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The Proceedings of the American Thoracic Society 4:117-120 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200605-128JG
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Gene Expression Profiling in Pulmonary Hypertension

Todd M. Bull, Christopher D. Coldren, Mark W. Geraci and Norbert F. Voelkel

Pulmonary and Critical Care Medicine Division, Pulmonary Hypertension Center, University of Colorado at Denver and Health Sciences Center, Denver, Colorado

Correspondence and requests for reprints should be addressed to Mark W. Geraci, M.D., Division of Pulmonary Sciences and Critical Care Medicine, Gene Expression Facility, UCDHSC, 4200 East Ninth Avenue, Campus Box C-272, Denver, CO 80262. E-mail: mark.geraci{at}uchsc.edu

ABSTRACT

The application of functional genomics toward the investigation of complex medical conditions has moved from a futuristic dream to a medical reality in less then a decade. The ability to examine the expression level of thousands of genes simultaneously has opened the door for entirely new approaches toward experimental observation and discovery. The resulting data from these genomic studies is being collected at an unprecedented scale. This wealth of data can present its own obstacles in terms of analysis. However, as new and more powerful means of examining these experiments are developed, medical science is reaping significant benefit. The power of microarray gene expression analysis has been directed at a diverse and complex array of diseases. As will be discussed in this article, the investigation of pulmonary hypertension has already benefited greatly from the application of this technology.

Key Words: gene expression profiling • pulmonary hypertension • gene microarray • pulmonary vascular disease

As part of the second (Evian) and third (Venice) World Health Organization symposia on pulmonary arterial hypertension (PAH), experts from both clinical and basic science arenas recommended revision of the classification scheme for pulmonary hypertension (PH; Table 1) (1–3). This scheme was designed to "individualize different categories sharing similarities in pathological mechanisms, clinical presentation and therapeutic options." The diseases that comprise PAH were stratified in a manner consistent with current understanding of the pathobiology, facilitating discussion and the enrollment in clinical trials. However, these changes simultaneously highlight our lack of understanding regarding the basic pathologic mechanisms underlying the development of PAH. For example, why do radically diverse conditions, such as systemic lupus erythematosus, anorexigen exposure, or HIV-1 infection, result in similar pathologic changes in the lung vasculature (4–8)? Why does one individual with a connective tissue disease such as scleroderma develop pulmonary vascular disease while another develops pulmonary fibrosis (9–12)? Why do patients with PAH associated with congenital cardiac shunts have a better survival rate than patients with idiopathic PAH (IPAH)? (13) Clearly, the pathogenesis of PAH is complex, involving multiple modulating genes and environmental factors. Such complexity lends itself to the use of microarray technology, allowing the efficient and accurate simultaneous expression measurement of thousands of genes. Gene microarray technology has most successfully been used in the investigation of cancer, including hematologic malignancies, and in the classification of histologically indistinct tumor types with divergent natural histories (14–18). The power of this technology has recently been directed toward the study of PAH.


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  		TABLE 1. REVISED CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL HYPERTENSION (VENICE CLASSIFICATION)

 
GENE EXPRESSION PROFILING IN PH

In the investigation of PH, gene microarrays have been used in a variety of study designs performed on a diverse array of cell types and animal species. Human studies have examined the gene expression profile of whole lung homogenates as well as individual cell types, such as smooth muscle cells (SMCs) isolated from the pulmonary arteries of patients and mononuclear cells isolated from peripheral blood (19, 20). Animal microarray studies have been performed on both whole lung tissue and microdissected pulmonary vasculature of hypoxic and monocrotaline-induced PAH (21, 22). In aggregate, these studies have used "hypothesis building" strategies, helping to focus attention on potentially novel pathologic pathways. However, gene expression has also been used as a biomarker, potentially useful in classification or identification of an individual's risk of disease (23).

