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Genomics and Proteomics of Pulmonary Vascular Disease

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Study of RNA and proteins in cells of both normal and diseased tissues is providing researchers with new knowledge of disease pathologies. While still in its early stages, high‐throughput expression analysis is improving our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). While many studies have used microarray and proteomic analyses as “hypothesis‐generating” tools, the technologies also have potential to identify and quantify biomarkers of disease. To date, many of the published studies have examined gene expression profiles of tissue biopsies, others have utilized cells from peripheral blood. Microarray technology has been employed successfully in the investigation of a diverse array of human diseases. The potential of high‐throughput expression analysis to improve our understanding of the pathogenesis of PAH is highlighted in this review. Proteomic studies of PAH and pulmonary vascular diseases in general have been little utilized thus far. To date, such studies are few and no consistent biomarker has emerged from studies of either plasma or blood cells from idiopathic pulmonary arterial hypertension (IPAH) patients. The studies of both lung tissue and lymphocytes are perhaps more revealing and suggest that changes in the cytoskeletal machinery may play a role in the pathogenesis of idiopathic pulmonary arterial hypertension. The oncology literature has demonstrated the utility of gene microarray analysis to predict important outcomes such as response to therapy and survival. It is likely that in the near future, gene microarrays and proteomic analyses will also be employed in a pharmacogenomics approach in PAH, helping to identify the most appropriate therapies for individual patients. © 2011 American Physiological Society. Compr Physiol 1:467‐483, 2011.

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Figure 1. Figure 1.

Dendrogram and heat map of protein expression from transformed lymphocytes from affected patients, obligate individuals, and married‐in control subjects both with and without a 4‐h treatment with bone morphogenic protein‐4 (BMP‐4). The dendrogram illustrates a distinct compartmentalization in protein‐expression patterns between the three groups. No differences are found between the samples with and without treatment with BMP‐4. The differences in protein expression are clearly seen in the heat map. Expression patterns in selected proteins are visually presented as horizontal lines in an expression matrix using a relative scale ranging from −0.5 (green) to +0.5 (red). Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society. Meyrick et al. . OFFICIAL JOURNAL OF THE AMERICAN THORACIC SOCIETY DIANE GERN, Publisher.

Figure 1.

Dendrogram and heat map of protein expression from transformed lymphocytes from affected patients, obligate individuals, and married‐in control subjects both with and without a 4‐h treatment with bone morphogenic protein‐4 (BMP‐4). The dendrogram illustrates a distinct compartmentalization in protein‐expression patterns between the three groups. No differences are found between the samples with and without treatment with BMP‐4. The differences in protein expression are clearly seen in the heat map. Expression patterns in selected proteins are visually presented as horizontal lines in an expression matrix using a relative scale ranging from −0.5 (green) to +0.5 (red). Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society. Meyrick et al. . OFFICIAL JOURNAL OF THE AMERICAN THORACIC SOCIETY DIANE GERN, Publisher.

 1. Abdul‐Salam VB, Paul GA, Ali JO, Gibbs SR, Rahman D, Taylor GW, Wilkins MR, Edwards RJ. Identification of plasma protein biomarkers associated with idiopathic pulmonary arterial hypertension. Proteomics 6: 2286–2294, 2006.
 2. Achcar RO, Demura Y, Rai PR, Taraseviciene‐Stewart L, Kasper M, Voelkel NF, Cool CD. Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension. Chest 129: 696–705, 2006.
 3. Alban A, David SO, Bjorkesten L, Andersson C, Sloge E, Lewis S, Currie I. A novel experimental design for comparative two‐dimensional gel analysis: Two‐dimensional difference gel electrophoresis incorporating a pooled internal standard. Proteomics 3: 36–44, 2003.
 4. Aldred MA, Comhair SA, Varella‐Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2010. Epub June 25, 2010.
 5. Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez‐Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, Humbert M, Morrell NW, Trembath RC. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 27: 212–213, 2006.
