The metabolic theory of pulmonary arterial hypertension

Circulation Research

Volumn 115, Issue 1, 2014, Pages 148-164

  Paulin, Roxane ^a   Michelakis, Evangelos D ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

Author keywords

hypertension, pulmonary; metabolism; mitochondria

Indexed keywords

BIOLOGICAL MARKER; ENDOTHELIN 1;

APOPTOSIS; ARTICLE; CELL PROLIFERATION; GLUCOSE OXIDATION; GLYCOLYSIS; HEART MUSCLE CELL; HEART RIGHT VENTRICLE; HUMAN; IMMUNOCOMPETENT CELL; METABOLIC DISORDER; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PULMONARY ARTERY; PULMONARY HYPERTENSION; SIGNAL TRANSDUCTION; THEORETICAL STUDY; UPREGULATION;

HYPERTENSION, PULMONARY; METABOLISM; MITOCHONDRIA;

ANIMALS; APOPTOSIS; ENDOPLASMIC RETICULUM STRESS; GLUCOSE; HEART VENTRICLES; HUMANS; HYPERTENSION, PULMONARY; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; ION CHANNELS; MITOCHONDRIA; MITOCHONDRIAL PROTEINS; MUSCLE, SMOOTH, VASCULAR; MYOCYTES, SMOOTH MUSCLE; PULMONARY ARTERY; SIGNAL TRANSDUCTION;

EID: 84902968590     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.115.301130     Document Type: Article

References (188)

1. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186:261-272.
2. West J, Niswender KD, Johnson JA, Pugh ME, Gleaves L, Fessel JP, Hemnes AR. A potential role for insulin resistance in experimental pulmonary hypertension. Eur Respir J. 2013;41:861-871.
3. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012;122:4306-4313.
4. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation. 2010;121:2045-2066.
5. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029-1033.
6. Dromparis P, Michelakis ED. Mitochondria in vascular health and disease. Annu Rev Physiol. 2013;75:95-126.
7. Sutendra G, Michelakis ED. Pulmonary arterial hypertension: challenges in translational research and a vision for change. Sci Transl Med. 2013;5:208sr5.
8. Jerkic M, Kabir MG, Davies A, Yu LX, McIntyre BA, Husain NW, Enomoto M, Sotov V, Husain M, Henkelman M, Belik J, Letarte M. Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress. Cardiovasc Res. 2011;92:375-384.
9. Trembath RC, Thomson JR, Machado RD, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001;345:325-334.
10. Said SI, Hamidi SA, Dickman KG, Szema AM, Lyubsky S, Lin RZ, Jiang YP, Chen JJ, Waschek JA, Kort S. Moderate pulmonary arterial hypertension in male mice lacking the vasoactive intestinal peptide gene. Circulation. 2007;115:1260-1268.
11. Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J. 2008;31:135-139.
12. Hoshikawa Y, Voelkel NF, Gesell TL, Moore MD, Morris KG, Alger LA, Narumiya S, Geraci MW. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med. 2001;164:314-318.
13. Cogolludo A, Moreno L, Bosca L, Tamargo J, Perez-Vizcaino F. Thromboxane A2-induced inhibition of voltage-gated K+ channels and pulmonary vasoconstriction: role of protein kinase Czeta. Circ Res. 2003;93:656-663.
14. Nagata T, Uehara Y, Hara K, Igarashi K, Hazama H, Hisada T, Kimura K, Goto A, Omata M. Thromboxane inhibition and monocrotaline-induced pulmonary hypertension in rats. Respirology. 1997;2:283-289.
15. Todorovich-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis. 1992;146:213-223.
16. Cowan KN, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med. 2000;6:698-702.
17. Tian W, Jiang X, Tamosiuniene R, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013;5:200ra117.
18. Abe K, Shimokawa H, Morikawa K, Uwatoku T, Oi K, Matsumoto Y, Hattori T, Nakashima Y, Kaibuchi K, Sueishi K, Takeshit A. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 2004;94:385-393.
19. Fagan KA, Oka M, Bauer NR, Gebb SA, Ivy DD, Morris KG, McMurtry IF. Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. Am J Physiol Lung Cell Mol Physiol. 2004;287:L656-L664.
20. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001;108:1141-1150.
21. Yeager ME, Belchenko DD, Nguyen CM, Colvin KL, Ivy DD, Stenmark KR. Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2012;46:14-22.
22. Paulin R, Courboulin A, Meloche J, Mainguy V, Dumas de la Roque E, Saksouk N, Côté J, Provencher S, Sussman MA, Bonnet S. Signal transducers and activators of transcription-3/pim1 axis plays a critical role in the pathogenesis of human pulmonary arterial hypertension. Circulation. 2011;123:1205-1215.
23. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732-1739.
24. Nong Z, Stassen JM, Moons L, Collen D, Janssens S. Inhibition of tissue angiotensin-converting enzyme with quinapril reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling. Circulation. 1996;94:1941-1947.
25. Farrow KN, Wedgwood S, Lee KJ, Czech L, Gugino SF, Lakshminrusimha S, Schumacker PT, Steinhorn RH. Mitochondrial oxidant stress increases PDE5 activity in persistent pulmonary hypertension of the newborn. Respir Physiol Neurobiol. 2010;174:272-281.
26. Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S, Carruba MO. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science. 2003;299:896-899.
27. Zuckerbraun BS, George P, Gladwin MT. Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/ nitric oxide synthase signalling. Cardiovasc Res. 2011;89:542-552.
28. Wharton J, Strange JW, Møller GM, Growcott EJ, Ren X, Franklyn AP, Phillips SC, Wilkins MR. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med. 2005;172:105-113.
29. Archer SL, Michelakis ED. Phosphodiesterase type 5 inhibitors for pulmonary arterial hypertension. N Engl J Med. 2009;361:1864-1871.
30. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330-340.
31. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214-221.
32. Attané C, Foussal C, Le Gonidec S, et al. Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes. 2012;61:310-320.
33. Chandra SM, Razavi H, Kim J, Agrawal R, Kundu RK, de Jesus Perez V, Zamanian RT, Quertermous T, Chun HJ. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2011;31:814-820.
34. Meloche J, Courchesne A, Barrier M, et al. Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology. J Am Heart Assoc. 2013;2:e005157.
