Is peroxisome proliferator-activated receptor gamma (PPARγ) a therapeutic target for the treatment of pulmonary hypertension?

Pulmonary Circulation

Volumn 1, Issue 1, 2011, Pages 33-47

  Green, David E ^a   Sutliff, Roy L ^a   Hart, C Michael ^a  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Peroxisome proliferator activated receptor gamma; Pulmonary hypertension; Therapy

Indexed keywords

EID: 84871342244     PISSN: 20458932     EISSN: 20458940     Source Type: Journal    
DOI: 10.4103/2045-8932.78101     Document Type: Review

References (175)

1. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in France: Results from a national registry. Am J Respir Crit Care Med 2006;173:1023-30.
2. Simonneau G, Robbins IM, Beghett i M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54.
3. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. 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;119:2250-94.
4. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev 1999;20:649-88.
5. Mandard S, Müller M, Kersten S. Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci 2004;61:393-416.
6. Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, et al. Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci U S A 2002;99:303-8.
7. Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol Cell Biol 2000;20:5119-28.
8. Zhu Y, Qi C, Korenberg JR, Chen XN, Noya D, Rao MS, et al. Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: Alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci U S A 1995;92:7921-5.
9. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611-7.
10. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 2005;437:759-63.
11. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest 2000;106:523-31.
12. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, et al. Molecular recognition of fatt y acids by peroxisome proliferator-activated receptors. Mol Cell 1999;3:397-403.
13. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003;92:1162-9.
14. Kim EK, Lee JH, Oh YM, Lee YS, Lee SD. Rosiglitazone att enuates hypoxia-induced pulmonary arterial hypertension in rats. Respirology 2010;15:659-68.
15. Nisbet RE, Bland JM, Kleinhenz DJ, Mitchell PO, Walp ER, SutliffRL, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 2010;42:482-90.
16. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999;4:585-95.
17. Guignabert C, Alvira CM, Alastalo TP, Sawada H, Hansmann G, Zhao M, et al. Tie2-Mediated loss of peroxisome proliferator-activated receptor-{gamma} in mice causes PDGF-receptor {beta}-dependant pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 2009;297:L1082-90.
18. Hansmann L, Groeger S, von Wulffen W, Bein G, Hackstein H. Human monocytes represent a competitive source of interferon-alpha in peripheral blood. Clin Immunol 2008;127:252-64.
19. Tian J, Smith A, Nechtman J, Podolsky R, Aggarwal S, Snead C, et al. Effect of PPARgamma inhibition on pulmonary endothelial cell gene expression: Gene profiling in pulmonary hypertension. Physiol Genomics 2009;40:48-60.
20. Matsuda Y, Hoshikawa Y, Ameshima S, Suzuki S, Okada Y, Tabata T, et al. [Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats]. Nihon Kokyuki Gakkai Zasshi 2005;43:283-8.
21. Crossno JT Jr, Garat CV, Reusch JE, Morris KG, Dempsey EC, McMurtry IF, et al. Rosiglitazone att enuates hypoxia-induced pulmonary arterial remodeling. Am J Physiol Lung Cell Mol Physiol 2007;292:L885-97.
22. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 2008;118:1846-57.
23. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 1992;327:70-5.
24. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-65.
25. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214-21.
26. Li H, Chen SJ, Chen YF, Meng QC, Durand J, Oparil S, et al. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J Appl Physiol 1994;77:1451-9.
27. Olschewski H, Rose F, Schermuly R, Ghofrani HA, Enke B, Olschewski A, et al. Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther 2004;102:139-53.
28. Hoshikawa Y, Voelkel NF, Gesell TL, Moore MD, Morris KG, Alger LA, et al. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am J Respir Crit Care Med 2001;164:314-8.
29. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925-32.
30. Robbins IM, Morrow JD, Christman BW. Oxidant stress but not thromboxane decreases with epoprostenol therapy. Free Radic Biol Med 2005;38:568-74.
31. Gupta RA, Tan J, Krause WF, Geraci MW, Willson TM, Dey SK, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci U S A 2000;97: 13275-80.
32. Lim H, Dey SK. A novel pathway of prostacyclin signaling-hanging out with nuclear receptors. Endocrinology 2002;143:3207-10.