 6. Bais C, Van GA, Eroles P, Mutlu A, Chiozzini C, Dias S, Silverstein RL, Rafii S, Mesri EA. Kaposi's sarcoma‐associated herpesvirus G‐protein‐coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor‐2/ KDR. Cancer Cell 3: 131–143, 2003.
 7. Basilico F, Nardini I, Mori F, Brambilla E, Benazzi L, De PA, Rosti E, Farina C, Mauri P. Characterization of factor VIII pharmaceutical preparations by means of MudPIT proteomic approach. J Pharm Biomed Anal 2010.
 8. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 98: 13790–13795, 2001.
 9. Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben‐Dor A, Sampas N, Dougherty E, Wang E, Marincola F, Gooden C, Lueders J, Glatfelter A, Pollock P, Carpten J, Gillanders E, Leja D, Dietrich K, Beaudry C, Berens M, Alberts D, Sondak V. Molecular classification of cutaneous malignant melanoma by gene‐expression profiling. Nature 406: 536–540, 2000.
 10. Bitton DA, Okoniewski MJ, Connolly Y, Miller CJ. Exon level integration of proteomics and microarray data. BMC Bioinformatics 9: 118, 2008.
 11. Blencowe BJ, Ahmad S, Lee LJ. Current‐generation high‐throughput sequencing: Deepening insights into mammalian transcriptomes. Genes Dev 23: 1379–1386, 2009.
 12. Boshoff C, Endo Y, Collins PD, Takeuchi Y, Reeves JD, Schweickart VL, Siani MA, Sasaki T, Williams TJ, Gray PW, Moore PS, Chang Y, Weiss RA. Angiogenic and HIV‐inhibitory functions of KSHV‐encoded chemokines. Science 278: 290–294, 1997.
 13. Buermans HP, Redout EM, Schiel AE, Musters RJ, Zuidwijk M, Eijk PP, van HC, Kasanmoentalib S, Visser FC, Ylstra B and Simonides WS. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 21: 314–323, 2005.
 14. Bull TM, Coldren CD, Moore M, Sotto‐Santiago SM, Pham DV, Nana‐Sinkam SP, Voelkel NF, Geraci MW. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med 170: 911–919, 2004.
 15. Bull TM, Meadows CA, Coldren CD, Moore M, Sotto‐Santiago SM, Nana‐Sinkam SP, Campbell TB, Geraci MW. Human herpesvirus‐8 infection of primary pulmonary microvascular endothelial cells. Am J Respir Cell Mol Biol 39: 706–716, 2008.
 16. Bullinger L, Dohner K, Bair E, Frohling S, Schlenk RF, Tibshirani R, Dohner H, Pollack JR. Use of gene‐expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 350: 1605–1616, 2004.
 17. Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southgate M, MacDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW, Baker AH. Dynamic changes in lung microRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arterioscler Thromb Vasc Biol 30: 716–723, 2010.
 18. Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, Humbert M. Endoglin germline mutation in a patient with hereditary hemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59: 446–448, 2004.
 19. Chatterjee SK, Zetter BR. Cancer biomarkers: knowing the present and predicting the future. Future Oncol 1: 37–50, 2005.
 20. Chaurand P, Latham JC, Lane KB, Mobley JA, Polosukhin VV, Wirth PS, Nanney LB, Caprioli RM. Imaging mass spectrometry of intact proteins from alcohol‐preserved tissue specimens: Bypassing formalin fixation. J Proteome Res 7: 3543–3555, 2008.
 21. 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 349: 1113–1122, 2003.
 22. Damania B, Desrosiers RC. Simian homologues of human herpesvirus 8. Philos Trans R Soc Lond B Biol Sci 356: 535–543, 2001.
 23. de Azevedo AB, Sampaio‐Barros PD, Torres RM, Moreira C. Prevalence of pulmonary hypertension in systemic sclerosis. Clin Exp Rheumatol 23: 447–454, 2005.
 24. Dempsey EC, Stenmark KR, McMurtry IF, O'Brien RF, Voelkel NF, Badesch DB. Insulin‐like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways. J Cell Physiol 144: 159–165, 1990.
