Mechanisms of disease: Pulmonary arterial hypertension

Nature Reviews Cardiology

Volumn 8, Issue 8, 2011, Pages 443-455

  Schermuly, Ralph T ^a   Ghofrani, Hossein A ^b   Wilkins, Martin R ^c   Grimminger, Friedrich ^b  

^a MAX PLANCK INSTITUTE FOR HEART AND LUNG RESEARCH   (Germany)

^b UNIVERSITY HOSPITAL GIESSEN   (Germany)

^c HAMMERSMITH HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BASIC FIBROBLAST GROWTH FACTOR; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CALCIUM CHANNEL; CHEMOKINE; CYTOKINE; ELASTASE; ENDOTHELIN 1; GROWTH FACTOR; INTERLEUKIN 6; MATRIX METALLOPROTEINASE; N(G),N(G) DIMETHYLARGININE; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; NOTCH RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PLATELET DERIVED GROWTH FACTOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR; POTASSIUM CHANNEL; PROTEINASE; ROSIGLITAZONE; SCATTER FACTOR; THROMBOXANE; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN; VASCULOTROPIN RECEPTOR 2;

ANGIOGENESIS; CELL INFILTRATION; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; DISEASE CLASSIFICATION; DRUG TARGETING; EISENMENGER COMPLEX; ENDOTHELIAL PROGENITOR CELL; HEART RIGHT VENTRICLE HYPERTROPHY; HEART RIGHT VENTRICLE PRESSURE; HEMATOPOIETIC STEM CELL; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; HYPOTHESIS; INFECTION; INFLAMMATION; MITOCHONDRIAL RESPIRATION; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PULMONARY HYPERTENSION; REVIEW; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; STEM CELL; THROMBOSIS; TISSUE REPAIR; VASCULAR ENDOTHELIUM; VASCULAR SMOOTH MUSCLE; WARBURG HYPOTHESIS;

ANIMALS; BLOOD COAGULATION; CELL PROLIFERATION; ENDOTHELIAL CELLS; HEMODYNAMICS; HUMANS; HYPERTENSION, PULMONARY; INFLAMMATION MEDIATORS; NEOVASCULARIZATION, PHYSIOLOGIC; SIGNAL TRANSDUCTION;

EID: 79960961583     PISSN: 17595002     EISSN: 17595010     Source Type: Journal    
DOI: 10.1038/nrcardio.2011.87     Document Type: Review

References (191)

1. Simonneau, G. et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S43-S54 (2009).
2. dos Santos Fernandes, C. J. et al. Survival in schistosomiasis-associated pulmonary arterial hypertension. J. Am. Coll. Cardiol. 56, 715-720 (2010).
3. Graham, B. B., Bandeira, A. P., Morrell, N. W., Butrous, G. & Tuder, R. M. Schistosomiasis-associated pulmonary hypertension: pulmonary vascular disease: the global perspective. Chest 137, 20S-29S (2010).
4. Lapa, M. et al. Cardiopulmonary manifestations of hepatosplenic schistosomiasis. Circulation 119, 1518-1523 (2009).
5. Butrous, G., Ghofrani, H. A. & Grimminger, F. Pulmonary vascular disease in the developing world. Circulation 118, 1758-1766 (2008).
6. Stenmark, K. R., Meyrick, B., Galie, N., Mooi, W. J. & McMurtry, I. F. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1013-L1032 (2009).
7. Tuder, R. M. et al. Development and pathology of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S3-S9 (2009).
8. Fourie, P. R., Coetzee, A. R. & Bolliger, C. T. Pulmonary artery compliance: its role in right ventricular-arterial coupling. Cardiovasc. Res. 26, 839-844 (1992).
9. Rabinovitch, M. Pathobiology of pulmonary hypertension. Annu. Rev. Pathol. 2, 369-399 (2007). (Pubitemid 46448070)
10. Frid, M. G. et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am. J. Pathol. 168, 659-669 (2006). (Pubitemid 43271163)
11. Zhao, Y. D. et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ. Res. 96, 442-450 (2005). (Pubitemid 40354538)
12. Christman, B. W. et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N. Engl. J. Med. 327, 70-75 (1992).
13. Kreymborg, K. et al. Identification of right heart-enriched genes in a murine model of chronic outflow tract obstruction. J. Mol. Cell. Cardiol. 49, 598-605 (2010).