CHRONIC HYPOXIC PH

Both species and strain differences exist in the response of the lung circulation to chronic hypoxia. Mice, for example, have significantly less pulmonary vascular remodeling in response to hypoxia than do rats. In support of this observation, Hoshikawa and colleagues demonstrated that whole lung gene expression patterns of these two species differ significantly when exposed to hypoxia (21). In this series of experiments, Sprague-Dawley rats and C57BL/6 mice were exposed to chronic hypobaric hypoxia for 1 and 3 wk. Although both species developed PH, microscopically the mice had significantly less pulmonary vascular remodeling than did the rats. Microarray analysis of the lung tissue demonstrated distinct differences in gene expression induced by hypoxia between the species. Hypoxic conditions in the rat increased expression of genes involved in endothelial cell proliferation and decreased those associated with apoptosis. The lung tissue from the rats showed a greater than sevenfold up-regulated gene expression in both major histocompatibility antigen (MHC) class 2 antigens and osteopontin, whereas tissue expression of these genes in mice did not change. The phosphoinositide 3-kinase gene was greatly up-regulated (sixfold) in its expression in rat lungs but not in mouse lungs. This kinase regulates the expression of p21, enhancing G1/S transition in vascular SMCs (VSMCs) and insulin growth factor (IGF)-1–stimulated VSMC migration and proliferation. The gene expression pattern of the mouse lungs were notable for down-regulation of genes responsible for VSMC proliferation, such as IGF binding protein (24).

More recently, Kwapiszewska and coworkers (22) have performed microarray experiments using hypoxic mouse models, furthering our understanding of hypoxia-induced PH. Several differences exist between the rodent models used by Kwapiszewska and colleagues and Hoshikawa and colleagues, including mouse strain differences, degree of hypoxia, and hypobaric versus normobaric hypoxia (21, 22). Although pulmonary arterial pressures were not presented in this study, this model should induce increases in pulmonary artery pressures with a modest extent of vascular remodeling. Gene expression changes within the pulmonary arteries were measured by first using laser microdissection to isolate intrapulmonary arteries, thereby avoiding the dilution of the expected changes by the bulk lung (25). By sharpening their focus in this manner, Fink and colleagues (25) were able to detect increases in 20 genes after 1 d of hypoxia, 75% of which were subsequently found to bear putative hypoxia-inducible factor-responsive elements within up- and downstream regulatory regions. These immediate changes in gene expression stand in contrast to those observed after 7 and 21 d of hypoxia, which include matrix-associated genes such as procollagens and matrix {gamma}-carboxyglutamate. This time-dependent change was further characterized through immunohistochemical staining of S100A4 and CD36, which were localized in VSMCs, and FKBP1a, which was localized in fibroblasts.

GENE EXPRESSION PATTERNS IN THE LUNGS FROM PATIENTS WITH SEVERE PH

Geraci and coworkers analyzed the gene expression profile of lung tissue obtained from six patients with IPAH (two with familial PAH [FPAH]) versus six normal control subjects (26). The normal lung tissue was obtained during surgery and was free from pathology on histologic review. All the patients included in the IPAH cohort had severe PAH (Formula > 50 mm Hg). Two of the patients with IPAH had been diagnosed with FPAH. Unsupervised cluster analysis demonstrated significant and reproducible differences in gene expression between patients with IPAH and normal control subjects. From a total of approximately 6,800 genes analyzed, 307 were differentially expressed between the cohorts. There was significant down-regulation of genes encoding for a variety of kinases and phosphatases, whereas several oncogenes and genes encoding ion channel proteins were up-regulated. A highly intriguing finding was that the gene expression pattern of the lung tissue from patients with FPAH was distinct and distinguishable from the samples of non-FPAH patients. One of the IPAH samples clustered with the FPAH samples. This patient was adopted and her family history was unknown. It was hypothesized that she may have an unrecognized familial form of the disease. The bone morphogenic receptor-2 (BMPR2) status of these lung samples was unknown. The ability of the gene expression pattern to discriminate between IPAH lung tissue and lung tissue from patients without PAH is remarkable. Furthermore, the ability to distinguish between FPAH and IPAH by microarray analysis demonstrates the potential power of this approach.

One of the concordantly differentially expressed genes in the study by Geraci and coworkers was caveolin-1 (26). This gene was decreased in its expression in IPAH when compared with normal lung tissue. Calveolin-1 is down-regulated in transformed cells and may be a tumor suppressor protein (27, 28). Based on the microarray experiment results, immunohistochemical (IHC) analysis of lungs from patients with severe PAH was undertaken and a decrease in caveolin-1 expression in the plexiform lesions was noted (29). There was no significant difference in calveolin-1 detected by Western blot analysis of PAH lung tissue compared with normal lung tissue. The authors hypothesized that the loss of protein detected by IHC was predominately in the plexiform lesions, with undiminished expression in the surrounding tissue; therefore, decreased total protein levels from calvolin-1 could not be detected by immunoblotting.

