Gender, sex hormones and pulmonary hypertension

Pulmonary Circulation

Volumn 3, Issue 2, 2013, Pages 294-314

  Austin, Eric D ^a   Lahm, Tim ^b   West, James ^a   Tofovic, Stevan P ^c   Johansen, Anne Katrine ^d   MacLean, Margaret R ^d   Alzoubi, Abdallah ^e   Oka, Masahiko ^e  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF GLASGOW   (United Kingdom)

^e UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE   (United States)

Author keywords

Bone morphogenetic protein receptor type II; Dehydroepiandrosterone; Estrogen; Pulmonary hypertension; Serotonin

Indexed keywords

EID: 84888169923     PISSN: 20458932     EISSN: 20458940     Source Type: Journal    
DOI: 10.4103/2045-8932.114756     Document Type: Review

References (222)

1. Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension. Circulation 2008;118:2190-9.
2. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, et al. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 2009;54:S3-9.
3. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-54.
4. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, et al. Pulmonary arterial hypertension: Baseline characteristics from the reveal registry. Chest 2010;137:376-87.
5. Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008;51:1527-38.
6. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Pulmonary arterial hypertension in france: Results from a national registry. Am J Respir Crit Care Med 2006;173:1023-30.
7. Dresdale DT, Schultz M, Michtom RJ. Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 1951;11:686-705.
8. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216-23.
9. McGoon MD, Krichman A, Farber HW, Barst RJ, Raskob GE, Liou TG, et al. Design of the reveal registry for us patients with pulmonary arterial hypertension. Mayo Clin Proc 2008;83:923-31.
10. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, et al. Predicting survival in pulmonary arterial hypertension: Insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (reveal). Circulation 2010;122:164-72.
11. Ling Y, Johnson MK, Kiely DG, Condliffe R, Elliot CA, Gibbs JS, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: Results from the pulmonary hypertension registry of the united kingdom and ireland. Am J Respir Crit Care Med 2012;186:790-6.
12. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156-63.
13. Humbert M, Sitbon O, Yaici A, Montani D, O’Callaghan DS, Jais X, et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010;36:549-55.
14. Tofovic SP. Estrogens and development of pulmonary hypertension: Interaction of estradiol metabolism and pulmonary vascular disease. J Cardiovasc Pharmacol 2010;56:696-708.
15. Kleiger RE, Boxer M, Ingham RE, Harrison DC. Pulmonary hypertension in patients using oral contraceptives. A report of six cases. Chest 1976;69:143-7.
16. Morse JH, Horn EM, Barst RJ. Hormone replacement therapy: A possible risk factor in carriers of familial primary pulmonary hypertension. Chest 1999;116:847.
17. Irey NS, Manion WC, Taylor HB. Vascular lesions in women taking oral contraceptives. Arch Pathol 1970;89:1-8.
18. Irey NS, Norris HJ. Intimal vascular lesions associated with female reproductive steroids. Arch Pathol 1973;96:227-34.
19. Sweeney L, Voelkel NF. Estrogen exposure, obesity and thyroid disease in women with severe pulmonary hypertension. Eur J Med Res 2009;14:433-42.
20. Roberts KE, Fallon MB, Krowka MJ, Brown RS, Trotter JF, Peter I, et al. Genetic risk factors for portopulmonary hypertension in patients with advanced liver disease. Am J Respir Crit Care Med 2009;179:835-42.
21. Parl FF, Dawling S, Roodi N, Crooke PS. Estrogen metabolism and breast cancer: A risk model. Ann N Y Acad Sci 2009;1155:68-75.
22. Gonzalez FJ. The molecular biology of cytochrome p450s. Pharmacol Rev 1988;40:243-88.
23. Nebert DW, Russell DW. Clinical importance of the cytochromes p450. Lancet 2002;360:1155-62.
24. Tsuchiya Y, Nakajima M, Yokoi T. Cytochrome p450-mediated metabolism of estrogens and its regulation in human. Cancer Lett 2005;227:115-24.
25. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006;354:270-82.