33. Peredo HA, Mayer MA, Carranza A, Puyó AM. Pioglitazone and losartan modify hemodynamic and metabolic parameters and vascular prostanoids in fructose-overloaded rats. Clin Exp Hypertens 2008;30:159-69.
34. Tesse A, Al-Massarani G, Wangensteen R, Reitenbach S, Martínez MC, Andriantsitohaina R. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, prevents microparticle-induced vascular hyporeactivity through the regulation of proinflammatory proteins. J Pharmacol Exp Ther 2008;324:539-47.
35. Adnot S, Raffestin B, Eddahibi S, Braquet P, Chabrier PE. Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia. J Clin Invest 1991;87:155-62.
36. Steinhorn RH, Russell JA, Lakshminrusimha S, Gugino SF, Black SM, Fineman JR. Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension. Am J Physiol Heart Circ Physiol 2001;280:H311-7.
37. McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S. Hypoxia inhibits expression of eNOS via transcriptional and postt ranscriptional mechanisms. Am J Physiol 1994;267:H1921-7.
38. Fagan KA, Fouty BW, Tyler RC, Morris KG Jr, Hepler LK, Sato K, et al. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 1999;103:291-9.
39. Champion HC, Bivalacqua TJ, Greenberg SS, Giles TD, Hyman AL, Kadowitz PJ. Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOSdeficient mice. Proc Natl Acad Sci U S A 2002;99:13248-53.
40. Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, et al. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension 2001;37:322-7.
41. Channick RN, Newhart JW, Johnson FW, Williams PJ, Auger WR, Fedullo PF, et al. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: An ambulatory delivery system and initial clinical tests. Chest 1996;109:1545-9.
42. Zhao YD, Courtman DW, Ng DS, Robb MJ, Deng YP, Trogadis J, et al. Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am J Respir Cell Mol Biol 2006;35:182-9.
43. Pritchard KA Jr, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, et al. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase. J Biol Chem 2001;276:17621-4.
44. Konduri GG, Ou J, Shi Y, Pritchard KA Jr. Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 2003;285:H204-11.
45. Murata T, Sato K, Hori M, Ozaki H, Karaki H. Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem 2002;277:44085-92.
46. Calnek DS, Mazzella L, Roser S, Roman J, Hart CM. Peroxisome proliferator-activated receptor gamma ligands increase release of nitric oxide from endothelial cells. Arterioscler Thromb Vasc Biol 2003;23:52-7.
47. Polikandriotis JA, Mazzella LJ, Rupnow HL, Hart CM. Peroxisome proliferator-activated receptor gamma ligands stimulate endothelial nitric oxide production through distinct peroxisome proliferator-activated receptor gamma-dependent mechanisms. Arterioscler Thromb Vasc Biol 2005;25:1810-6.
48. Borchert M, Schöndorf T, Lübben G, Forst T, Pfützner A. Review of the pleiotropic effects of peroxisome proliferator-activated receptor gamma agonists on platelet function. Diabetes Technol Ther 2007;9:410-20.
49. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, et al. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S20-31.
50. Wakino S, Hayashi K, Tatematsu S, Hasegawa K, Takamatsu I, Kanda T, et al. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens Res 2005;28:255-62.
51. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6.
52. Azuma H, Ishikawa M, Sekizaki S. Endothelium-dependent inhibition of platelet aggregation. Br J Pharmacol 1986;88:411-5.
53. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989;83:1774-7.
54. Bath PM, Hassall DG, Gladwin AM, Palmer RM, Martin JF. Nitric oxide and prostacyclin. Divergence of inhibitory effects on monocyte chemotaxis and adhesion to endothelium in vitro. Arterioscler Thromb 1991;11:254-60.
55. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: Implications for uncoupling endothelial nitric-oxide synthase. J Biol Chem 2003;278:22546-54.
56. Jernigan NL, Walker BR, Resta TC. Endothelium-derived reactive oxygen species and endothelin-1 att enuate NO-dependent pulmonary vasodilation following chronic hypoxia. Am J Physiol Lung Cell Mol Physiol 2004;287:L801-8.
57. 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:L2-10.
58. Delerive P, Martin-Nizard F, Chinett i G, Trott ein F, Fruchart JC, Najib J, et al. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 1999;85:394-402.