The study from Geraci and colleagues provided a wealth of data that require further investigation. For example, this study indicated increased expression of the gene encoding the antiapoptotic protein B-cell leukemia/lymphoma-2 (BCL-2). Indeed, IHC again confirmed overexpression of BCL-2 protein in the plexiform lesions from patients with IPAH (unpublished data, personal communication with N.F.V.). Zhang and colleagues have demonstrated that BMP-2 and BMP-7 induce apoptosis in cultured pulmonary artery SMCs (PASMCs) associated with a marked down-regulation of BCL-2 (30). When exposed to BMP-2 and BMP-7, PASMCs isolated from patients with IPAH had decreased apoptosis as compared with PASMCs from patients with other secondary causes of PAH.

MICROARRAY GENE EXPRESSION OF PERIPHERAL BLOOD MONOCYTES

Inflammation and autoimmunity are possible contributing factors in the development of PAH (31–34). We hypothesized that the gene expression of peripheral blood mononuclear cells (PBMCs) would be altered in patients with PAH as compared with normal control subjects. Furthermore, we hypothesized that PBMCs could serve as a readily available surrogate tissue in patients with PAH, and that the gene expression profile of these cells could act as a biomarker of disease. The gene expression of PBMCs from 15 patients with PAH (including IPAH and PAH associated with a variety of other conditions, such as celcinosis cutis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangectasias (CREST), portal hypertension, and thromboembolic disease) was compared with the PBMC gene expression of six normal control subjects. We identified a signature set of 106 genes that discriminated with high certainty (p <= 0.002) between patients with PAH and normal control subjects. A subset of these genes was then validated by quantitative polymerase chain reaction both retrospectively on the initial group, and prospectively on a novel cohort of patients. The 106-gene signature identified genes previously recognized to be associated with PAH (e.g., adrenomedullin) as well as genes, such as endothelial cell growth factor-1 (ECGF-1), which may play a currently unrecognized role in the disease (35). Notably, we were unable to identify a gene expression signature that discriminated between IPAH and PAH associated with other conditions such as scleroderma or thromboembolic disease by unsupervised analysis in this study. This inability may have been due to inadequate sample size or to the diverse nature of diseases included in the non-IPAH cohort (36). A third possibility is that a unique expression profile for IPAH does not exist in peripheral blood cells; however, a supervised cluster analysis performed on these samples identified genes that may be differentially expressed between the groups. This strategy identified a list of 28 genes differentially expressed between IPAH and PAH associated with secondary conditions, such as CREST syndrome, thromboembolic disease, and portal hypertension (20). One of these genes, herpesvirus entry mediator (HVEM), was retrospectively and prospectively confirmed by quantitative polymerase chain reaction. This study again represents two potential uses of microarray gene expression in PAH. These include the following: (1) a hypothesis-generating tool to identify previously unsuspected genes or pathways that contribute to disease and (2) use of gene expression as a biomarker of disease. If a gene expression pattern predictive of PAH could be identified, then "at risk" populations could be screened. Patients who are identified as being at high risk for disease could initiate therapy early in hopes of impacting the natural history of PAH. The strategy of gene expression as a biomarker has been successfully demonstrated in acute myeloid leukemia (17, 18).

GENE EXPRESSION OF PASMCs

BMPs regulate cell proliferation and apoptosis. Mutations of BMPR2 have been associated with the development of severe PAH. As discussed above in the work of Zhang and Morrell and colleagues, SMCs isolated from patients with BMPR2 mutations and cultured in vitro behave very differently in response to exogenous BMP-2 than PASMCs from normal individuals (30, 37). BMP-2 inhibits apoptosis and reduces proliferation in normal PASMCs while inducing proliferation in SMCs from patients with IPAH. Fantozzi and coworkers examined differences in gene expression of cultured human PASMCs from normal individuals versus patients with IPAH (38). In this interesting study, PASMCs were isolated from two normal lungs and from two patients diagnosed with severe IPAH (PA mean > 50 mm Hg; BMPR2 status unknown). The cultured cells were incubated with 200 nM of BMP-2 in vitro for 24 h, and changes in gene expression were assessed by microarray analysis. BMP-2 treatment altered the expression of 6,206 genes. Of these, 1,063 genes were divergent in their expression in normal PASMCs compared with the PASMCs from patients with IPAH (i.e., increased in expression in cells from normal individuals and decreased in IPAH or decreased in cells from normal pulmonary arteries and increased in IPAH). These divergent genes were hypothesized to be relevant to the previously identified divergent phenotypic response of the cultured SMCs to BMP-2. Fantozzi and colleagues also attempted to correlate gene expression of the genes altered by BMP-2 exposure, either negatively or positively, with the pulmonary arterial pressure of the patients. Interestingly, several of these genes, such as caveolin-1 and voltage-gated Na+ and K+ channels, are consistent with those reported by Geraci and coworkers in the whole lung studies of patients with IPAH compared with normal control subjects (26). Although the authors admit to the significant potential problems of interpreting data with such a very small sample size (two patients in each group), this study again demonstrates the power of this approach.