26. Nebert DW. Elevated estrogen 16 alpha-hydroxylase activity: Is this a genotoxic or nongenotoxic biomarker in human breast cancer risk? J Natl Cancer Inst 1993;85:1888-91.
27. Roy D, Cai Q, Felty Q, Narayan S. Estrogen-induced generation of reactive oxygen and nitrogen species, gene damage, and estrogen-dependent cancers. J Toxicol Environ Health B Crit Rev 2007;10:235-57.
28. Bolton JL, Thatcher GR. Potential mechanisms of estrogen quinone carcinogenesis. Chem Res Toxicol 2008;21:93-101.
29. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, et al. Estrogen metabolism and risk of breast cancer: A prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 2000;11:635-40.
30. Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF. Cytochrome p450 1b1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation. Cancer Res 2007;67:812-7.
31. Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE. Circulating 2-hydroxy-and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev 2008;17:2029-35.
32. Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: The european prospective investigation into cancer and nutrition. Endocr Relat Cancer 2005;12:1071-82.
33. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 2004;96:1856-65.
34. Muti P, Westerlind K, Wu T, Grimaldi T, De Berry J 3rd, Schunemann H, et al. Urinary estrogen metabolites and prostate cancer: A case-control study in the united states. Cancer Causes Control 2002;13:947-55.
35. Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, et al. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:892-6.
36. West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips JA, et al. Gene expression in bmpr2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics 2008;1:45.
37. Agundez JA. Cytochrome p450 gene polymorphism and cancer. Curr Drug Metab 2004;5:211-24.
38. Greenlee H, Chen Y, Kabat GC, Wang Q, Kibriya MG, Gurvich I, et al. Variants in estrogen metabolism and biosynthesis genes and urinary estrogen metabolites in women with a family history of breast cancer. Breast Cancer Res Treat 2007;102:111-7.
39. Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, et al. Alterations in oestrogen metabolism: Implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J 2009;34:1093-9.
40. Austin ED, Hamid R, Hemnes AR, Loyd JE, Blackwell T, Yu C, et al. BMPR2 expression is suppressed by signaling through the estrogen receptor. Biol Sex Differ 2012;3:6.
41. Murphy E. Estrogen signaling and cardiovascular disease. Circ Res 2011;109:687-96.
42. Mendelsohn ME, Karas RH. Molecular and cellular basis of cardiovascular gender differences. Science 2005;308:1583-7.
43. Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med 1999;340:1801-11.
44. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. Estrogen receptors: How do they signal and what are their targets. Physiol Rev 2007;87:905-31.
45. Simoncini T, Mannella P, Fornari L, Caruso A, Varone G, Genazzani AR. Genomic and non-genomic effects of estrogens on endothelial cells. Steroids 2004;69:537-42.
46. Hsieh YC, Yu HP, Frink M, Suzuki T, Choudhry MA, Schwacha MG, et al. G protein-coupled receptor 30-dependent protein kinase a pathway is critical in nongenomic effects of estrogen in attenuating liver injury after trauma-hemorrhage. Am J Pathol 2007;170:1210-8.
47. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-oh kinase. Nature 2000;407:538-41.
48. Pedram A, Razandi M, Wallace DC, Levin ER. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol Biol Cell 2006;17:2125-37.
49. Simpkins JW, Yang SH, Sarkar SN, Pearce V. Estrogen actions on mitochondria--physiological and pathological implications. Mol Cell Endocrinol 2008;290:51-9.
50. Curtis SW, Washburn T, Sewall C, DiAugustine R, Lindzey J, Couse JF, et al. Physiological coupling of growth factor and steroid receptor signaling pathways: Estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci U S A 1996;93:12626-30.
51. Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, et al. Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem 2001;276:3459-67.
52. Chambliss KL, Yuhanna IS, Anderson RG, Mendelsohn ME, Shaul PW. Erbeta has nongenomic action in caveolae. Mol Endocrinol 2002;16:938-46.
53. Sherman TS, Chambliss KL, Gibson LL, Pace MC, Mendelsohn ME, Pfister SL, et al. Estrogen acutely activates prostacyclin synthesis in ovine fetal pulmonary artery endothelium. Am J Respir Cell Mol Biol 2002;26:610-6.
54. Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999;103:401-6.
55. Shaul PW. Rapid activation of endothelial nitric oxide synthase by estrogen. Steroids 1999;64:28-34.
56. Yu HP, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, Bland KI, et al. Mechanism of the nongenomic effects of estrogen on intestinal myeloperoxidase activity following trauma-hemorrhage: Upregulation of the pi-3k/Akt pathway. J Leukoc Biol 2007;82:774-80.
57. Suzuki T, Yu HP, Hsieh YC, Choudhry MA, Bland KI, Chaudry IH. Estrogenmediated activation of non-genomic pathway improves macrophages cytokine production following trauma-hemorrhage. J Cell Physiol 2008;214:662-72.
58. Ba ZF, Lu A, Shimizu T, Szalay L, Schwacha MG, Rue LW 3rd, et al. 17betaestradiol modulates vasoconstriction induced by endothelin-1 following trauma-hemorrhage. Am J Physiol Heart Circ Physiol 2007;292:H245-50.
59. Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, et al. Molecular cloning and characterization of human estrogen receptor betacx: A potential inhibitor ofestrogen action in human. Nucleic Acids Res 1998;26:3505-12.
60. Pare G, Krust A, Karas RH, Dupont S, Aronovitz M, Chambon P, et al. Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circ Res 2002;90:1087-92.
61. Toutain CE, Filipe C, Billon A, Fontaine C, Brouchet L, Guery JC, et al. Estrogen receptor alpha expression in both endothelium and hematopoietic cells is required for the accelerative effect of estradiol on reendothelialization. Arterioscler Thromb Vasc Biol 2009;29:1543-50.
62. Chambliss KL, Wu Q, Oltmann S, Konaniah ES, Umetani M, Korach KS, et al. Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. J Clin Invest 2010;120:2319-30.
63. Wu Q, Chambliss K, Umetani M, Mineo C, Shaul PW. Non-nuclear estrogen receptor signaling in the endothelium. J Biol Chem 2011;286:14737-43.
64. Haas E, Bhattacharya I, Brailoiu E, Damjanovic M, Brailoiu GC, Gao X, et al. Regulatory role of g protein-coupled estrogen receptor for vascular function and obesity. Circ Res 2009;104:288-91.
65. Peter I, Shearman AM, Zucker DR, Schmid CH, Demissie S, Cupples LA, et al. Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the framingham heart study. J Hypertens 2005;23:2193-200.
66. Shearman AM, Cooper JA, Kotwinski PJ, Humphries SE, Mendelsohn ME, Housman DE, et al. Estrogen receptor alpha gene variation and the risk of stroke. Stroke 2005;36:2281-2.
67. Shearman AM, Cooper JA, Kotwinski PJ, Miller GJ, Humphries SE, Ardlie KG, et al. Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts. Circ Res 2006;98:590-2.
68. Peter I, Shearman AM, Vasan RS, Zucker DR, Schmid CH, Demissie S, et al. Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women. Am J Hypertens 2005;18:1388-95.
69. Venkov CD, Rankin AB, Vaughan DE. Identification of authentic estrogen receptor in cultured endothelial cells. A potential mechanism for steroid hormone regulation of endothelial function. Circulation 1996;94:727-33.
70. Hamidi SA, Dickman KG, Berisha H, Said SI. 17beta-estradiol protects the lung against acute injury: Possible mediation by vasoactive intestinal polypeptide. Endocrinology 2011;152:4729-37.
71. Vegeto E, Cuzzocrea S, Crisafulli C, Mazzon E, Sala A, Krust A, et al. Estrogen receptor-alpha as a drug target candidate for preventing lung inflammation. Endocrinology 2010;151:174-84.
72. Karas RH, Patterson BL, Mendelsohn ME. Human vascular smooth muscle cells contain functional estrogen receptor. Circulation 1994;89:1943-50.
73. Jia S, Zhang X, He DZ, Segal M, Berro A, Gerson T, et al. Expression and function of a novel variant of estrogen receptor-alpha36 in murine airways. Am J Respir Cell Mol Biol 2011;45:1084-9.