14. Ghofrani, H. A., Osterloh, I. H. & Grimminger, F. Sildenafil: from angina to erectile dysfunction to pulmonary hypertension and beyond. Nat. Rev. Drug Discov. 5, 689-702 (2006). (Pubitemid 44151606)
15. Wharton, J. et al. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am. J. Respir. Crit. Care Med. 172, 105-113 (2005). (Pubitemid 40923321)
16. Leiper, J. et al. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat. Med. 13, 198-203 (2007).
17. Pullamsetti, S. et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J. 19, 1175-1177 (2005). (Pubitemid 40946456)
18. Launay, J. M. et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 8, 1129-1135 (2002).
19. Eddahibi, S. et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. Circulation 113, 1857-1864 (2006). (Pubitemid 43739397)
20. Uchida, S. et al. An integrated approach for the systematic identification and characterization of heart-enriched genes with unknown functions. BMC Genomics 10, 100 (2009).
21. Yuan, X. J., Wang, J., Juhaszova, M., Gaine, S. P. & Rubin, L. J. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351, 726-727 (1998). (Pubitemid 28105348)
22. Mandegar, M. & Yuan, J. X. Role of K+ channels in pulmonary hypertension. Vascul. Pharmacol. 38, 25-33 (2002).
23. Moudgil, R., Michelakis, E. D. & Archer, S. L. The role of K+ channels in determining pulmonary vascular tone, oxygen sensing, cell proliferation, and apoptosis: Implications in hypoxic pulmonary vasoconstriction and pulmonary arterial hypertension. Microcirculation 13, 615-632 (2006). (Pubitemid 44696118)
24. Yu, Y. et al. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc. Natl Acad. Sci. U.S.A. 101, 13861-13866 (2004). (Pubitemid 39298498)
25. Weissmann, N. et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange. Proc. Natl Acad. Sci. U.S.A. 103, 19093-19098 (2006). (Pubitemid 350002833)
26. Davie, N. et al. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am. J. Respir. Crit. Care Med. 165, 398-405 (2002). (Pubitemid 34118516)
27. Burg, E. D., Remillard, C. V. & Yuan, J. X. Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications. Br. J. Pharmacol. 153, S99-S111 (2008). (Pubitemid 351341007)
28. Tabima, D. M. & Chesler, N. C. The effects of vasoactivity and hypoxic pulmonary hypertension on extralobar pulmonary artery biomechanics. J. Biomech. 43, 1864-1869 (2010).
29. Tozzi, C. A., Christiansen, D. L., Poiani, G. J. & Riley, D. J. Excess collagen in hypertensive pulmonary arteries decreases vascular distensibility. Am. J. Respir. Crit. Care Med. 149, 1317-1326 (1994). (Pubitemid 24147076)
30. Ooi, C. Y., Wang, Z., Tabima, D. M., Eickhoff, J. C. & Chesler, N. C. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension. Am. J. Physiol. Heart Circ. Physiol. 299, H1823-H1831 (2010).
31. Geiger, R. et al. Enhanced expression of vascular endothelial growth factor in pulmonary plexogenic arteriopathy due to congenital heart disease. J. Pathol. 191, 202-207 (2000). (Pubitemid 30394900)
32. Tuder, R. M. et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J. Pathol. 195, 367-374 (2001).
33. Partovian, C. et al. Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension. Am. J. Physiol. 275, H1948-H1956 (1998).