35. Greenway S, van Suylen RJ, Du Marchie Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, Rabinovitch M. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol. 2004;164:253-262.
36. Courboulin A, Paulin R, Giguère NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Côté J, Simard MJ, Bonnet S. Role for miR-204 in human pulmonary arterial hypertension. J Exp Med. 2011;208:535-548.
37. Caruso P, Dempsie Y, Stevens HC, et al. A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res. 2012;111:290-300.
38. Rabinovitch M. PPARgamma and the pathobiology of pulmonary arterial hypertension. Adv Exp Med Biol. 2010;661:447-458.
39. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA, III, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet. 2000;26:81-84.
40. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation. 2002;105:1672-1678.
41. Wilkins MR, Gibbs JS, Shovlin CL. A gene for primary pulmonary hypertension. Lancet. 2000;356:1207-1208.
42. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med. 2013;19:557-566.
43. Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. 2007;115:1275-1284.
44. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest. 2008;118:1846-1857.
45. Ihalainen S, Soliymani R, Iivanainen E, Mykkänen K, Sainio A, Pöyhönen M, Elenius K, Järveläinen H, Viitanen M, Kalimo H, Baumann M. Proteome analysis of cultivated vascular smooth muscle cells from a CADASIL patient. Mol Med. 2007;13:305-314.
46. Li X, Zhang X, Leathers R, Makino A, Huang C, Parsa P, Macias J, Yuan JX, Jamieson SW, Thistlethwaite PA. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat Med. 2009;15:1289-1297.
47. Park MT, Choi JA, Kim MJ, Um HD, Bae S, Kang CM, Cho CK, Kang S, Chung HY, Lee YS, Lee SJ. Suppression of extracellular signal-related kinase and activation of p38 MAPK are two critical events leading to caspase- 8- and mitochondria-mediated cell death in phytosphingosine-treated human cancer cells. J Biol Chem. 2003;278:50624-50634.
48. Welsh DJ, Peacock AJ, MacLean M, Harnett M. Chronic hypoxia induces constitutive p38 mitogen-activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries. Am J Respir Crit Care Med. 2001;164:282-289.
49. Patel M, Predescu D, Tandon R, Bardita C, Pogoriler J, Bhorade S, Wang M, Comhair S, Hemnes AR, Ryan-Hemnes A, Chen J, Machado R, Husain A, Erzurum S, Predescu S. A novel p38 mitogen-activated protein kinase/ Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension. J Biol Chem. 2013;288:25701-25716.
50. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703-707.
51. Mizuno S, Bogaard HJ, Kraskauskas D, Alhussaini A, Gomez-Arroyo J, Voelkel NF, Ishizaki T. p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice. Am J Physiol Lung Cell Mol Physiol. 2011;300:L753-L761.
52. Fouty BW, Grimison B, Fagan KA, Le Cras TD, Harral JW, Hoedt-Miller M, Sclafani RA, Rodman DM. p27(Kip1) is important in modulating pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol. 2001;25:652-658.
53. Kanno S, Wu YJ, Lee PC, Billiar TR, Ho C. Angiotensin-converting enzyme inhibitor preserves p21 and endothelial nitric oxide synthase expression in monocrotaline-induced pulmonary arterial hypertension in rats. Circulation. 2001;104:945-950.
54. Hitosugi T, Fan J, Chung TW, et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol Cell. 2011;44:864-877.
55. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation. 2005;112:423-431.
56. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005;115:2811-2821.
57. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009;324:1076-1080.
58. Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17-30.
59. Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wang D, Li M, McKinsey TA, Stenmark KR, Wilkins MR. Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation. 2012;126:455-467.
60. Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009;10:273-284.
61. Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS, Wharton J, Wilkins MR. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol. 2011;58:300-309.
62. Rhodes CJ, Wharton J, Howard L, Gibbs JS, Vonk-Noordegraaf A, Wilkins MR. Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur Respir J. 2011;38:1453-1460.
63. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest. 2005;115:1479-1491.
64. Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, Lopaschuk GD, Puttagunta L, Waite R, Archer SL. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltagegated potassium channels. Circulation. 2002;105:244-250.
65. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004;95:830-840.
66. Sutendra G, Bonnet S, Rochefort G, Haromy A, Folmes KD, Lopaschuk GD, Dyck JR, Michelakis ED. Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension. Sci Transl Med. 2010;2:44ra58.
67. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. 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. 2006;113:2630-2641.
68. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thébaud B, Husain AN, Cipriani N, Rehman J. Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation. 2010;121:2661-2671.
69. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A. 2007;104:11418-11423.
70. Archer SL, Souil E, Dinh-Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, Nguyen-Huu L, Reeve HL, Hampl V. Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest. 1998;101:2319-2330.
71. Yuan XJ, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet. 1998;351:726-727.
72. Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X, Fang YH, Thenappan T, Piao L, Zhang HJ, Pogoriler J, Chen Y, Morrow E, Weir EK, Rehman J, Archer SL. Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res. 2012;110:1484-1497.
73. Ryan JJ, Marsboom G, Fang YH, Toth PT, Morrow E, Luo N, Piao L, Hong Z, Ericson K, Zhang HJ, Han M, Haney CR, Chen CT, Sharp WW, Archer SL. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187:865-878.
74. Sutendra G, Dromparis P, Wright P, Bonnet S, Haromy A, Hao Z, McMurtry MS, Michalak M, Vance JE, Sessa WC, Michelakis ED. The role of Nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci Transl Med. 2011;3:88ra55.
75. Dromparis P, Paulin R, Stenson TH, Haromy A, Sutendra G, Michelakis ED. Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension. Circulation. 2013;127:115-125.
76. Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED. Uncoupling protein 2 deficiency mimics the effects of hypoxia and endoplasmic reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vascular remodeling and pulmonary hypertension. Circ Res. 2013;113:126-136.
77. Pak O, Sommer N, Hoeres T, et al. Mitochondrial hyperpolarization in pulmonary vascular remodeling. Mitochondrial uncoupling protein deficiency as disease model. Am J Respir Cell Mol Biol. 2013; 49:358-367.
78. Sutendra G, Michelakis ED. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front Oncol. 2013;3:38.
79. Zamzami N, Marchetti P, Castedo M, Hirsch T, Susin SA, Masse B, Kroemer G. Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett. 1996;384:53-57.
80. Zamzami N, Kroemer G. The mitochondrion in apoptosis: how Pandora's box opens. Nat Rev Mol Cell Biol. 2001;2:67-71.
81. Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11:37-51.
82. Pastorino JG, Hoek JB, Shulga N. Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapyinduced cytotoxicity. Cancer Res. 2005;65:10545-10554.
83. Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005;5:472-484.
84. Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED. A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med (Berl). 2013;91:1315-1327.
85. Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J, Chen CT, Archer SL. Lung 18F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;185:670-679.
86. Platoshyn O, Golovina VA, Bailey CL, Limsuwan A, Krick S, Juhaszova M, Seiden JE, Rubin LJ, Yuan JX. Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation. Am J Physiol Cell Physiol. 2000;279:C1540-C1549.
87. Huang LE, Arany Z, Livingston DM, Bunn HF. Activation of hypoxiainducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem. 1996;271:32253-32259.
88. MacKenzie ED, Selak MA, Tennant DA, Payne LJ, Crosby S, Frederiksen CM, Watson DG, Gottlieb E. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol. 2007;27:3282-3289.
89. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM. Hypoxia inducible- factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol. 2010; 176:1130-1138.
90. Ward JP. Point: hypoxic pulmonary vasoconstriction is mediated by increased production of reactive oxygen species. J Appl Physiol (1985). 2006;101:993-995; discussion 999.
91. Weir EK, Archer SL. Counterpoint: hypoxic pulmonary vasoconstriction is not mediated by increased production of reactive oxygen species. J Appl Physiol (1985). 2006;101:995-998.
92. Waypa GB, Marks JD, Guzy R, Mungai PT, Schriewer J, Dokic D, Schumacker PT. Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells. Circ Res. 2010;106:526-535.
93. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3:187-197.
94. Kepp O, Galluzzi L, Kroemer G. Mitochondrial control of the NLRP3 inflammasome. Nat Immunol. 2011;12:199-200.
95. Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851-860.
96. Shao W, Yeretssian G, Doiron K, Hussain SN, Saleh M. The caspase-1 digestome identifies the glycolysis pathway as a target during infection and septic shock. J Biol Chem. 2007;282:36321-36329.
97. Xu W, Koeck T, Lara AR, Neumann D, DiFilippo FP, Koo M, Janocha AJ, Masri FA, Arroliga AC, Jennings C, Dweik RA, Tuder RM, Stuehr DJ, Erzurum SC. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci U S A. 2007;104:1342-1347.
98. Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998;329 (Pt 1):191-196.
99. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL. 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. 2006;113:2630-2641.
100. Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med. 2010;181:158-167.
101. Farha S, Asosingh K, Xu W, Sharp J, George D, Comhair S, Park M, Tang WH, Loyd JE, Theil K, Tubbs R, Hsi E, Lichtin A, Erzurum SC. Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities. Blood. 2011;117:3485-3493.
102. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010;2:31ra34.
103. Piao L, Fang YH, Cadete VJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J, Lopaschuk GD, Archer SL. The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med (Berl). 2010;88:47-60.
104. Nagendran J, Gurtu V, Fu DZ, Dyck JR, Haromy A, Ross DB, Rebeyka IM, Michelakis ED. A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted. J Thorac Cardiovasc Surg. 2008;136:168-178, 178.e1.
105. Garland PB, Newsholme EA, Randle PJ. Effect of fatty acids, ketone bodies, diabetes and starvation on pyruvate metabolism in rat heart and diaphragm muscle. Nature. 1962;195:381-383.
106. Gellerich FN, Gizatullina Z, Trumbeckaite S, Nguyen HP, Pallas T, Arandarcikaite O, Vielhaber S, Seppet E, Striggow F. The regulation of OXPHOS by extramitochondrial calcium. Biochim Biophys Acta. 2010;1797:1018-1027.
107. Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA. A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell. 2006;124:573-586.
108. Rizzuto R, Duchen MR, Pozzan T. Flirting in little space: the ER/mitochondria Ca2+ liaison. Sci STKE. 2004;2004:re1.
109. Szabadkai G, Duchen MR. Mitochondria: the hub of cellular Ca2+ signaling. Physiology (Bethesda). 2008;23:84-94.
110. Sobolewski A, Rudarakanchana N, Upton PD, Yang J, Crilley TK, Trembath RC, Morrell NW. Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. Hum Mol Genet. 2008;17:3180-3190.
111. Sitbon O, Lascoux-Combe C, Delfraissy JF, Yeni PG, Raffi F, De Zuttere D, Gressin V, Clerson P, Sereni D, Simonneau G. Prevalence of HIVrelated pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med. 2008;177:108-113.
112. Sehgal PB, Mukhopadhyay S, Patel K, Xu F, Almodóvar S, Tuder RM, Flores SC. Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques. Am J Physiol Lung Cell Mol Physiol. 2009;297:L729-L737.
113. Voelkel NF, Cool CD, Flores S. From viral infection to pulmonary arterial hypertension: a role for viral proteins?. AIDS. 2008;22(suppl 3):S49-S53.
114. Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med. 2003;349:1113-1122.
115. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010;140:900-917.
116. Yeager ME, Reddy MB, Nguyen CM, Colvin KL, Ivy DD, Stenmark KR. Activation of the unfolded protein response is associated with pulmonary hypertension. Pulm Circ. 2012;2:229-240.
117. Smith P, Heath D. Electron microscopy of the plexiform lesion. Thorax. 1979;34:177-186.
118. Hansmann G, Zamanian RT. PPARgamma activation: a potential treatment for pulmonary hypertension. Sci Transl Med. 2009;1:12ps14.
119. Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, Koskenvuo M, Wang L, Freeman BA, Chang HY, Rabinovitch M. Disruption of PPARγ/β- catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest. 2011;121:3735-3746.
120. Frier BC, Williams DB, Wright DC. The effects of apelin treatment on skeletal muscle mitochondrial content. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1761-R1768.
121. Archer SL. Mitochondrial dynamics-mitochondrial fission and fusion in human diseases. N Engl J Med. 2013;369:2236-2251.
122. Picard M, Shirihai OS, Gentil BJ, Burelle Y. Mitochondrial morphology transitions and functions: implications for retrograde signaling?. Am J Physiol Regul Integr Comp Physiol. 2013;304:R393-R406.
123. Dimmer KS, Scorrano L. (De)constructing mitochondria: what for?. Physiology (Bethesda). 2006;21:233-241.
124. Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, Salgia R, Husain AN, Wietholt C, Archer SL. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J. 2012;26:2175-2186.
125. Jheng HF, Tsai PJ, Guo SM, Kuo LH, Chang CS, Su IJ, Chang CR, Tsai YS. Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol. 2012;32:309-319.
126. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, Smith CL, Youle RJ. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell. 2001;1:515-525.
127. Parone PA, James DI, Da Cruz S, Mattenberger Y, Donzé O, Barja F, Martinou JC. Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis. Mol Cell Biol. 2006;26:7397-7408.
128. Michelakis ED. Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: heterogeneous BMP signaling may have therapeutic implications. Circ Res. 2006;98:172-175.
129. Ryan JJ, Marsboom G, Fang YH, Toth PT, Morrow E, Luo N, Piao L, Hong Z, Ericson K, Zhang HJ, Han M, Haney CR, Chen CT, Sharp WW, Archer SL. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187:865-878.
130. Twig G, Elorza A, Molina AJ, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433-446.