74. Patrone C, Cassel TN, Pettersson K, Piao YS, Cheng G, Ciana P, et al. Regulation of postnatal lung development and homeostasis by estrogen receptor beta. Mol Cell Biol 2003;23:8542-52.
75. Suzuki T, Shimizu T, Yu HP, Hsieh YC, Choudhry MA, Schwacha MG, et al. Tissue compartment-specific role of estrogen receptor subtypes in immune cell cytokine production following trauma-hemorrhage. J Appl Physiol 2007;102:163-8.
76. Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS. Tissue distribution and quantitative analysis of estrogen receptor-alpha (eralpha) and estrogen receptor-beta (erbeta) messenger ribonucleic acid in the wildtype and eralpha-knockout mouse. Endocrinology 1997;138:4613-21.
77. Mollerup S, Jorgensen K, Berge G, Haugen A. Expression of estrogen receptors alpha and beta in human lung tissue and cell lines. Lung Cancer 2002;37:153-9.
78. Lahm T, Crisostomo PR, Markel TA, Wang M, Wang Y, Tan J, et al. Selective estrogen receptor-{alpha} and estrogen receptor-{beta} agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxidedependent mechanism. Am J Physiol Regul Integr Comp Physiol 2008;295:R1486-93.
79. Umar S, Iorga A, Matori H, Nadadur RD, Li J, Maltese F, et al. Estrogen rescues preexisting severe pulmonary hypertension in rats. Am J Respir Crit Care Med 2011;184:715-23.
80. Lahm T, Albrecht M, Fisher AJ, Selej M, Patel NG, Brown JA, et al. 17betaestradiol attenuates hypoxic pulmonary hypertension via estrogen receptormediated effects. Am J Respir Crit Care Med 2012;185:965-980.
81. Rajkumar R, Konishi K, Richards TJ, Ishizawar DC, Wiechert AC, Kaminski N, et al. Genomewide RNA expression profiling in lung identifies distinct signatures in idiopathic pulmonary arterial hypertension and secondary pulmonary hypertension. Am J Physiol Heart Circ Physiol 2010;298:H1235-48.
82. Wang M, Wang Y, Weil B, Abarbanell A, Herrmann J, Tan J, et al. Estrogen receptor beta mediates increased activation of pi3k/Akt signaling and improved myocardial function in female hearts following acute ischemia. Am J Physiol Regul Integr Comp Physiol 2009;296:R972-8.
83. Wang M, Crisostomo P, Wairiuko GM, Meldrum DR. Estrogen receptor-alpha mediates acute myocardial protection in females. Am J Physiol Heart Circ Physiol 2006;290:H2204-9.
84. Fliegner D, Schubert C, Penkalla A, Witt H, Kararigas G, Dworatzek E, et al. Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. Am J Physiol Regul Integr Comp Physiol 2010;298:R1597-606.
85. Lin J, Steenbergen C, Murphy E, Sun J. Estrogen receptor-beta activation results in s-nitrosylation of proteins involved in cardioprotection. Circulation 2009;120:245-54.
86. Kawut SM, Al-Naamani N, Agerstrand C, Rosenzweig EB, Rowan C, Barst RJ, et al. Determinants of right ventricular ejection fraction in pulmonary arterial hypertension. Chest 2009;135:752-9.
87. Ventetuolo CE, Ouyang P, Bluemke DA, Tandri H, Barr RG, Bagiella E, et al. Sex hormones are associated with right ventricular structure and function: The mesa-right ventricle study. Am J Respir Crit Care Med 2011;183:659-67.
88. Almeida M, Martin-Millan M, Ambrogini E, Bradsher R 3rd, Han L, Chen XD, et al. Estrogens attenuate oxidative stress and the differentiation and apoptosis of osteoblasts by DNA-binding-independent actions of the eralpha. J Bone Miner Res 2010;25:769-81.
89. Min HJ, Lee MJ, Kim JY, Cho SW, Park HD, Lee SI, et al. Alteration of bmp-4 and runx2 expression patterns in mouse temporomandibular joint after ovariectomy. Oral Dis 2007;13:220-7.