34. Partovian, C. et al. Cardiac and lung VEGF mRNA expression in chronically hypoxic and monocrotaline-treated rats. Chest 114, 45S-46S (1998). (Pubitemid 28334858)
35. Kasahara, Y. et al. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J. Clin. Invest. 106, 1311-1319 (2000).
36. Tuder, R. M. et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. Am. J. Respir. Cell Mol. Biol. 29, 88-97 (2003). (Pubitemid 36783320)
37. Taraseviciene-Stewart, L. et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15, 427-438 (2001). (Pubitemid 32141434)
38. Taraseviciene-Stewart, L. et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L668-L676 (2006). (Pubitemid 44498478)
39. Campbell, A. I., Zhao, Y., Sandhu, R. & Stewart, D. J. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension. Circulation 104, 2242-2248 (2001). (Pubitemid 33043307)
40. Farkas, L. et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J. Clin. Invest. 119, 1298-1311 (2009).
41. Partovian, C. et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am. J. Respir. Cell Mol. Biol. 23, 762-771 (2000). (Pubitemid 32013268)
42. Klein, M. et al. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 118, 2081-2090 (2008).
43. Moreno-Vinasco, L. et al. Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol. Genomics 33, 278-291 (2008). (Pubitemid 351629535)
44. Tuder, R. M. & Yun, J. H. Vascular endothelial growth factor of the lung: friend or foe. Curr. Opin. Pharmacol. 8, 255-260 (2008).
45. Benisty, J. I. et al. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126, 1255-1261 (2004). (Pubitemid 39391258)
46. Li, P., Oparil, S., Sun, J. Z., Thompson, J. A. & Chen, Y. F. Fibroblast growth factor mediates hypoxia-induced endothelin- a receptor expression in lung artery smooth muscle cells. J. Appl. Physiol. 95, 643-651 (2003). (Pubitemid 36944287)
47. Quinn, T. P., Schlueter, M., Soifer, S. J. & Gutierrez, J. A. Cyclic mechanical stretch induces VEGF and FGF-2 expression in pulmonary vascular smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L897-L903 (2002). (Pubitemid 34654604)
48. Wedgwood, S. et al. Fibroblast growth factor 2 expression is altered in lambs with increased pulmonary blood flow and pulmonary hypertension. Pediatr. Res. 61, 32-36 (2007). (Pubitemid 46352312)
49. Kwapiszewska, G. et al. Expression profiling of laser-microdissected intrapulmonary arteries in hypoxia-induced pulmonary hypertension. Respir. Res. 6, 109 (2005).
50. Izikki, M. et al. Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J. Clin. Invest 119, 512-523 (2009).
51. Le Cras, T. D., Hardie, W. D., Fagan, K., Whitsett, J. A. & Korfhagen, T. R. Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-alpha. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L1046-L1054 (2003). (Pubitemid 37310094)
52. Jones, P. L. & Rabinovitch, M. Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ. Res. 79, 1131-1142 (1996). (Pubitemid 26404145)
53. Schultz, K., Fanburg, B. L. & Beasley, D. Hypoxia and hypoxia-inducible factor-1alpha promote growth factor-induced proliferation of human vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 290, H2528-H2534 (2006). (Pubitemid 43846084)
54. Dahal, B. K. et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 181, 158-167 (2010).
55. Merklinger, S. L., Jones, P. L., Martinez, E. C. & Rabinovitch, M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112, 423-431 (2005). (Pubitemid 41022085)
56. Grimminger, F. & Schermuly, R. T. PDGF receptor and its antagonists: role in treatment of PAH. Adv. Exp. Med. Biol. 661, 435-446 (2010).
57. Yu, Y. et al. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am. J. Physiol. Cell Physiol. 284, C316-C330 (2003). (Pubitemid 36120070)
58. Humbert, M. et al. Platelet-derived growth factor expression in primary pulmonary hypertension: comparison of HIV seropositive and HIV seronegative patients. Eur. Respir. J. 11, 554-559 (1998). (Pubitemid 28194842)
59. Schermuly, R. T. et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J. Clin. Invest. 115, 2811-2821 (2005). (Pubitemid 41434408)
60. Perros, F. et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 178, 81-88 (2008). (Pubitemid 351919196)
61. Cohen, E. D. et al. Wnt signaling regulates smooth muscle precursor development in the mouse lung via a tenascin C/PDGFR pathway. J. Clin. Invest 119, 2538-2549 (2009).