 25. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. 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.
 26. Desrosiers RC, Sasseville VG, Czajak SC, Zhang X, Mansfield KG, Kaur A, Johnson RP, Lackner AA, Jung JU. A herpesvirus of rhesus monkeys related to the human Kaposi's sarcoma‐associated herpesvirus. J Virol 71: 9764–9769, 1997.
 27. Echan LA, Tang HY, Ali‐Khan N, Lee K, Speicher DW. Depletion of multiple high‐abundance proteins improves protein‐profiling capacities of human serum and plasma. Proteomics 5: 3292–3303, 2005.
 28. Estep RD, Axthelm MK, Wong SW. A G‐protein‐coupled receptor encoded by rhesus rhadinovirus is similar to ORF74 of Kaposi's sarcoma‐associated herpesvirus. J Virol 77: 1738–1746, 2003.
 29. Fantozzi I, Huang W, Zhang J, Zhang S, Platoshyn O, Remillard CV, Thistlethwaite PA, Yuan JX. Divergent effects of BMP‐2 on gene expression in pulmonary artery smooth muscle cells from normal subjects and patients with idiopathic pulmonary arterial hypertension. Exp Lung Res 31: 783–806, 2005.
 30. Fink L, Kohlhoff S, Stein MM, Hanze J, Weissmann N, Rose F, Akkayagil E, Manz D, Grimminger F, Seeger W, Bohle RM. cDNA array hybridization after laser‐assisted microdissection from nonneoplastic tissue. Am J Pathol 160: 81–90, 2002.
 31. Fiorencis R, Zonzin P, Carraro M, Zampieri P, Roncon L, Baracca E, Masiero G, Bilato C. Pulmonary hypertension associated with human immunodeficiency virus infection. Report of two cases and review of the literature. G Ital Cardiol 28: 1404–1408, 1998.
 32. Fishman AP. Clinical classification of pulmonary hypertension. Clin Chest Med 22: 385–91, vii, 2001.
 33. Friedman DB. An introduction to proteomic technologies for the genomics scientist. In: Genomics: Essential Methods, Chichester: Wiley‐Blackwell, 2011. In press.
 34. Friedman DB, Hill S, Keller JW, Merchant NB, Levy SE, Coffey RJ, Caprioli RM. Proteome analysis of human colon cancer by two‐dimensional difference gel electrophoresis and mass spectrometry. Proteomics 4: 793–811, 2004.
 35. Galambos C, Montgomery J, Jenkins FJ. No role for kaposi sarcoma‐associated herpesvirus in pediatric idiopathic pulmonary hypertension. Pediatr Pulmonol 41: 122–125, 2006.
 36. 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 88: 555–562, 2001.
 37. Grigoryev DN, Mathai SC, Fisher MR, Girgis RE, Zaiman AL, Housten‐Harris T, Cheadle C, Gao L, Hummers LK, Champion HC, Garcia JG, Wigley FM, Tuder RM, Barnes KC, Hassoun PM. Identification of candidate genes in scleroderma‐related pulmonary arterial hypertension. Transl Res 151: 197–207, 2008.
 38. Groseclose MR, Massion PP, Chaurand P, Caprioli RM. High‐throughput proteomic analysis of formalin‐fixed, paraffin‐embedded tissue microarrays using MALDI imaging mass spectrometry. Proteomics 8: 3715–3724, 2008.
 39. Gross SB, Lepor NE. Anorexigen‐related cardiopulmonary toxicity. Rev Cardiovasc Med 1: 80–9, 102, 2000.
 40. Guo HG, Sadowska M, Reid W, Tschachler E, Hayward G, Reitz M. Kaposi's sarcoma‐like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J Virol 77: 2631–2639, 2003.