59. Martin-Nizard F, Furman C, Delerive P, Kandoussi A, Fruchart JC, Staels B, et al. Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. J Cardiovasc Pharmacol 2002;40:822-31.
60. Fukunaga Y, Itoh H, Doi K, Tanaka T, Yamashita J, Chun TH, et al. Thiazolidinediones, peroxisome proliferator-activated receptor gamma agonists, regulate endothelial cell growth and secretion of vasoactive peptides. Atherosclerosis 2001;158:113-9.
61. Wang TD, Chen WJ, Cheng WC, Lin JW, Chen MF, Lee YT. Relation of improvement in endothelium-dependent flow-mediated vasodilation aft er rosiglitazone to changes in asymmetric dimethylarginine, endothelin-1, and C-reactive protein in nondiabetic patients with the metabolic syndrome. Am J Cardiol 2006;98:1057-62.
62. Iglarz M, Touyz RM, Amiri F, Lavoie MF, Diep QN, Schiffrin EL. Effect of peroxisome proliferator-activated receptor-alpha and-gamma activators on vascular remodeling in endothelin-dependent hypertension. Arterioscler Thromb Vasc Biol 2003;23:45-51.
63. Jeffery TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 2002;45:173-202.
64. Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 2009;54:S10-9.
65. 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;144:275-85.
66. Tuder RM, Voelkel NF. Pulmonary hypertension and inflammation. J Lab Clin Med 1998;132:16-24.
67. Balabanian K, Foussat A, Dorfmüller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, et al. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:1419-25.
68. Dorfmüller P, Zarka V, Durand-Gasselin I, Monti G, Balabanian K, Garcia G, et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;165:534-9.
69. Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007;176:1041-7.
70. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ Res 2000;86:494-501.
71. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007;87:245-313.
72. Lambeth JD. Nox/Duox family of nicotinamide adenine dinucleotide (phosphate) oxidases. Curr Opin Hematol 2002;9:11-7.
73. Mitt al M, Roth M, König P, Hofmann S, Dony E, Goyal P, et al. Hypoxiadependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res 2007;101:258-67.
74. Ambasta RK, Kumar P, Griendling KK, Schmidt HH, Busse R, Brandes RP. Direct interaction of the novel Nox proteins with p22phox is required for the formation of a functionally active NADPH oxidase. J Biol Chem 2004;279:45935-41.
75. Djordjevic T, BelAiba RS, Bonello S, Pfeilschift er J, Hess J, Görlach A. Human urotensin II is a novel activator of NADPH oxidase in human pulmonary artery smooth muscle cells. Arterioscler Thromb Vasc Biol 2005;25:519-25.
76. Serrander L, Cartier L, Bedard K, BanfiB, Lardy B, Plastre O, et al. NOX4 activity is determined by mRNA levels and reveals a unique patt ern of ROS generation. Biochem J 2007;406:105-14.
77. Lambeth JD, Kawahara T, Diebold B. Regulation of Nox and Duox enzymatic activity and expression. Free Radic Biol Med 2007;43:319-31.
78. Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res 2004;95:773-9.
79. Hwang J, Kleinhenz DJ, Lassègue B, Griendling KK, Dikalov S, Hart CM. Peroxisome proliferator-activated receptor-gamma ligands regulate endothelial membrane superoxide production. Am J Physiol Cell Physiol 2005;288:C899-905.
80. Lu X, Murphy TC, Nanes MS, Hart CM. 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 2010;299:L559-66.
81. Zhang L, Sheppard OR, Shah AM, Brewer AC. Positive regulation of the NADPH oxidase NOX4 promoter in vascular smooth muscle cells by E2F. Free Radic Biol Med 2008;45:679-85.
82. Chen K, Kirber MT, Xiao H, Yang Y, Keaney JF Jr. Regulation of ROS signal transduction by NADPH oxidase 4 localization. J Cell Biol 2008;181:1129-39.
83. Fredriksson L, Li H, Eriksson U. The PDGF family: Four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 2004;15:197-204.
84. Raines EW. PDGF and cardiovascular disease. Cytokine Growth Factor Rev 2004;15:237-54.
85. Tallquist M, Kazlauskas A. PDGF signaling in cells and mice. Cytokine Growth Factor Rev 2004;15:205-13.
86. Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 2003;284:L826-33.
87. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412-3.