62. Balasubramaniam, V. et al. Role of platelet-derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am. J. Physiol. Lung Cell Mol. Physiol. 284, L826-L833 (2003). (Pubitemid 36459029)
63. Hayashi, S. et al. Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: downregulation of HGF in response to hypoxia in vascular cells. Circulation 100, II301-II308 (1999). (Pubitemid 29523551)
64. Ono, M. et al. Hepatocyte growth factor suppresses vascular medial hyperplasia and matrix accumulation in advanced pulmonary hypertension of rats. Circulation 110, 2896-2902 (2004). (Pubitemid 39473615)
65. Ono, M. et al. Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats. Eur. J. Cardiothorac. Surg. 26, 1092-1097 (2004). (Pubitemid 39487453)
66. Machado, R. D. et al. Genetics and genomics of pulmonary arterial hypertension. J. Am. Coll. Cardiol. 54, S32-S42 (2009).
67. Heath, D. & Yacoub, M. Lung mast cells in plexogenic pulmonary arteriopathy. J. Clin. Pathol. 44, 1003-1006 (1991).
68. Mitani, Y. et al. Mast cell chymase in pulmonary hypertension. Thorax 54, 88-90 (1999). (Pubitemid 29103760)
69. Nicolls, M. R., Taraseviciene-Stewart, L., Rai, P. R., Badesch, D. B. & Voelkel, N. F. Autoimmunity and pulmonary hypertension: a perspective. Eur. Respir. J. 26, 1110-1118 (2005). (Pubitemid 41829945)
70. Tucker, A., McMurtry, I. F., Alexander, A. F., Reeves, J. T. & Grover, R. F. Lung mast cell density and distribution in chronically hypoxic animals. J. Appl. Physiol. 42, 174-178 (1977). (Pubitemid 8038589)
71. Rabinovitch, M. Elastase and the pathobiology of unexplained pulmonary hypertension. Chest 114, 213S-224S (1998). (Pubitemid 28435971)
72. Lepetit, H. et al. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur. Respir. J. 25, 834-842 (2005). (Pubitemid 40667681)
73. Benisty, J. I. et al. Matrix metalloproteinases in the urine of patients with pulmonary arterial hypertension. Chest 128 (Suppl. 6), 572S (2005). (Pubitemid 43054123)
74. Cowan, K. N. et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. J. Am. Coll. Cardiol. 35, 545A-545A (2000).
75. Cowan, K. N., Jones, P. L. & Rabinovitch, M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J. Clin. Invest. 105, 21-34 (2000). (Pubitemid 30036384)
76. Lane, K. B. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat. Genet. 26, 81-84 (2000).
77. Deng, Z. et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am. J. Hum. Genet. 67, 737-744 (2000). (Pubitemid 30659603)
78. Trembath, R. C. et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 345, 325-334 (2001). (Pubitemid 32703235)
79. Rudarakanchana, N. et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum. Mol. Genet. 11, 1517-1525 (2002). (Pubitemid 34679252)
80. Yang, X. et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ. Res. 96, 1053-1063 (2005). (Pubitemid 40791377)
81. Machado, R. D. et al. Functional interaction between BMPR-II and Tctex-1, a light chain of Dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Hum. Mol. Genet. 12, 3277-3286 (2003). (Pubitemid 37541073)
82. Foletta, V. C. et al. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1 J. Cell Biol. 162, 1089-1098 (2003). (Pubitemid 37174191)
83. Eickelberg, O. & Morty, R. E. Transforming growth factor beta/bone morphogenic protein signaling in pulmonary arterial hypertension: Remodeling revisited. Trends Cardiovasc. Med. 17, 263-269 (2007). (Pubitemid 350087696)
84. Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770-776 (1999). (Pubitemid 29291335)
85. Alva, J. A. & Iruela-Arispe, M. L. Notch signaling in vascular morphogenesis. Curr. Opin. Hematol. 11, 278-283 (2004). (Pubitemid 39120957)
86. Villa, N. et al. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech. Dev. 108, 161-164 (2001). (Pubitemid 32918185)
87. Domenga, V. et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730-2735 (2004). (Pubitemid 39507766)
88. Proweller, A., Pear, W. S. & Parmacek, M. S. Notch signaling represses myocardin-induced smooth muscle cell differentiation. J. Biol. Chem. 280, 8994-9004 (2005). (Pubitemid 40409591)
89. Campos, A. H., Wang, W., Pollman, M. J. & Gibbons, G. H. Determinants of Notch-3 receptor expression and signaling in vascular smooth muscle cells: implications in cell-cycle regulation. Circ. Res. 91, 999-1006 (2002). (Pubitemid 35416636)
90. Gustafsson, M. V. et al. Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev. Cell 9, 617-628 (2005). (Pubitemid 41555144)