131. Sutendra G, Dromparis P, Bonnet S, Haromy A, McMurtry MS, Bleackley RC, Michelakis ED. Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension. J Mol Med (Berl). 2011;89:771-783.
132. Cannon B, Shabalina IG, Kramarova TV, Petrovic N, Nedergaard J. Uncoupling proteins: a role in protection against reactive oxygen species- or not?. Biochim Biophys Acta. 2006;1757:449-458.
133. Echtay KS. Mitochondrial uncoupling proteins-what is their physiological role?. Free Radic Biol Med. 2007;43:1351-1371.
134. Trenker M, Malli R, Fertschai I, Levak-Frank S, Graier WF. Uncoupling proteins 2 and 3 are fundamental for mitochondrial Ca2+ uniport. Nat Cell Biol. 2007;9:445-452.
135. Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi- Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997;15:269-272.
136. Derdák Z, Fülöp P, Sabo E, Tavares R, Berthiaume EP, Resnick MB, Paragh G, Wands JR, Baffy G. Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress. Carcinogenesis. 2006;27:956-961.
137. Fisler JS, Warden CH. Uncoupling proteins, dietary fat and the metabolic syndrome. Nutr Metab (Lond). 2006;3:38.
138. Vogler S, Goedde R, Miterski B, Gold R, Kroner A, Koczan D, Zettl UK, Rieckmann P, Epplen JT, Ibrahim SM. Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. J Mol Med (Berl). 2005;83:806-811.
139. Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W. A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes. 2002;51:3331-3335.
140. Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W. A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet. 2001;28:178-183.
141. Sasahara M, Nishi M, Kawashima H, Ueda K, Sakagashira S, Furuta H, Matsumoto E, Hanabusa T, Sasaki H, Nanjo K. Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes. 2004;53:482-485.
142. Oberkofler H, Iglseder B, Klein K, Unger J, Haltmayer M, Krempler F,
143. Yu X, Wieczorek S, Franke A, et al. Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases. Genes Immun. 2009;10:601-605.
144. Cheurfa N, Dubois-Laforgue D, Ferrarezi DA, Reis AF, Brenner GM, Bouché C, Le Feuvre C, Fumeron F, Timsit J, Marre M, Velho G. The common -866G A variant in the promoter of UCP2 is associated with decreased risk of coronary artery disease in type 2 diabetic men. Diabetes. 2008;57:1063-1068.
145. Dhamrait SS, Stephens JW, Cooper JA, Acharya J, Mani AR, Moore K, Miller GJ, Humphries SE, Hurel SJ, Montgomery HE. Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2. Eur Heart J. 2004;25:468-475.
146. Palmer BR, Devereaux CL, Dhamrait SS, Mocatta TJ, Pilbrow AP, Frampton CM, Skelton L, Yandle TG, Winterbourn CC, Richards AM, Montgomery HE, Cameron VA. The common G-866A polymorphism of the UCP2 gene and survival in diabetic patients following myocardial infarction. Cardiovasc Diabetol. 2009;8:31.
147. Rouault TA, Tong WH. Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis. Nat Rev Mol Cell Biol. 2005;6:345-351.
148. Rouault TA, Tong WH. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 2008;24:398-407.
149. Bogaard HJ, Abe K, Vonk Noordegraaf A, Voelkel NF. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest. 2009;135:794-804.
150. Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation. 2008;117:1717-1731.
151. McLaughlin VV, Archer SL, Badesch DB, et al; ACCF/AHA. 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. 2009;119:2250-2294.
152. Haddad F, Ashley E, Michelakis ED. New insights for the diagnosis and management of right ventricular failure, from molecular imaging to targeted right ventricular therapy. Curr Opin Cardiol. 2010;25: 131-140.
153. Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED. A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med (Berl). 2013;91:1315-1327.
154. Qipshidze N, Tyagi N, Metreveli N, Lominadze D, Tyagi SC. Autophagy mechanism of right ventricular remodeling in murine model of pulmonary artery constriction. Am J Physiol Heart Circ Physiol. 2012;302:H688-H696.
155. Enache I, Charles AL, Bouitbir J, Favret F, Zoll J, Metzger D, Oswald- Mammosser M, Geny B, Charloux A. Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension. Mol Cell Biochem. 2013;373:161-170.
156. Srivastava D. Making or breaking the heart: from lineage determination to morphogenesis. Cell. 2006;126:1037-1048.
157. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860-867.
158. Zamanian RT, Hansmann G, Snook S, Lilienfeld D, Rappaport KM, Reaven GM, Rabinovitch M, Doyle RL. Insulin resistance in pulmonary arterial hypertension. Eur Respir J. 2009;33:318-324.
159. Dorfmüller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22:358-363.
160. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest. 1998;114:225S-230S.
161. Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144:275-285.
162. Stenmark KR, Yeager ME, El Kasmi KC, Nozik-Grayck E, Gerasimovskaya EV, Li M, Riddle SR, Frid MG. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol. 2013;75:23-47.
163. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454.
164. Bargagli E, Galeazzi M, Bellisai F, Volterrani L, Rottoli P. Infliximab treatment in a patient with systemic sclerosis associated with lung fibrosis and pulmonary hypertension. Respiration. 2008;75:346-349.
165. Pugh ME, Robbins IM, Rice TW, West J, Newman JH, Hemnes AR. Unrecognized glucose intolerance is common in pulmonary arterial hypertension. J Heart Lung Transplant. 2011;30:904-911.
166. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, Wick M, Nemenoff RA, Geraci MW, Voelkel NF. Peroxisome proliferator- activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res. 2003;92:1162-1169.
167. Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G, Olson P, Wilkes J, Evans RM, Olefsky J. Muscle-specific Pparg deletion causes insulin resistance. Nat Med. 2003;9:1491-1497.
168. Lehrke M, Lazar MA. The many faces of PPARgamma. Cell. 2005;123:993-999.
169. Geraci MW, Moore M, Gesell T, Yeager ME, Alger L, Golpon H, Gao B, Loyd JE, Tuder RM, Voelkel NF. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res. 2001;88:555-562.
170. Greenow K, Pearce NJ, Ramji DP. The key role of apolipoprotein E in atherosclerosis. J Mol Med (Berl). 2005;83:329-342.
171. Durieux J, Wolff S, Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011;144:79-91.
172. He W, Miao FJ, Lin DC, Schwandner RT, Wang Z, Gao J, Chen JL, Tian H, Ling L. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature. 2004;429:188-193.
173. Bos R, van Der Hoeven JJ, van Der Wall E, van Der Groep P, van Diest PJ, Comans EF, Joshi U, Semenza GL, Hoekstra OS, Lammertsma AA, Molthoff CF. Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J Clin Oncol. 2002;20:379-387.
174. Zhao L, Ashek A, Wang L, et al. Heterogeneity in lung (18)FDG uptake in pulmonary arterial hypertension: potential of dynamic (18)FDG positron emission tomography with kinetic analysis as a bridging biomarker for pulmonary vascular remodeling targeted treatments. Circulation. 2013;128:1214-1224.
175. Can MM, Kaymaz C, Tanboga IH, Tokgoz HC, Canpolat N, Turkyilmaz E, Sonmez K, Ozdemir N. Increased right ventricular glucose metabolism in patients with pulmonary arterial hypertension. Clin Nucl Med. 2011;36:743-748.
176. Lundgrin EL, Park MM, Sharp J, Tang WH, Thomas JD, Asosingh K, Comhair SA, DiFilippo FP, Neumann DR, Davis L, Graham BB, Tuder RM, Dostanic I, Erzurum SC. Fasting 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography to detect metabolic changes in pulmonary arterial hypertension hearts over 1 year. Ann Am Thorac Soc. 2013;10:1-9.
177. Fang W, Zhao L, Xiong CM, Ni XH, He ZX, He JG, Wilkins MR. Comparison of 18F-FDG uptake by right ventricular myocardium in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. Pulm Circ. 2012;2:365-372.
178. Serkova NJ, Glunde K. Metabolomics of cancer. Methods Mol Biol. 2009;520:273-295.
179. Zuppi C, Messana I, Forni F, Rossi C, Pennacchietti L, Ferrari F, Giardina B. 1H NMR spectra of normal urines: reference ranges of the major metabolites. Clin Chim Acta. 1997;265:85-97.
180. Woo HM, Kim KM, Choi MH, Jung BH, Lee J, Kong G, Nam SJ, Kim S, Bai SW, Chung BC. Mass spectrometry based metabolomic approaches in urinary biomarker study of women's cancers. Clin Chim Acta. 2009;400:63-69.
181. Lindon JC, Holmes E, Bollard ME, Stanley EG, Nicholson JK. Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers. 2004;9:1-31.
182. Fessel JP, Hamid R, Wittmann BM, Robinson LJ, Blackwell T, Tada Y, Tanabe N, Tatsumi K, Hemnes AR, West JD. Metabolomic analysis of bone morphogenetic protein receptor type 2 mutations in human pulmonary endothelium reveals widespread metabolic reprogramming. Pulm Circ. 2012;2:201-213.
183. Phillips M, Gleeson K, Hughes JM, Greenberg J, Cataneo RN, Baker L, McVay WP. Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study. Lancet. 1999;353:1930-1933.
184. Phillips M, Cataneo RN, Ditkoff BA, Fisher P, Greenberg J, Gunawardena R, Kwon CS, Tietje O, Wong C. Prediction of breast cancer using volatile biomarkers in the breath. Breast Cancer Res Treat. 2006;99:19-21.
185. van de Kant KD, van der Sande LJ, Jobsis Q, van Schayck OC, Dompeling E. Clinical use of exhaled volatile organic compounds in pulmonary diseases: a systematic review. Respir Res. 2012;13:117.
186. Dymerski T, G?bicki J, Wi?niewska P, Sliwi?ska M, Wardencki W, Namie?nik J. Application of the electronic nose technique to differentiation between model mixtures with COPD markers. Sensors (Basel). 2013;13:5008-5027.
187. Samara MA, Tang WH, Cikach F Jr, Gul Z, Tranchito L, Paschke KM, Viterna J, Wu Y, Laskowski D, Dweik RA. Single exhaled breath metabolomic analysis identifies unique breathprint in patients with acute decompensated heart failure. J Am Coll Cardiol. 2013;61:1463-1464.
188. Michelakis ED, Wilkins MR, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation. 2008;118:1486-1495.