The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation

American Journal of Respiratory Cell and Molecular Biology

Volumn 47, Issue 5, 2012, Pages 718-726

  Green, David E ^a   Murphy, Tamara C ^a   Kang, Bum Yong ^a   Kleinhenz, Jennifer M ^a   Szyndralewiez, Cédric ^b   Page, Patrick ^b   Sutliff, Roy L ^a   Hart, C Michael ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b GENKYOTEX SA   (Switzerland)

Author keywords

PPAR ; Pulmonary hypertension; Rosiglitazone; TGF

Indexed keywords

GKT 137831; HYDROGEN PEROXIDE; MESSENGER RNA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; ROSIGLITAZONE; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTERIAL WALL THICKNESS; ARTICLE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EXPOSURE; ENDOTHELIUM CELL; HEART RIGHT VENTRICLE HYPERTROPHY; HYPOXIA; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PROTEIN EXPRESSION; PULMONARY ARTERY; PULMONARY HYPERTENSION; SMOOTH MUSCLE FIBER; SYSTOLIC BLOOD PRESSURE;

ANIMALS; CELL HYPOXIA; CELL PROLIFERATION; CELLS, CULTURED; ENDOTHELIAL CELLS; ENDOTHELIUM, VASCULAR; GENE EXPRESSION; GENE KNOCKDOWN TECHNIQUES; HUMANS; HYDROGEN PEROXIDE; HYPERTENSION, PULMONARY; LUNG; MICE; MICE, INBRED C57BL; MYOCYTES, SMOOTH MUSCLE; NADPH OXIDASE; PPAR GAMMA; PROLIFERATING CELL NUCLEAR ANTIGEN; PULMONARY ARTERY; PYRAZOLES; PYRIDINES; RNA INTERFERENCE; THIAZOLIDINEDIONES; TRANSFORMING GROWTH FACTOR BETA1; VENTRICULAR REMODELING;

MUS;

EID: 84868315535     PISSN: 10441549     EISSN: None     Source Type: Journal    
DOI: 10.1165/rcmb.2011-0418OC     Document Type: Article

References (50)

1. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156-163.
2. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation 2010;121:2045-2066.
3. Fresquet F, Pourageaud F, Leblais V, Brandes RP, Savineau JP, Marthan R, Muller B. Role of reactive oxygen species and gp91phox in endothelial dysfunction of pulmonary arteries induced by chronic hypoxia. Br J Pharmacol 2006;148:714-723.
4. Sorescu D, Weiss D, Lassegue B, Clempus RE, Szocs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, et al. Superoxide production and expression of nox family proteins in human atherosclerosis. Circulation 2002;105:1429-1435.
5. Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM. NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 2006;8:691-728.
6. Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ. Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 2006;290:L2-L10.
7. Bedard K, Krause KH. The Nox family of Ros-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 2007;87:245-313.
8. Lassegue B, Griendling KK. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol 2010;30: 653-661.
9. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK. Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2004;24:677-683.
10. Mittal M, Roth M, Konig P, Hofmann S, Dony E, Goyal P, Selbitz AC, Schermuly RT, Ghofrani HA, Kwapiszewska G, et al. Hypoxiadependent regulation of nonphagocytic NADPH oxidase subunit Nox4 in the pulmonary vasculature. Circ Res 2007;101:258-267.
11. Ahmad M, Kelly MR, Zhao X, Kandhi S, Wolin MS. Roles for Nox4 in the contractile response of bovine pulmonary arteries to hypoxia. Am J Physiol Heart Circ Physiol 2010;298:H1879-H1888.
12. Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, Sutliff RL, Hart CM. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 2010; 42:482-490.
13. Lu X, Murphy TC, Nanes MS, Hart CM. PPAR gamma regulates hypoxiainduced Nox4 expression in human pulmonary artery smooth muscle cells through NF-kappa B. Am J Physiol Lung Cell Mol Physiol 2010; 299:L559-L566.
14. Fukunaga Y, Itoh H, Doi K, Tanaka T, Yamashita J, Chun TH, Inoue M, Masatsugu K, Sawada N, Saito T, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001; 158:113-119.
15. 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.
16. de Dios ST, Bruemmer D, Dilley RJ, Ivey ME, Jennings GL, Law RE, Little PJ. Inhibitory activity of clinical thiazolidinedione peroxisome proliferator activating receptor-gamma ligands toward internal mammary artery, radial artery, and saphenous vein smooth muscle cell proliferation. Circulation 2003;107:2548-2550.
17. Kim EK, Lee JH, Oh YM, Lee YS, Lee SD. Rosiglitazone attenuates hypoxia-induced pulmonary arterial hypertension in rats. Respirology 2010;15:659-668.
18. Crossno JT Jr, Garat CV, Reusch JE, Morris KG, Dempsey EC, McMurtry IF, Stenmark KR, Klemm DJ. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol Lung Cell Mol Physiol 2007;292:L885-L897.
19. ten Freyhaus H, Huntgeburth M, Wingler K, Schnitker J, Baumer AT, VantlerM, BekhiteMM,Wartenberg M, Sauer H, Rosenkranz S. Novel Nox inhibitor VAS2870 attenuates PDGF-dependent smooth muscle cell chemotaxis, but not proliferation. Cardiovasc Res 2006;71:331-341.
20. Jaquet V, Scapozza L, Clark RA, Krause KH, Lambeth JD. Smallmolecule Nox inhibitors: ROS-generating NADPH oxidases as therapeutic targets. Antioxid Redox Signal 2009;11:2535-2552.
21. Aoyama TPY-H, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, et al. Nicotinamide adenine dinucleotide phosphate oxidase (Nox) in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology (In press)
22. Jiang JX, Chen X, Serizawa N, Szyndralewiez C, Page P, Schroder K, Brandes RP, Devaraj S, Torok NJ. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel Nox4/Nox1 inhibitor in vivo. Free Radic Biol Med 2012;2:289-296.
23. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A, Drazba J, Anand-Apte B, Erzurum SC. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:L548-L554.
24. Ismail S, Sturrock A, Wu P, Cahill B, Norman K, Huecksteadt T, Sanders K, Kennedy T, Hoidal J. Nox4 mediates hypoxia-induced proliferation of human pulmonary artery smooth muscle cells: the role of autocrine production of transforming growth factor-{beta}1 and insulin-like growth factor binding protein-3. Am J Physiol Lung Cell Mol Physiol 2009;296:L489-L499.
25. Diebold I, Petry A, Hess J, Gorlach A. The NADPH oxidase subunit Nox4 is a new target gene of the hypoxia-inducible factor-1. Mol Biol Cell 2010;21:2087-2096.
26. Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic Biol Med 2009;47:1239-1253.
27. Martyn KD, Frederick LM, von Loehneysen K, Dinauer MC, Knaus UG. Functional analysis of Nox4 reveals unique characteristics compared to other NADPH oxidases. Cell Signal 2006;18:69-82.
28. Sturrock A, Huecksteadt TP, Norman K, Sanders K, Murphy TM, Chitano P, Wilson K, Hoidal JR, Kennedy TP. Nox4 mediates TGFbeta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2007;292:L1543-L1555.
29. Sturrock A, Cahill B, Norman K, Huecksteadt TP, Hill K, Sanders K, Karwande SV, Stringham JC, Bull DA, Gleich M, et al. 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 2006;290:L661-L673.
30. Cucoranu I, Clempus R, Dikalova A, Phelan PJ, Ariyan S, Dikalov S, Sorescu D. NAD(P)H oxidase 4 mediates transforming growth factorbeta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res 2005;97:900-907.
31. Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, Phipps RP, Sime PJ. PPAR gamma agonists inhibit TGFbeta induced pulmonary myofibroblast differentiation and collagen production: implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2005;288:L1146-L1153.
32. Nicola T, Ambalavanan N, Zhang W, James ML, Rehan V, Halloran B, Olave N, Bulger A, Oparil S, Chen YF. Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferatoractivated receptor-gamma agonist rosiglitazone. Am J Physiol Lung Cell Mol Physiol 2011;301:L125-L134.
33. Gong K, Xing D, Li P, Aksut B, Ambalavanan N, Yang Q, Nozell SE, Oparil S, Chen YF. Hypoxia induces downregulation of PPAR{gamma} in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-beta signaling. Am J Physiol Lung Cell Mol Physiol 2011;301:L899-L907.
34. Borbely G, Szabadkai I, Horvath Z, Marko P, Varga Z, Breza N, Baska F, Vantus T, Huszar M, Geiszt M, et al. Small-molecule inhibitors of NADPH oxidase 4. J Med Chem 2010;53:6758-6762.
35. O'Donnell BV, Tew DG, Jones OT, England PJ. Studies on the inhibitory mechanism of iodonium compounds with special reference to neutrophil NADPH oxidase. Biochem J 1993;290:41-49.
36. Stolk J, Hiltermann TJ, Dijkman JH, Verhoeven AJ. Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir CellMol Biol 1994;11:95-102.
37. Heumuller S, Wind S, Barbosa-Sicard E, Schmidt HH, Busse R, Schroder K, Brandes RP. Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant. Hypertension 2008;51:211-217.
38. Kim JA, Neupane GP, Lee ES, Jeong BS, Park BC, Thapa P. NADPH oxidase inhibitors: a patent review. Expert Opin Ther Pat 2011.
39. Laleu B, Gaggini F, OrchardM, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, Gradia A, Duboux G, Merlot C, Heitz F, et al. First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. JMed Chem 2010; 53:7715-7730.
40. Griendling KK, Sorescu D, Lassegue B, Ushio-Fukai M. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol 2000;20:2175-2183.
41. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003;285:R277-R297.
42. Blanquicett C, Kang BY, Ritzenthaler JD, Jones DP, Hart CM. Oxidative stress modulates PPAR gamma in vascular endothelial cells. Free Radic Biol Med 2010;48:1618-1625.
43. Meredith D, Panchatcharam M, Miriyala S, Tsai YS, Morris AJ, Maeda N, Stouffer GA, Smyth SS. Dominant-negative loss of PPAR gamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling. Arterioscler Thromb Vasc Biol 2009; 29:465-471.
44. Guignabert C, Alvira CM, Alastalo TP, Sawada H, Hansmann G, Zhao M, Wang L, El-Bizri N, Rabinovitch M. Tie2-mediated loss of peroxisome proliferator-activated receptor-gamma in mice causes PDGF receptor-beta- dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 2009;297:L1082-L1090.
45. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, et al. 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.
46. Matsuda Y, Hoshikawa Y, Ameshima S, Suzuki S, Okada Y, Tabata T, Sugawara T,Matsumura Y, Kondo T. Effects of peroxisome proliferatoractivated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats (in Japanese). Nihon Kokyuki Gakkai Zasshi 2005; 43:283-288.
47. 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.
48. Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 2007;93:903-907.
49. Byrne JA, Grieve DJ, Bendall JK, Li JM, Gove C, Lambeth JD, Cave AC, Shah AM. Contrasting roles of NADPH oxidase isoforms in pressure-overload versus angiotensin II-induced cardiac hypertrophy. Circ Res 2003;93:802-805.
50. GenKyoTex N. GKT137831 granted orphan drug status for idiopathic pulmonary fibrosis by the EC (EMEA). 2010. [accessed July 17, 2011]. Available from: http://www.genkyotex.com/index.php?rubID=7