91. Jin, S. et al. Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ. Res. 102, 1483-1491 (2008).
92. Li, X. D. et al. Notch3 signaling promotes the development of pulmonary arterial hypertension. Nat. Med. 15, 1289-1297 (2009).
93. Issemann, I. & Green, S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645-650 (1990).
94. Rios-Vazquez, R., Marzoa-Rivas, R., Gil-Ortega, I. & Kaski, J. C. Peroxisome proliferator-activated receptor-gamma agonists for management and prevention of vascular disease in patients with and without diabetes mellitus. Am. J. Cardiovasc. Drugs 6, 231-242 (2006). (Pubitemid 44285132)
95. Duan, S. Z., Usher, M. G. & Mortensen, R. M. Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature. Circ. Res. 102, 283-294 (2008). (Pubitemid 351271648)
96. Chinetti, G. et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. 273, 25573-25580 (1998). (Pubitemid 28475776)
97. Jiang, C., Ting, A. T. & Seed, B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82-86 (1998). (Pubitemid 28079219)
98. Panigrahy, D. et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J. Clin. Invest. 110, 923-932 (2002).
99. Takeda, K., Ichiki, T., Tokunou, T., Iino, N. & Takeshita, A. 15-Deoxy-delta 12,14-prostaglandin J2 and thiazolidinediones activate the MEK/ERK pathway through phosphatidylinositol 3-kinase in vascular smooth muscle cells. J. Biol. Chem. 276, 48950-48955 (2001).
100. Spiegelman, B. M. & Flier, J. S. Adipogenesis and obesity: rounding out the big picture. Cell 87, 377-389 (1996). (Pubitemid 26374313)
101. Ameshima, S. et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ. Res. 92, 1162-1169 (2003). (Pubitemid 36665863)
102. Barak, Y. et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585-595 (1999). (Pubitemid 29531138)
103. Hansmann, G. et al. An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J. Clin. Invest. 118, 1846-1857 (2008). (Pubitemid 351632387)
104. Guignabert, C. et al. 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. 297, L1082-L1090 (2009).
105. Hansmann, G. et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 115, 1275-1284 (2007). (Pubitemid 46594772)
106. Martin-Nizard, F. et al. Peroxisome proliferator-activated receptor activators inhibit oxidized low-density lipoprotein-induced endothelin-1 secretion in endothelial cells. J. Cardiovasc. Pharmacol. 40, 822-831 (2002). (Pubitemid 35365080)
107. Wakino, S. et al. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens. Res. 28, 255-262 (2005). (Pubitemid 40812611)
108. Kielstein, J. T. et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol. 25, 1414-1418 (2005). (Pubitemid 40923361)
109. Li, M. et al. Heme oxygenase-1/p21WAF1 mediates peroxisome proliferator-activated receptor-gamma signaling inhibition of proliferation of rat pulmonary artery smooth muscle cells. FEBS J. 277, 1543-1550 (2010).
110. Matsuda, Y. et al. Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats [Japanese]. Nihon Kokyuki Gakkai Zasshi 43, 283-238 (2005).
111. Crossno, J. T., Jr et al. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling. Am. J. Physiol. Lung Cell Mol. Physiol. 292, L885-L897 (2007). (Pubitemid 46608235)
112. Nisbet, R. E. et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am. J. Respir. Cell Mol. Biol. 42, 482-490 (2010).