 41. Hardie WD, Korfhagen TR, Sartor MA, Prestridge A, Medvedovic M, Le Cras TD, Ikegami M, Wesselkamper SC, Davidson C, Dietsch M, Nichols W, Whitsett JA, Leikauf GD. Genomic profile of matrix and vasculature remodeling in TGF‐alpha induced pulmonary fibrosis. Am J Respir Cell Mol Biol 37: 309–321, 2007.
 42. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, Gruenig E, Kermeen F, Halme M, Raisanen‐Sokolowski A, Laitinen T, Morrell NW, Trembath RC. Molecular and functional analysis identifies ALK‐1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 40: 865–871, 2003.
 43. Hassel S, Eichner A, Yakymovych M, Hellman U, Knaus P, Souchelnytskyi S. Proteins associated with type II bone morphogenetic protein receptor (BMPR‐II) and identified by two‐dimensional gel electrophoresis and mass spectrometry. Proteomics 4: 1346–1358, 2004.
 44. Henke‐Gendo C, Mengel M, Hoeper MM, Alkharsah K, Schulz TF. Absence of Kaposi's sarcoma‐associated herpesvirus in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 172: 1581–1585, 2005.
 45. Hoshikawa Y, Nana‐Sinkam P, Moore MD, Sotto‐Santiago S, Phang T, Keith RL, Morris KG, Kondo T, Tuder RM, Voelkel NF, Geraci MW. Hypoxia induces different genes in the lungs of rats compared with mice. Physiol Genomics 12: 209–219, 2003.
 46. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot‐Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin‐1 and interleukin‐6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151: 1628–1631, 1995.
 47. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43: 13S‐24S, 2004.
 48. Irizarry RA, Ladd‐Acosta C, Carvalho B, Wu H, Brandenburg SA, Jeddeloh JA, Wen B, Feinberg AP. Comprehensive high‐throughput arrays for relative methylation (CHARM). Genome Res 18: 780–790, 2008.
 49. Isern RA, Yaneva M, Weiner E, Parke A, Rothfield N, Dantzker D, Rich S, Arnett FC. Autoantibodies in patients with primary pulmonary hypertension: Association with anti‐Ku. Am J Med 93: 307–312, 1992.
 50. Johnson SR, Gladman DD, Urowitz MB, Ibanez D, Granton JT. Pulmonary hypertension in systemic lupus. Lupus 13: 506–509, 2004.
 51. Katano H, Ito K, Shibuya K, Saji T, Sato Y, Sata T. Lack of human herpesvirus 8 infection in lungs of Japanese patients with primary pulmonary hypertension. J Infect Dis 191: 743–745, 2005.
 52. Khalsa‐Moyers G, McDonald WH. Developments in mass spectrometry for the analysis of complex protein mixtures. Brief Funct Genomic Proteomic 5: 98–111, 2006.
 53. Khan J, Wei JS, Ringner M, Saal LH, Ladanyi M, Westermann F, Berthold F, Schwab M, Antonescu CR, Peterson C, Meltzer PS. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 7: 673–679, 2001.
 54. Korstjens IJ, Rouws CH, Van Der Laarse WJ, Van Der Zee L, Stienen GJ. Myocardial force development and structural changes associated with monocrotaline induced cardiac hypertrophy and heart failure. J Muscle Res Cell Motil 23: 93–102, 2002.
 55. Kwapiszewska G, Wilhelm J, Wolff S, Laumanns I, Koenig IR, Ziegler A, Seeger W, Bohle RM, Weissmann N, Fink L. Expression profiling of laser‐microdissected intrapulmonary arteries in hypoxia‐induced pulmonary hypertension. Respir Res 6: 109, 2005.
 56. Kwapiszewska G, Wygrecka M, Marsh LM, Schmitt S, Trosser R, Wilhelm J, Helmus K, Eul B, Zakrzewicz A, Ghofrani HA, Schermuly RT, Bohle RM, Grimminger F, Seeger W, Eickelberg O, Fink L, Weissmann N. Fhl‐1, a new key protein in pulmonary hypertension. Circulation 118: 1183–1194, 2008.