GENE EXPRESSION ANALYSIS OF THE RIGHT VENTRICLE

Buermanns and colleagues used spotted oligonucleotide arrays to examine the difference in gene expression between right ventricular (RV) failure and RV compensation in response to PH (39). Compensated RV hypertrophy or uncompensated RV failure was induced in Wistar rats by varying the amount of monocrotaline administered. Monocrotaline is an established means of inducing pulmonary vascular disease, PAH, and RV failure (40). The gene expression of the hypertrophied right ventricle was compared between these two groups (compensated vs. uncompensated) and to the RV gene expression of control animals. The ventricles "destined" to progress to failure showed activation of proapoptotic pathways, whereas the animals that developed compensated RV hypertrophy had significant up-regulation of mitogen-activated protein kinase (MAPK) phosphatase-1, presumably blocking the apoptotic pathway via p38-MAPK. Western analysis of phosphorylated p38-MAPK demonstrated marked activation in the compensated RV hypertrophied group only. The microarray expression profiles showed both quantitative and qualitative differences in gene expression, implying a fundamental shift in the balance of proapoptotic versus antiapoptotic signaling in the hypertrophic phenotypes studied. These observations serve to improve our understanding of the basic mechanisms behind RV failure as well as potentially providing new therapeutic targets for treatment of RV failure.

CONCLUSIONS

Gene microarray technology has successfully been used 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 clear from the studies presented in this review. However, it is equally as clear that we are early on in the use of microarray analysis toward the study this disease. Although many studies to date have used microarray analysis as a hypothesis-generating tool, this technology also has vast potential as means of identifying and quantifying biomarkers of disease. The oncologic literature has demonstrated the utility of gene microarray analysis to predict important outcomes such as response to therapy and survival (41, 42). Although many of these studies have examined the gene expression of tissue biopsies, others have examined less invasive options, such as expression analysis of cells obtained from peripheral blood (43, 44). It is likely that, in the near future, gene microarray analyses will also be used in a pharmacogenomics approach in PAH, helping to identify the most appropriate therapies for individual patients (45, 46). These goals are ambitious, but certainly accomplishable. Such approaches will significantly increase our understanding of the pathobiology of PAH and aid in our struggle against this disabling and deadly disease.

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form May 18, 2006; accepted in final form June 26, 2006)