113. Juurlink, D. N. et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 339, b2942 (2009).
114. Khakoo, A. Y. & Finkel, T. Endothelial progenitor cells. Annu. Rev. Med. 56, 79-101 (2005). (Pubitemid 40299775)
115. Asahara, T. & Kawamoto, A. Endothelial progenitor cells for postnatal vasculogenesis. Am. J. Physiol. Cell Physiol. 287, C572-C579 (2004). (Pubitemid 39095841)
116. Tuder, R. M., Groves, B., Badesch, D. B. & Voelkel, N. F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275-285 (1994). (Pubitemid 24165948)
117. Spees, J. L. et al. Bone marrow progenitor cells contribute to repair and remodeling of the lung and heart in a rat model of progressive pulmonary hypertension. FASEB J. 22, 1226-1236 (2008). (Pubitemid 351519976)
118. Hayashida, K. et al. Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension. Chest 127, 1793-1798 (2005). (Pubitemid 46218809)
119. Angelini, D. J. et al. Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELM alpha) recruits bone marrow-derived cells to the murine pulmonary vasculature. PLoS ONE 5, e11251 (2010).
120. Frid, M. G. et al. Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am. J. Pathol. 168, 659-669 (2006). (Pubitemid 43271163)
121. Satoh, K. et al. Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice. Circulation 113, 1442-1450 (2006). (Pubitemid 43739441)
122. Sahara, M. et al. Diverse contribution of bone marrow-derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation 115, 509-517 (2007). (Pubitemid 46184202)
123. Marsboom, G. et al. Sustained endothelial progenitor cell dysfunction after chronic hypoxia-induced pulmonary hypertension. Stem Cells 26, 1017-1026 (2008).
124. Diller, G. P. et al. Circulating endothelial progenitor cells in patients with Eisenmenger syndrome and idiopathic pulmonary arterial hypertension. Circulation 117, 3020-3030 (2008).
125. Junhui, Z. et al. Reduced number and activity of circulating endothelial progenitor cells in patients with idiopathic pulmonary arterial hypertension. Respir. Med. 102, 1073-1079 (2008).
126. Toshner, M. et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 180, 780-787 (2009).
127. Asosingh, K. et al. Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am. J. Pathol. 172, 615-627 (2008). (Pubitemid 351354535)
128. de Jesus Perez, V. A. et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J. Cell Biol. 184, 83-99 (2009).
129. Howell, K., Costello, C. M., Sands, M., Dooley, I. & McLoughlin, P. L-Arginine promotes angiogenesis in the chronically hypoxic lung: a novel mechanism ameliorating pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L1042-L1050 (2009).
130. Zhao, Y. D. et al. Microvascular regeneration in established pulmonary hypertension by angiogenic gene transfer. Am. J. Respir. Cell Mol. Biol. 35, 182-189 (2006). (Pubitemid 44175317)
131. Teng, R. J., Eis, A., Bakhutashvili, I., Arul, N. & Konduri, G. G. Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L184-L195 (2009).
132. Hassoun, P. M. et al. Inflammation, growth factors, and pulmonary vascular remodeling. J. Am. Coll. Cardiol. 54, S10-S19 (2009).
133. Pullamsetti, S. S. et al. Inflammation, immunological reaction and role of infection in pulmonary hypertension. Clin. Microbiol. Infect. 17, 7-14 (2011).