 57. Lacayo NJ, Meshinchi S, Kinnunen P, Yu R, Wang Y, Stuber CM, Douglas L, Wahab R, Becton DL, Weinstein H, Chang MN, Willman CL, Radich JP, Tibshirani R, Ravindranath Y, Sikic BI, Dahl GV. Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes. Blood 104: 2646–2654, 2004.
 58. 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 26: 81–84, 2000.
 59. Laney AS, De MT, Peters JS, Malloy M, Teehankee C, Moore PS, Chang Y. Kaposi sarcoma‐associated herpesvirus and primary and secondary pulmonary hypertension. Chest 127: 762–767, 2005.
 60. Laudi S, Steudel W, Jonscher K, Schoning W, Schniedewind B, Kaisers U, Christians U, Trump S. Comparison of lung proteome profiles in two rodent models of pulmonary arterial hypertension. Proteomics 7: 2469–2478, 2007.
 61. Laumanns IP, Fink L, Wilhelm J, Wolff JC, Mitnacht‐Kraus R, Graef‐Hoechst S, Stein MM, Bohle RM, Klepetko W, Hoda MA, Schermuly RT, Grimminger F, Seeger W, Voswinckel R. The noncanonical WNT pathway is operative in idiopathic pulmonary arterial hypertension. Am J Respir Cell Mol Biol 40: 683–691, 2009.
 62. Lee SW, Reimer CL, Oh P, Campbell DB, Schnitzer JE. Tumor cell growth inhibition by caveolin re‐expression in human breast cancer cells. Oncogene 16: 1391–1397, 1998.
 63. Leonard MO, Howell K, Madden SF, Costello CM, Higgins DG, Taylor CT, McLoughlin P. Hypoxia selectively activates the CREB family of transcription factors in the in vivo lung. Am J Respir Crit Care Med 178: 977–983, 2008.
 64. Li W, Ruan K. MicroRNA detection by microarray. Anal Bioanal Chem 394: 1117–1124, 2009.
 65. Li Y, Elashoff D, Oh M, Sinha U, St John MA, Zhou X, Abemayor E, Wong DT. Serum circulating human mRNA profiling and its utility for oral cancer detection. J Clin Oncol 24: 1754–1760, 2006.
 66. Link AJ, Eng J, Schieltz DM, Carmack E, Mize GJ, Morris DR, Garvik BM, Yates JR, III. Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol 17: 676–682, 1999.
 67. Lohrig K, Wolters D. Multidimensional protein identification technology. Methods Mol Biol 564: 143–153, 2009.
 68. MacCoss MJ, McDonald WH, Saraf A, Sadygov R, Clark JM, Tasto JJ, Gould KL, Wolters D, Washburn M, Weiss A, Clark JI, Yates JR, III. Shotgun identification of protein modifications from protein complexes and lens tissue. Proc Natl Acad Sci U S A 99: 7900–7905, 2002.
 69. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA, III, Soubrier F, Trembath RC, Chung WK. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54: S32–S42, 2009.
 70. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G. Prognosis of pulmonary arterial hypertension: ACCP evidence‐based clinical practice guidelines. Chest 126: 78S‐92S, 2004.
 71. Meyrick B, Reid L. Hypoxia‐induced structural changes in the media and adventitia of the rat hilar pulmonary artery and their regression. Am J Pathol 100: 151–178, 1980.
 72. Meyrick BO, Friedman DB, Billheimer DD, Cogan JD, Prince MA, Phillips JA, III, Loyd JE. Proteomics of transformed lymphocytes from a family with familial pulmonary arterial hypertension. Am J Respir Crit Care Med 177: 99–107, 2008.
 73. Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor‐beta(1) and bone morphogenetic proteins. Circulation 104: 790–795, 2001.
 74. Murali S. Pulmonary arterial hypertension. Curr Opin Crit Care 12: 228–234, 2006.
 75. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 102: 865–870, 2000.