90. van den Wijngaard A, Mulder WR, Dijkema R, Boersma CJ, Mosselman S, van Zoelen EJ, et al. Antiestrogens specifically up-regulate bone morphogenetic protein-4 promoter activity in human osteoblastic cells. Mol Endocrinol 2000;14:623-33.
91. Monroe DG, Jin DF, Sanders MM. Estrogen opposes the apoptotic effects of bone morphogenetic protein 7 on tissue remodeling. Mol Cell Biol 2000;20:4626-34.
92. Zhang M, Yan JD, Zhang L, Wang Q, Lu SJ, Zhang J, et al. Activation of bone morphogenetic protein-6 gene transcription in mcf-7 cells by estrogen. Chin Med J (Engl) 2005;118:1629-36.
93. Wang D, Huang P, Zhu B, Sun L, Huang Q, Wang J. Induction of estrogen receptor alpha-36 expression by bone morphogenetic protein 2 in breast cancer cell lines. Mol Med Report 2012;6:591-6.
94. Wu L, Wu Y, Gathings B, Wan M, Li X, Grizzle W, et al. Smad4 as a transcription corepressor for estrogen receptor alpha. J Biol Chem 2003;278:15192-200.
95. Giacomini D, Paez-Pereda M, Stalla J, Stalla GK, Arzt E. Molecular interaction of bmp-4, tgf-beta, and estrogens in lactotrophs: Impact on the prl promoter. Mol Endocrinol 2009;23:1102-14.
96. Ebeling S, Topfer D, Weitzel JM, Meinecke B. Bone morphogenetic protein-6 (bmp-6): mRNA expression and effect on steroidogenesis during in vitro maturation of porcine cumulus oocyte complexes. Reprod Fertil Dev 2011;23:1034-42.
97. Donn R, Berry A, Stevens A, Farrow S, Betts J, Stevens R, et al. Use of gene expression profiling to identify a novel glucocorticoid sensitivity determining gene, bmprii. FASEB J 2007;21:402-14.
98. West J, Niswender KD, Johnson JA, Pugh ME, Gleaves L, Fessel JP, et al. A potential role for insulin resistance in experimental pulmonary hypertension. Eur Respir J 2012.
99. Ruegg J, Holsboer F, Turck C, Rein T. Cofilin 1 is revealed as an inhibitor of glucocorticoid receptor by analysis of hormone-resistant cells. Mol Cell Biol 2004;24:9371-82.
100. Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, et al. Direct signaling by the bmp type ii receptor via the cytoskeletal regulator limk1. J Cell Biol 2003;162:1089-98.
101. Johnson JA, Hemnes AR, Perrien DS, Schuster M, Robinson LJ, Gladson S, et al. Cytoskeletal defects in Bmpr2-associated pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2012;302:L474-84.
102. Wong WK, Knowles JA, Morse JH. Bone morphogenetic protein receptor type ii c-terminus interacts with c-src: Implication for a role in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2005;33:438-46.
103. Machado RD, Rudarakanchana N, Atkinson C, Flanagan JA, Harrison R, Morrell NW, 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 2003;12:3277-86.
104. 2+-dependent phospholipase a2 in estradiol-induced lysosome activation. Am J Physiol Cell Physiol 2002;283:C1461-8.
105. Durrington HJ, Upton PD, Hoer S, Boname J, Dunmore BJ, Yang J, et al. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type ii. J Biol Chem 2010;285:37641-9.
106. de Jesus Perez VA, Alastalo TP, Wu JC, Axelrod JD, Cooke JP, Amieva M, et al. Bone morphogenetic protein 2 induces pulmonary angiogenesis via wnt-beta-catenin and wnt-rhoa-rac1 pathways. J Cell Biol 2009;184:83-99.
107. Swaneck GE, Fishman J. Covalent binding of the endogenous estrogen 16 alpha-hydroxyestrone to estradiol receptor in human breast cancer cells: Characterization and intranuclear localization. Proc Natl Acad Sci USA 1988;85:7831-5.