88. Schermuly RT, Dony E, Ghofrani HA, Pullamsett i S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811-21.
89. Goetze S, Xi XP, Kawano H, Gotlibowski T, Fleck E, Hsueh WA, et al. PPAR gamma-ligands inhibit migration mediated by multiple chemoatt ractants in vascular smooth muscle cells. J Cardiovasc Pharmacol 1999;33:798-806.
90. Marx N, Schönbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998;83:1097-103.
91. Law RE, Goetze S, Xi XP, Jackson S, Kawano Y, Demer L, et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation 2000;101:1311-8.
92. Gericke A, Munson M, Ross AH. Regulation of the PTEN phosphatase. Gene 2006;374:1-9.
93. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273:13375-8.
94. Schwartzbauer G, Robbins J. The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem 2001;276:35786-93.
95. Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res 2000;87:309-15.
96. Han SW, Roman J. Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: Pro-oncogenic effects mediated by PI3-kinase and NF-kappa B. Oncogene 2006;25:4341-9.
97. Wang Q, Zhou Y, Wang X, Chung DH, Evers BM. Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. Cancer Res 2007;67: 7773-81.
98. Farrow B, Evers BM. Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun 2003;301:50-3.
99. Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH. Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol 2001;11:764-8.
100. Huang J, Kontos CD. Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. Arterioscler Thromb Vasc Biol 2002;22:745-51.
101. Huang J, Niu XL, Pippen AM, Annex BH, Kontos CD. Adenovirusmediated intraarterial delivery of PTEN inhibits neointimal hyperplasia. Arterioscler Thromb Vasc Biol 2005;25:354-8.
102. Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 2002;277:20336-42.
103. Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP. Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 2003;22:5501-10.
104. Kwon J, Lee SR, Yang KS, Ahn Y, Kim YJ, Stadtman ER, et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci U S A 2004;101:16419-24.
105. Goumans MJ, Liu Z, ten Dij ke P. TGF-beta signaling in vascular biology and dysfunction. Cell Res 2009;19:116-27.
106. Upton PD, Morrell NW. TGF-beta and BMPR-II pharmacology--implications for pulmonary vascular diseases. Curr Opin Pharmacol 2009;9:274-80.
107. Miyazono K. Transforming growth factor-beta signaling in epithelialmesenchymal transition and progression of cancer. Proc Jpn Acad Ser B Phys Biol Sci 2009;85:314-23.
108. Richter A, Yeager ME, Zaiman A, Cool CD, Voelkel NF, Tuder RM. Impaired transforming growth factor-beta signaling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;170:1340-8.
109. Cogan JD, Vnencak-Jones CL, Phillips JA 3rd, Lane KB, Wheeler LA, Robbins IM, et al. Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension. Genet Med 2005;7:169-74.
110. Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, et al. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 2003;348:500-9.
111. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:13S-24S.
112. Long L, Crosby A, Yang X, Southwood M, Upton PD, Kim DK, et al. Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: Potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 2009;119:566-76.
113. Sturrock A, Cahill B, Norman K, Huecksteadt TP, Hill K, Sanders K, 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:L661-73.
114. Ismail S, Sturrock A, Wu P, Cahill B, Norman K, Huecksteadt T, et al. 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:L489-99.
115. Ambalavanan N, Nicola T, Hagood J, Bulger A, Serra R, Murphy-Ullrich J, et al. Transforming growth factor-beta signaling mediates hypoxiainduced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung. Am J Physiol Lung Cell Mol Physiol 2008;295:L86-95.
116. Chen G, Khalil N. TGF-beta1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Respir Res 2006;7:2.
117. Burgess HA, Daugherty LE, Thatcher TH, Lakatos HF, Ray DM, Redonnet M, et al. PPARgamma agonists inhibit TGF-beta induced pulmonary myofibroblast differentiation and collagen production: Implications for therapy of lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2005;288:L1146-53.
118. Saika S, Yamanaka O, Nishikawa-Ishida I, Kitano A, Flanders KC, Okada Y, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse model. Arch Ophthalmol 2007;125:647-54.
119. Zou R, Xu G, Liu XC, Han M, Jiang JJ, Huang Q, et al. PPARgamma agonists inhibit TGF-beta-PKA signaling in glomerulosclerosis. Acta Pharmacol Sin 2010;31:43-50.
