endothelial cells. Am J Respir Cell Mol Biol 26(1):22–30

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Michael G. Risbano & Mark T. Gladwin

  2. Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Michael G. Risbano & Mark T. Gladwin

Authors
  1. Michael G. Risbano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark T. Gladwin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark T. Gladwin .

Editor information

Editors and Affiliations

  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Risbano, M.G., Gladwin, M.T. (2013). Therapeutics Targeting of Dysregulated Redox Equilibrium and Endothelial Dysfunction. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_13

Download citation

Publish with us

Policies and ethics

Search

Navigation