108. Miyairi S, Maeda K, Oe T, Kato T, Naganuma A. Effect of metal ions on the stable adduct formation of 16alpha-hydroxyestrone with a primary amine via the heyns rearrangement. Steroids 1999;64:252-8.
109. Caja S, Puerta M. Control by reproduction-related hormones of resistin expression and plasma concentration. Horm Metab Res 2007;39:501-6.
110. Helmestam M, Andersson H, Stavreus-Evers A, Brittebo E, Olovsson M. Tamoxifen modulates cell migration and expression of angiogenesis-related genes in human endometrial endothelial cells. Am J Pathol 2012;180:2527-35.
111. Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res 2010;126:5-11.
112. Anderson JA, Weitz JI. Hypercoagulable states. Clin Chest Med 2010;31:659-73.
113. Escribano-Subias P, Blanco I, Lopez-Meseguer M, Lopez-Guarch CJ, Roman A, Morales P, et al. Survival in pulmonary hypertension in Spain: Insights from the spanish registry. Eur Respir J 2012;40:596-603.
114. Tofovic SP, Jackson EK. Complexities of oestradiol pharmacology in pulmonary arterial hypertension. Eur Respir J 2012.
115. Fishman J, Martucci C. Biological properties of 16 alpha-hydroxyestrone: Implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab 1980;51:611-5.
116. Zuckerman SH, Ahmari SE, Bryan-Poole N, Evans GF, Short L, Glasebrook AL. Estriol: A potent regulator of tnf and IL-6 expression in a murine model of endotoxemia. Inflammation 1996;20:581-97.
117. Lippert C, Seeger H, Mueck AO. The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells. Life Sci 2003;72:877-83.
118. Cullinan-Bove K, Koos RD. Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: Rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology 1993;133:829-37.
119. Ball P, Emons G, Kayser H, Teichmann J. Metabolic clearance rates of catechol estrogens in rats. Endocrinology 1983;113:1781-3.
120. Lakhani NJ, Sarkar MA, Venitz J, Figg WD. 2-methoxyestradiol, a promising anticancer agent. Pharmacotherapy 2003;23:165-72.
121. Dubey RK, Tofovic SP, Jackson EK. Cardiovascular pharmacology of estradiol metabolites. J Pharmacol Exp Ther 2004;308:403-9.
122. Sutherland TE, Anderson RL, Hughes RA, Altmann E, Schuliga M, Ziogas J, et al. 2-methoxyestradiol--a unique blend of activities generating a new class of anti-tumour/anti-inflammatory agents. Drug Discov Today 2007;12:577-84.
123. Tofovic SP, Dubey RK, Jackson EK. 2-hydroxyestradiol attenuates the development of obesity, the metabolic syndrome, and vascular and renal dysfunction in obese zsf1 rats. J Pharmacol Exp Ther 2001;299:973-7.
124. Zhang X, Jia Y, Jackson EK, Tofovic SP. 2-methoxyestradiol and 2-ethoxyestradiol retard the progression of renal disease in aged, obese, diabetic zsf1 rats. J Cardiovasc Pharmacol 2007;49:56-63.
125. Tofovic SP, Dubey R, Salah EM, Jackson EK. 2-hydroxyestradiol attenuates renal disease in chronic puromycin aminonucleoside nephropathy. J Am Soc Nephrol 2002;13:2737-47.
126. Tofovic SP, Salah EM, Dubey RK, Melhem MF, Jackson EK. Estradiol metabolites attenuate renal and cardiovascular injury induced by chronic nitric oxide synthase inhibition. J Cardiovasc Pharmacol 2005;46:25-35.
127. Tofovic SP, Zhang X, Zhu H, Jackson EK, Rafikova O, Petrusevska G. 2-ethoxyestradiol is antimitogenic and attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling. Vascul Pharmacol 2008;48:174-83.
128. Barchiesi F, Jackson EK, Fingerle J, Gillespie DG, Odermatt B, Dubey RK. 2-methoxyestradiol, an estradiol metabolite, inhibits neointima formation and smooth muscle cell growth via double blockade of the cell cycle. Circ Res 2006;99:266-74.