120. Zhao C, Chen W, Yang L, Chen L, Stimpson SA, Diehl AM. PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells. Biochem Biophys Res Commun 2006;350:385-91.
121. Fu M, Zhang J, Zhu X, Myles DE, Willson TM, Liu X, et al. Peroxisome proliferator-activated receptor gamma inhibits transforming growth factor beta-induced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3. J Biol Chem 2001;276:45888-94.
122. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 2000;105:21-34.
123. Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res 2006;99:675-91.
124. Zaidi SH, You XM, Ciura S, Husain M, Rabinovitch M. Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 2002;105:516-21.
125. Hao GH, Niu XL, Gao DF, Wei J, Wang NP. Agonists at PPAR-gamma suppress angiotensin II-induced production of plasminogen activator inhibitor-1 and extracellular matrix in rat cardiac fibroblasts. Br J Pharmacol 2008;153:1409-19.
126. Makino N, Sugano M, Satoh S, Oyama J, Maeda T. Peroxisome proliferatoractivated receptor-gamma ligands att enuate brain natriuretic peptide production and affect remodeling in cardiac fibroblasts in reoxygenation aft er hypoxia. Cell Biochem Biophys 2006;44:65-71.
127. Peng Y, Liu H, Liu F, Liu Y, Li J, Chen X. Troglitazone inhibits synthesis of transforming growth factor-beta1 and reduces matrix production in human peritoneal mesothelial cells. Nephrology (Carlton) 2006;11:516-23.
128. Bakouboula B, Morel O, Faure A, Zobairi F, Jesel L, Trinh A, et al. Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;177: 536-43.
129. Perros F, Dorfmüller P, Souza R, Durand-Gasselin I, Godot V, Capel F, et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 2007;29:937-43.
130. Molet S, Furukawa K, Maghazechi A, Hamid Q, Giaid A. Chemokine-and cytokine-induced expression of endothelin 1 and endothelin-converting enzyme 1 in endothelial cells. J Allergy Clin Immunol 2000;105:333-8.
131. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, et al. The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci U S A 2007;104:11418-23.
132. Szanto A, Nagy L. The many faces of PPARgamma: Anti-inflammatory by any means? Immunobiology 2008;213:789-803.
133. Hontecillas R, Bassaganya-Riera J. Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol 2007;178:2940-9.
134. Wohlfert EA, Nichols FC, Nevius E, Clark RB. Peroxisome proliferatoractivated receptor gamma (PPARgamma) and immunoregulation: Enhancement of regulatory T cells through PPARgamma-dependent and-independent mechanisms. J Immunol 2007;178:4129-35.
135. Gurbanov E, Shiliang X. The key role of apoptosis in the pathogenesis and treatment of pulmonary hypertension. Eur J Cardiothorac Surg 2006;30:499-507.
136. Haunstett er A, Izumo S. Apoptosis: Basic mechanisms and implications for cardiovascular disease. Circ Res 1998;82:1111-29.
137. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, et al. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2003;285:L740-54.
138. Okura T, Nakamura M, Takata Y, Watanabe S, Kitami Y, Hiwada K. Troglitazone induces apoptosis via the p53 and Gadd45 pathway in vascular smooth muscle cells. Eur J Pharmacol 2000;407:227-35.
139. Aizawa Y, Kawabe J, Hasebe N, Takehara N, Kikuchi K. Pioglitazone enhances cytokine-induced apoptosis in vascular smooth muscle cells and reduces intimal hyperplasia. Circulation 2001;104:455-60.
140. Bishop-Bailey D, Hla T. Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2. J Biol Chem 1999;274:17042-8.
141. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A, et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:L548-54.
142. Park EJ, Park SY, Joe EH, Jou I. 15d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia. J Biol Chem 2003;278:14747-52.
143. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964-7.
144. Rosenzweig A. Circulating endothelial progenitors--cells as biomarkers. N Engl J Med 2005;353:1055-7.
145. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003;348:593-600.
146. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005;353:999-1007.
147. Sata M. Role of circulating vascular progenitors in angiogenesis, vascular healing, and pulmonary hypertension: Lessons from animal models. Arterioscler Thromb Vasc Biol 2006;26:1008-14.
148. Satoh K, Kagaya Y, Nakano M, Ito Y, Ohta J, Tada H, et al. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 2006;113:1442-50.