134. Tuder, R. M., Groves, B., Badesch, D. B. & Voelkel, N. F. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am. J. Pathol. 144, 275-285 (1994). (Pubitemid 24165948)
135. Cool, C. D., Kennedy, D., Voelkel, N. F. & Tuder, R. M. Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum. Pathol. 28, 434-442 (1997). (Pubitemid 27175084)
136. Hamamdzic, D., Kasman, L. M. & LeRoy, E. C. The role of infectious agents in the pathogenesis of systemic sclerosis. Curr. Opin. Rheumatol. 14, 694-698 (2002). (Pubitemid 35191558)
137. Cool, C. D. et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N. Engl. J. Med. 349, 1113-1122 (2003). (Pubitemid 37122323)
138. Henke-Gendo, C., Mengel, M., Hoeper, M. M., Alkharsah, K. & Schulz, T. F. Absence of Kaposi's sarcoma-associated herpesvirus in patients with pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 172, 1581-1585 (2005). (Pubitemid 43076549)
139. Shan, B. et al. Activation of proMMP-2 and Src by HHV8 vGPCR in human pulmonary arterial endothelial cells. J. Mol. Cell. Cardiol. 42, 517-525 (2007). (Pubitemid 46357551)
140. Bull, T. M. et al. Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells. Am. J. Respir. Cell Mol. Biol. 39, 706-716 (2008).
141. Graham, B. B. et al. Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am. J. Pathol. 177, 1549-1561 (2010).
142. Freitas, T. C., Jung, E. & Pearce, E. J. TGF-beta signaling controls embryo development in the parasitic flatworm Schistosoma mansoni. PLoS Pathog. 3, e52 (2007).
143. Crosby, A. et al. Pulmonary vascular remodeling correlates with lung eggs and cytokines in murine schistosomiasis. Am. J. Respir. Crit. Care Med. 181, 279-288
144. Humbert, M. et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 151, 1628-1631 (1995).
145. Itoh, T. et al. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology 11, 158-163 (2006). (Pubitemid 43356895)
146. Tuder, R. M. & Voelkel, N. F. Pulmonary hypertension and inflammation. J. Lab. Clin. Med. 132, 16-24 (1998). (Pubitemid 28329606)
147. Bhargava, A., Kumar, A., Yuan, N., Gewitz, M. H. & Mathew, R. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis. 1, 126-132 (1999).
148. Miyata, M. et al. Pulmonary hypertension in rats. 2 Role of interleukin-6 Int. Arch. Allergy Immunol. 108, 287-291 (1995).
149. Steiner, M. K. et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ. Res. 104, 236-244 (2009).
150. Savale, L. et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir. Res. 10, 6 (2009).
151. Hagen, M. et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am. J. Physiol. Lung Cell Mol. Physiol. 292, L1473-L1479 (2007). (Pubitemid 47077364)
152. Brock, M. et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ. Res. 104, 1184-1191 (2009).
153. Zlotnik, A. & Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12, 121-127 (2000). (Pubitemid 30398626)
154. Dorfmuller, P. et al. Chemokine RANTES in severe pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 165, 534-539 (2002). (Pubitemid 34165478)
155. Balabanian, K. et al. CX3C chemokine fractalkine in pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 165, 1419-1425 (2002). (Pubitemid 34522947)
156. Bazan, J. F. et al. A new class of membrane-bound chemokine with a CX3C motif. Nature 385, 640-644 (1997).
157. Papadopoulos, E. J. et al. Fractalkine, a CX3C chemokine, is expressed by dendritic cells and is up-regulated upon dendritic cell maturation. Eur. J. Immunol. 29, 2551-2559 (1999). (Pubitemid 29378126)
158. Fong, A. M. et al. Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J. Exp. Med. 188, 1413-1419 (1998). (Pubitemid 28489578)
159. Perros, F. et al. Fractalkine-induced smooth muscle cell proliferation in pulmonary hypertension. Eur. Respir. J. 29, 937-943 (2007). (Pubitemid 46711898)
160. McDermott, D. H. et al. Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis. Circ. Res. 89, 401-407 (2001). (Pubitemid 34132655)
161. Sanchez, O. et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med. 176, 1041-1047 (2007). (Pubitemid 350127849)
162. Tournier, A. et al. Calibrated automated thrombography demonstrates hypercoagulability in patients with idiopathic pulmonary arterial hypertension. Thromb. Res. 126, e418-e422 (2010).