129. Tofovic SP, Salah EM, Mady HH, Jackson EK, Melhem MF. Estradiol metabolites attenuate monocrotaline-induced pulmonary hypertension in rats. J Cardiovasc Pharmacol 2005;46:430-7.
130. Tofovic SP, Zhang X, Jackson EK, Dacic S, Petrusevska G. 2-methoxyestradiol mediates the protective effects of estradiol in monocrotaline-induced pulmonary hypertension. Vascul Pharmacol 2006;45:358-67.
131. Tofovic SP, Zhang X, Jackson EK, Zhu H, Petrusevska G. 2-methoxyestradiol attenuates bleomycin-induced pulmonary hypertension and fibrosis in estrogen-deficient rats. Vascul Pharmacol 2009;51:190-7.
132. Tofovic SP, Zhang X, Jones T, Jackson EK, Petrusevska G, 2005. 2-methoxyestradiol attenuates the development and retards the progression of chronic hypoxia-induced pulmonary hypertension in rats. Circulation 2005;112:II98-9.
133. Tofovic SP, Jones TJ, Bilan VP, Jackson EK, Petrusevska G. Synergistic therapeutic effects of 2-methoxyestradiol with either sildenafil or bosentan on amelioration of monocrotaline-induced pulmonary hypertension and vascular remodeling. J Cardiovasc Pharmacol 2010;56:475-83.
134. Yuan PW, Wu WH, Gao L, Zheng ZQ, Liu D, Mei HY, et al. Oestradiol ameliorates monocrotaline pulmonary hypertension via NO, PGI2 AND ET-1 pathways. Eur Respir J 2012.
135. Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, 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 2001;15:427-38.
136. Tofovic SP, Rafikova O. Preventive and therapeutic effects of 2-methoxyestradiol, but not estradiol, in severe occlusive pulmonary arterial hypertension in female rats. Am J Respir Crit Care Med 2009;179.1_ MeetingAbstracts.A1802.
137. Tofovic SP, Rafikova O, Champion H. Estrogens exacerbates development of occlusive pulmonary arterial hypertension and formation of plexiform lesions. Am J Crit Care Med 2012;185.1_MeetingAbstracts.A6803.
138. Rafikova O, Rafikov R, Kumar S, Sharma S, Aggarwal S, Schneider F, et al. Bosentan inhibits oxidative and nitrosative stress and rescues occlusive pulmonaryhypertension. Free Radic Biol Med 2013;56:28-43.
139. Tofovic SP, Zhu H, Jackson EK, Rafikova O. 2-methoxyestrone inhibits vascular remodeling and attenuates monocrotaline-induced pulmonary hypertension. Eur Respir J 2008;32:S164.
140. Newman SP, Ireson CR, Tutill HJ, Day JM, Parsons MF, Leese MP, et al. The role of 17beta-hydroxysteroid dehydrogenases in modulating the activity of 2-methoxyestradiol in breast cancer cells. Cancer Res 2006;66:324-30.
141. Bayard F, Clamens S, Meggetto F, Blaes N, Delsol G, Faye JC. Estrogen synthesis, estrogen metabolism, and functional estrogen receptors in rat arterial smooth muscle cells in culture. Endocrinology 1995;136:1523-9.
142. Piao YS, Peltoketo H, Jouppila A, Vihko R. Retinoic acids increase 17 beta-hydroxysteroid dehydrogenase type 1 expression in JEG-3 and T47D cells, but the stimulation is potentiated by epidermal growth factor, 12-o-tetradecanoylphorbol-13-acetate, and cyclic adenosine 3’,5’-monophosphate only in jeg-3 cells. Endocrinology 1997;138:898-904.
143. Tofovic SP, Jackson EK, Rafikova O. Synergistic effects of 2-methoxyestradiol and retinoic acid on amelioration of monocrotaline-induced pulmonary hypertension. Am J Res Crit Care Med 2008;177:A592.