 76. Nicastri E, Vizza CD, Carletti F, Cicalini S, Badagliacca R, Poscia R, Ippolito G, Fedele F, Petrosillo N. Human herpesvirus 8 and pulmonary hypertension. Emerg Infect Dis 11: 1480–1482, 2005.
 77. Nomura F, Tomonaga T, Sogawa K, Ohashi T, Nezu M, Sunaga M, Kondo N, Iyo M, Shimada H, Ochiai T. Identification of novel and downregulated biomarkers for alcoholism by surface enhanced laser desorption/ionization‐mass spectrometry. Proteomics 4: 1187–1194, 2004.
 78. Odhiambo A, Perlman DH, Huang H, Costello CE, Farber HW, Steinberg MH, McComb ME, Klings ES. Identification of oxidative post‐translational modification of serum albumin in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension of sickle cell anemia. Rapid Commun Mass Spectrom 21: 2195–2203, 2007.
 79. Rabilloud T. Membrane proteins and proteomics: Love is possible, but so difficult. Electrophoresis 30 (Suppl 1): S174–S180, 2009.
 80. Rafeq S, Shah AM, Preston IR. Biomarkers in pulmonary arterial hypertension. Int J Clin Pract Suppl 36–41, 2009.
 81. Rajkumar R, Konishi K, Richards TJ, Ishizawar DC, Wiechert AC, Kaminski N, Ahmad F. Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension. Am J Physiol Heart Circ Physiol 298: H1235–H1248, 2010.
 82. Razani B, Schlegel A, Liu J, Lisanti MP. Caveolin‐1, a putative tumor suppressor gene. Biochem Soc Trans 29: 494–499, 2001.
 83. Reis‐Filho JS, Westbury C, Pierga JY. The impact of expression profiling on prognostic and predictive testing in breast cancer. J Clin Pathol 59: 225–231, 2006.
 84. Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L. Anorexigens and pulmonary hypertension in the United States: Results from the surveillance of North American pulmonary hypertension. Chest 117: 870–874, 2000.
 85. Ronci M, Bonanno E, Colantoni A, Pieroni L, Di IC, Spagnoli LG, Federici G, Urbani A. Protein unlocking procedures of formalin‐fixed, paraffin‐embedded tissues: Application to MALDI‐TOF imaging MS investigations. Proteomics 8: 3702–3714, 2008.
 86. Seeley EH, Caprioli RM. Molecular imaging of proteins in tissues by mass spectrometry. Proc Natl Acad Sci U S A 105: 18126–18131, 2008.
 87. Servettaz A, Agard C, Tamby MC, Guilpain P, Guillevin L, Mouthon L. Systemic sclerosis: Pathophysiology of a multifaceted disease. Presse Med 35: 1903–1915, 2006.
 88. Sheppard D. Fishing in the bloodstream: Insights into the mechanisms of pulmonary hypertension?. Am J Respir Crit Care Med 170: 827–828, 2004.
 89. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43: 5S‐12S, 2004.
 90. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 54: S43–S54, 2009.
 91. Sorace JM, Zhan M. A data review and re‐assessment of ovarian cancer serum proteomic profiling. BMC Bioinformatics 4: 24, 2003.
 92. Spees JL, Whitney MJ, Sullivan DE, Lasky JA, Laboy M, Ylostalo J, Prockop DJ. 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.
 93. Steen VD. The lung in systemic sclerosis. J Clin Rheumatol 11: 40–46, 2005.
 94. Stenmark KR, Gerasimovskaya E, Nemenoff RA, Das M. Hypoxic activation of adventitial fibroblasts: Role in vascular remodeling. Chest 122: 326S‐334S, 2002.
 95. Stupi AM, Steen VD, Owens GR, Barnes EL, Rodnan GP, Medsger TA, Jr. Pulmonary hypertension in the CREST syndrome variant of systemic sclerosis. Arthritis Rheum 29: 515–524, 1986.
 96. Tada Y, Majka S, Carr M, Harral J, Crona D, Kuriyama T, West J. Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH. Am J Physiol Lung Cell Mol Physiol 292: L1556–L1563, 2007.