163. White, R. J. et al. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am. J. Physiol. Lung Cell. Mol. Physiol. 293, L583-L590 (2007). (Pubitemid 47358820)
164. Johnson, S. R., Granton, J. T. & Mehta, S. Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. Chest 130, 545-552 (2006). (Pubitemid 44267025)
165. Giaid, A. & Saleh, D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N. Engl. J. Med. 333, 214-221 (1995).
166. Warburg, O. On metabolism of tumors. (Constable, London, 1930).
167. Xu, W. et al. Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc. Natl Acad. Sci. U.S.A. 104, 1342-1347 (2007). (Pubitemid 46184006)
168. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37-51 (2007). (Pubitemid 46054520)
169. Michelakis, E. D. et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 105, 244-250 (2002). (Pubitemid 34084326)
170. McMurtry, M. S. et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ. Res. 95, 830-840 (2004). (Pubitemid 39390586)
171. Guignabert, C. et al. Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J. 23, 4135-4147 (2009).
172. Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).
173. US NIH. ClinicalTrials.gov. Dichloroacetate (DCA) for the treatment of pulmonary arterial hypertension [online], http://clinicaltrials.gov/ct2/show/ NCT01083524?term=NCT01083524&rank=1 (2010).
174. Oikawa, M. et al. Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol. J. Am. Coll. Cardiol. 45, 1849-1855 (2005). (Pubitemid 40779867)
175. Piao, L. et al. 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. 88, 47-60 (2010).
176. Piao, L., Marsboom, G. & Archer, S. L. Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure. J. Mol. Med. 88, 1011-1020 (2010).
177. Bogaard, H. J., Abe, K., Vonk Noordegraaf, A. & Voelkel, N. F. The right ventricle under pressure: cellular and molecular mechanisms of right-heart failure in pulmonary hypertension. Chest 135, 794-804 (2009).
178. Haworth, S. The cell and molecular biology of right ventricular dysfunction in pulmonary hypertension. Eur. Heart J. 9 (Suppl. H), H10-H16 (2007).
179. Pokreisz, P., Marsboom, G. & Janssens, S. Pressure overload-induced right ventricular dysfunction and remodelling in experimental pulmonary hypertension: the right heart revisited. Eur. Heart J. 9 (Suppl. H), H75-H84 (2007).
180. Gomez, A. et al. Right ventricular ischemia in patients with primary pulmonary hypertension. J. Am. Coll. Cardiol. 38, 1137-1142 (2001). (Pubitemid 32912723)
181. van Wolferen, S. A. et al. Right coronary artery flow impairment in patients with pulmonary hypertension. Eur. Heart J. 29, 120-127 (2008).
182. Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001-12004 (2004). (Pubitemid 38445760)
183. Umar, S. et al. Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension. Pathol. Res. Pract. 203, 863-872 (2007). (Pubitemid 350048629)
184. Broderick, T. L. & King, T. M. Upregulation of GLUT-4 in right ventricle of rats with monocrotaline-induced pulmonary hypertension. Med. Sci. Monit. 14, BR261-BR264 (2008).
185. Bogaard, H. J. et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 120, 1951-1960 (2009).
186. Hessel, M., Steendijk, P., den Adel, B., Schutte, C. & van der Laarse, A. Pressure overload-induced right ventricular failure is associated with re-expression of myocardial tenascin-C and elevated plasma tenascin-C levels. Cell Physiol. Biochem. 24, 201-210 (2009).
187. Kwapiszewska, G. et al. Fhl-1, a new key protein in pulmonary hypertension. Circulation 118, 1183-1194 (2008).
188. Abdul-Salam, V. B. et al. Identification of plasma protein biomarkers associated with idiopathic pulmonary arterial hypertension. Proteomics 6, 2286-2294 (2006).
189. Abdul-Salam, V. B. et al. Proteomic analysis of lung tissues from patients with pulmonary arterial hypertension. Circulation 122, 2058-2067(2010).
190. Champion, H. C., Michelakis, E. D. & Hassoun, P. M. Comprehensive invasive and noninvasive approach to the right ventricle-pulmonary circulation unit: state of the art and clinical and research implications. Circulation 120, 992-1007 (2009).
191. Sitbon, O. et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111, 3105-3111 (2005). (Pubitemid 40847788)