149. Nagaya N, Kangawa K, Kanda M, Uematsu M, Horio T, Fukuyama N, et al. Hybrid cell-gene therapy for pulmonary hypertension based on phagocytosing action of endothelial progenitor cells. Circulation 2003;108:889-95.
150. Wang CH, Ciliberti N, Li SH, Szmitko PE, Weisel RD, Fedak PW, et al. Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: A new paradigm in glitazone pleiotropy. Circulation 2004;109:1392-400.
151. Gensch C, Clever YP, Werner C, Hanhoun M, Böhm M, Laufs U. The PPARgamma agonist pioglitazone increases neoangiogenesis and prevents apoptosis of endothelial progenitor cells. Atherosclerosis 2007;192:67-74.
152. Chaouat A, Weitzenblum E, Higenbott am T. The role of thrombosis in severe pulmonary hypertension. Eur Respir J 1996;9:356-63.
153. Herve P, Humbert M, Sitbon O, Parent F, Nunes H, Legal C, et al. Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med 2001;22:451-8.
154. Welsh CH, Hassell KL, Badesch DB, Kressin DC, Marlar RA. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996;110:710-7.
155. Hoeper MM, Sosada M, Fabel H. Plasma coagulation profiles in patients with severe primary pulmonary hypertension. Eur Respir J 1998;12:1446-9.
156. Eisenberg PR, Lucore C, Kaufman L, Sobel BE, Jaffe AS, Rich S. Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 1990;82:841-7.
157. Altman R, Scazziota A, Rouvier J, Gurfinkel E, Favaloro R, Perrone S, et al. Coagulation and fibrinolytic parameters in patients with pulmonary hypertension. Clin Cardiol 1996;19:549-54.
158. Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: Evidence for a process of disordered angiogenesis. J Pathol 2001;195:367-74.
159. Akbiyik F, Ray DM, Gett ings KF, Blumberg N, Francis CW, Phipps RP. Human bone marrow megakaryocytes and platelets express PPARgamma, and PPARgamma agonists blunt platelet release of CD40 ligand and thromboxanes. Blood 2004;104:1361-8.
160. Schönbeck U, Libby P. CD40 signaling and plaque instability. Circ Res 2001;89:1092-103.
161. Henn V, Slupsky JR, Gräfe M, Anagnostopoulos I, Förster R, Müller-Berghaus G, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998;391:591-4.
162. Bodary PF, Vargas FB, King SA, Jongeward KL, Wickenheiser KJ, Eitzman DT. Pioglitazone protects against thrombosis in a mouse model of obesity and insulin resistance. J Thromb Haemost 2005;3:2149-53.
163. Li D, Chen K, Sinha N, Zhang X, Wang Y, Sinha AK, et al. The effects of PPAR-gamma ligand pioglitazone on platelet aggregation and arterial thrombus formation. Cardiovasc Res 2005;65:907-12.
164. Smyth SS, Jennings JL. PPARgamma agonists: A new strategy for antithrombotic therapy. J Thromb Haemost 2005;3:2147-8.
165. Cylwik D, Mogielnicki A, Buczko W. L-arginine and cardiovascular system. Pharmacol Rep 2005;57:14-22.
166. Fonseca VA, Reynolds T, Hemphill D, Randolph C, Wall J, Valiquet TR, et al. Effect of troglitazone on fibrinolysis and activated coagulation in patients with non-insulin-dependent diabetes mellitus. J Diabetes Complications 1998;12:181-6.
167. Kato K, Yamada D, Midorikawa S, Sato W, Watanabe T. Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus. Metabolism 2000;49:662-5.
168. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: The hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 2009;297:L1013-32.
169. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, et al. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010;121:2747-54.
170. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457-71.
171. Rosen CJ. The rosiglitazone story--lessons from an FDA Advisory Committ ee meeting. N Engl J Med 2007;357:844-6.
172. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedett i M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005;366:1279-89.
173. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedett i M, Moules IK, Skene AM, et al. The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: Results from the PROactive (PROactive 05) Study. J Am Coll Cardiol 2007;49:1772-80.
174. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: A metaanalysis of randomized trials. JAMA 2007;298:1180-8.
175. Wilcox R, Bousser MG, Bett eridge DJ, Schernthaner G, Pirags V, Kupfer S, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: Results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007;38:865-73.