 97. Terrier B, Tamby MC, Camoin L, Guilpain P, Broussard C, Bussone G, Yaici A, Hotellier F, Simonneau G, Guillevin L, Humbert M, Mouthon L. Identification of target antigens of antifibroblast antibodies in pulmonary arterial hypertension. Am J Respir Crit Care Med 177: 1128–1134, 2008.
 98. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR‐II, a receptor member of the TGF‐beta family. J Med Genet 37: 741–745, 2000.
 99. Trad S, Amoura Z, Beigelman C, Haroche J, Costedoat N, Boutin le TH, Cacoub P, Frances C, Wechsler B, Grenier P, Piette JC. Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. Arthritis Rheum 54: 184–191, 2006.
 100. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345: 325–334, 2001.
 101. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn‐Khosrovani, Boer JM, Beverloo HB, Moorhouse MJ, Van Der Spek PJ, Lowenberg B, Delwel R. Prognostically useful gene‐expression profiles in acute myeloid leukemia. N Engl J Med 350: 1617–1628, 2004.
 102. Vizza CD, Letizia C, Sciomer S, Naeije R, Della RG, Di RA, Musaro S, Quattrucci S, Gaudio C, Battagliese A, Badagliacca R, D'Erasmo E, Fedele F. Increased plasma levels of adrenomedullin, a vasoactive peptide, in patients with end‐stage pulmonary disease. Regul Pept 124: 187–193, 2005.
 103. Voelkel NF, Tuder R. Interleukin‐1 receptor antagonist inhibits pulmonary hypertension induced by inflammation. Ann N Y Acad Sci 725: 104–109, 1994.
 104. Wang W, Carvalho B, Miller ND, Pevsner J, Chakravarti A, Irizarry RA. Estimating genome‐wide copy number using allele‐specific mixture models. J Comput Biol 15: 857–866, 2008.
 105. West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips JA, Lane K, Meyrick B, Loyd J. Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics 1: 45, 2008.
 106. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward‐Able C. The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community‐based rheumatologists (the UNCOVER study). Arthritis Rheum 52: 2125–2132, 2005.
 107. Wolters DA, Washburn MP, Yates JR, III. An automated multidimensional protein identification technology for shotgun proteomics. Anal Chem 73: 5683–5690, 2001.
 108. Woodcock J. Pharmacogenetics: On the road to ‘personalized medicine’. FDA Consum 39: 44, 2005.
 109. Yang TY, Chen SC, Leach MW, Manfra D, Homey B, Wiekowski M, Sullivan L, Jenh CH, Narula SK, Chensue SW, Lira SA. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J Exp Med 191: 445–454, 2000.
 110. Yip TT, Cho WC, Cheng WW, Chan JW, Ma VW, Yip TT, Lau Yip CN, Ngan RK, Law SC. Application of protein chip array profiling in serum biomarker discovery for patients suffering from severe acute respiratory syndrome. Methods Mol Biol 382: 313–331, 2007.
 111. Yu M, Wang XX, Zhang FR, Shang YP, Du YX, Chen HJ, Chen JZ. Proteomic analysis of the serum in patients with idiopathic pulmonary arterial hypertension. J Zhejiang Univ Sci B 8: 221–227, 2007.
 112. Yuditskaya S, Tumblin A, Hoehn GT, Wang G, Drake SK, Xu X, Ying S, Chi AH, Remaley AT, Shen RF, Munson PJ, Suffredini AF, Kato GJ. Proteomic identification of altered apolipoprotein patterns in pulmonary hypertension and vasculopathy of sickle cell disease. Blood 113: 1122–1128, 2009.
 113. Zhang B, Kirov S, Snoddy J. WebGestalt: An integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 33: W741–W748, 2005.
 114. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285: L740–L754, 2003.

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Mark Geraci, Barbara Meyrick. Genomics and Proteomics of Pulmonary Vascular Disease. Compr Physiol 2011, 1: 467-483. doi: 10.1002/cphy.c100031