REFERENCES

  1. Fishman AP. Clinical classification of pulmonary hypertension. Clin Chest Med 2001;22:385–391.[CrossRef][Medline]
  2. Rich S. Executive summary from the World Symposium on Primary Pulmonary Hypertension 1998. Geneva, Switzerland: World Health Organization; 1998.
  3. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S–12S.[Abstract/Free Full Text]
  4. Johnson SR, Gladman DD, Urowitz MB, Ibanez D, Granton JT. Pulmonary hypertension in systemic lupus. Lupus 2004;13:506–509.[Abstract/Free Full Text]
  5. 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 2000;117:870–874.
  6. Gross SB, Lepor NE. Anorexigen-related cardiopulmonary toxicity. Rev Cardiovasc Med 2000;1:80–89, 102.[Medline]
  7. 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 1998;28:1404–1408.[Medline]
  8. 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 1986;29:515–524.[Medline]
  9. de Azevedo AB, Sampaio-Barros PD, Torres RM, Moreira C. Prevalence of pulmonary hypertension in systemic sclerosis. Clin Exp Rheumatol 2005;23:447–454.[Medline]
  10. Trad S, Amoura Z, Beigelman C, Haroche J, Costedoat N, Boutin LT, Cacoub P, Frances C, Wechsler B, Grenier P, et al. Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease. Arthritis Rheum 2006;54:184–191.[CrossRef][Medline]
  11. 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 2005;52:2125–2132.[CrossRef][Medline]
  12. Steen VD. The lung in systemic sclerosis. J Clin Rheumatol 2005;11:40–46.
  13. 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 2004;126:78S–92S.
  14. Khan J, Wei JS, Ringner M, Saal LH, Ladanyi M, Westermann F, Berthold F, Schwab M, Antonescu CR, Peterson C, et al. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med 2001;7:673–679.[CrossRef][Medline]
  15. Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben Dor A, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 2000;406:536–540.[CrossRef][Medline]
  16. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 2001;98:13790–13795.[Abstract/Free Full Text]
  17. 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 2004;350:1605–1616.[Abstract/Free Full Text]
  18. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Lowenberg B, et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004;350:1617–1628.[Abstract/Free Full Text]
  19. 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 2005;31:783–806.[CrossRef][Medline]
  20. 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 2004;170:911–919.[Abstract/Free Full Text]
  21. Hoshikawa Y, Nana-Sinkam P, Moore MD, Sotto-Santiago S, Phang T, Keith RL, Morris KG, Kondo T, Tuder RM, Voelkel NF, et al. Hypoxia induces different genes in the lungs of rats compared with mice. Physiol Genomics 2003;12:209–219.[Abstract/Free Full Text]
  22. 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 2005;6:109.[CrossRef][Medline]
  23. Buermans HP, Redout EM, Schiel AE, Musters RJ, Zuidwijk M, Eijk PP, van Hardeveld C, Kasanmoentalib S, Visser FC, Ylstra B, et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 2005;21:314–323.[Abstract/Free Full Text]
  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 1990;144: 159–165.[CrossRef][Medline]
  25. Fink L, Kohlhoff S, Stein MM, Hanze J, Weissmann N, Rose F, Akkayagil E, Manz D, Grimminger F, Seeger W, et al. cDNA array hybridization after laser-assisted microdissection from nonneoplastic tissue. Am J Pathol 2002;160:81–90.[Abstract/Free Full Text]
  26. Geraci MW, Moore M, Gesell T, Yeager ME, Alger L, Golpon H, Gao B, Loyd JE, Tuder RM, Voelkel NF. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res 2001;88:555–562.[Abstract/Free Full Text]
  27. Razani B, Schlegel A, Liu J, Lisanti MP. Caveolin-1, a putative tumour suppressor gene. Biochem Soc Trans 2001;29:494–499.[CrossRef][Medline]
  28. Lee SW, Reimer CL, Oh P, Campbell DB, Schnitzer JE. Tumor cell growth inhibition by caveolin re-expression in human breast cancer cells. Oncogene 1998;16:1391–1397.[CrossRef][Medline]
  29. 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 2006;129:696–705.
  30. 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 2003;285:L740–L754.[Abstract/Free Full Text]
  31. 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 1995;151:1628–1631.[Abstract]
  32. 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 1992;93:307–312.[CrossRef][Medline]
  33. Voelkel NF, Tuder R. Interleukin-1 receptor antagonist inhibits pulmonary hypertension induced by inflammation. Ann N Y Acad Sci 1994;725:104–109.[Medline]
  34. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114:225S–230S.
  35. Vizza CD, Letizia C, Sciomer S, Naeije R, Della RG, Di Roma A, Musaro S, Quattrucci S, Gaudio C, Battagliese A, et al. Increased plasma levels of adrenomedullin, a vasoactive peptide, in patients with end-stage pulmonary disease. Regul Pept 2005;124:187–193.[CrossRef][Medline]
  36. Sheppard D. Fishing in the bloodstream: insights into the mechanisms of pulmonary hypertension? Am J Respir Crit Care Med 2004;170:827–828.[Free Full Text]
  37. 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 2001;104:790–795.
  38. 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 2005;31:783–806.[CrossRef][Medline]
  39. Buermans HP, Redout EM, Schiel AE, Musters RJ, Zuidwijk M, Eijk PP, van Hardeveld C, Kasanmoentalib S, Visser FC, Ylstra B, et al. Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure. Physiol Genomics 2005;21:314–323.[Abstract/Free Full Text]
  40. 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 2002;23:93–102.[Medline]
  41. Chatterjee SK, Zetter BR. Cancer biomarkers: knowing the present and predicting the future. Future Oncol 2005;1:37–50.
  42. Reis-Filho JS, Westbury C, Pierga JY. The impact of expression profiling on prognostic and predictive testing in breast cancer. J Clin Pathol 2006;59:225–231.[Abstract/Free Full Text]
  43. 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 2006;24:1754–1760.[Abstract/Free Full Text]
  44. Lacayo NJ, Meshinchi S, Kinnunen P, Yu R, Wang Y, Stuber CM, Douglas L, Wahab R, Becton DL, Weinstein H, et al. Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes. Blood 2004;104:2646–2654.[Abstract/Free Full Text]
  45. Murali S. Pulmonary arterial hypertension. Curr Opin Crit Care 2006;12:228–234.[Medline]
  46. Woodcock J. Pharmacogenetics: on the road to "personalized medicine." FDA Consum 2005;39:44.[Medline]
  47. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5s–12s.



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