144. Welter BH, Hansen EL, Saner KJ, Wei Y, Price TM. Membrane-bound progesterone receptor expression in human aortic endothelial cells. J Histochem Cytochem 2003;51:1049-55.
145. Barberis MC, Veronese S, Bauer D, De Juli E, Harari S. Immunocytochemical detection of progesterone receptors. A study in a patient with primary pulmonary hypertension. Chest 1995;107:869-72.
146. Vazquez F, Rodriguez-Manzaneque JC, Lydon JP, Edwards DP, O’Malley BW, Iruela-Arispe ML. Progesterone regulates proliferation of endothelial cells. J Biol Chem 1999;274:2185-92.
147. English KM, Jones RD, Jones TH, Morice AH, Channer KS. Gender differences in the vasomotor effects of different steroid hormones in rat pulmonary and coronary arteries. Horm Metab Res 2001;33:645-52.
148. Tofovic PS, Zhang X, Petrusevska G. Progesterone inhibits vascular remodeling and attenuates monocrotaline-induced pulmonary hypertension in estrogen-deficient rats. Prilozi 2009;30:25-44.
149. Jones T, Zhang X, Jackson EK, Tofovic SP. Medroxyprogesterone acetate attenuates and tibolone prevents the development of monocrotaline-induced pulmonary hypertension. FASEB J 2006;20:A402.
150. Rochefort GY, Lemaire MC, Eder V, Hanton G, Hyvelin JM, Bonnet P, et al. Dexfenfluramine does not worsen but moderates progression of chronic hypoxia-induced pulmonary hypertension. Eur J Pharmacol 2006;550:149-54.
151. Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation 1999;100:869-75.
152. Eddahibi S, Adnot S, Frisdal E, Levame M, Hamon M, Raffestin B. Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats. J Pharmacol Exp Ther 2001;297:148-54.
153. Dempsie Y, Morecroft I, Welsh DJ, MacRitchie NA, Herold N, Loughlin L, et al. Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 2008;117:2928-37.
154. Liu M, Wang Y, Wang HM, Bai Y, Zhang XH, Sun YX, et al. Fluoxetine attenuates chronic methamphetamine-induced pulmonary arterial remodeling: Possible involvement of serotonin transporter and serotonin 1B receptor. Basic Clin Pharmacol Toxicol 2013;112:77-82.
155. Abid S, Houssaini A, Chevarin C, Marcos E, Tissot CM, Gary-Bobo G, et al. Inhibition of gut-and lung-derived serotonin attenuates pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 2012;303:L500-8.
156. Izikki M, Hanoun N, Marcos E, Savale L, Barlier-Mur AM, Saurini F, et al. Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: Effects on hypoxic pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol 2007;293:L1045-52.
157. Morecroft I, Dempsie Y, Bader M, Walther DJ, Kotnik K, Loughlin L, et al. Effect of tryptophan hydroxylase 1 deficiency on the development of hypoxia-induced pulmonary hypertension. Hypertension 2007;49:232-6.
158. Morecroft I, White K, Caruso P, Nilsen M, Loughlin L, Alba R, et al. Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial TPH1 attenuates hypoxia-induced pulmonary hypertension. Mol Ther 2012;20:1516-28.
159. Ciuclan L, Hussey MJ, Burton V, Good R, Duggan N, Beach S J et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. Am J Respir Crit Care Med 2013;187:78-89.
160. Eddahibi S, Guignabert C, Barlier-Mur AM, Dewachter L, Fadel E, Dartevelle P, et al. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: Critical role for serotonin-induced smooth muscle hyperplasia. Circulation 2006;113:1857-64.
161. MacLean MR, Deuchar GA, Hicks MN, Morecroft I, Shen S, Sheward J, et al. Overexpression of the 5-hydroxytryptamine transporter gene: Effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 2004;109:2150-5.
162. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, et al. Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 2000;105:1555-62.
163. Marcos E, Fadel E, Sanchez O, Humbert M, Dartevelle P, Simonneau G, et al. Serotonin-induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 2004;94:1263-70.
164. Liu Y, Li M, Warburton RR, Hill NS, Fanburg BL. The 5-ht transporter transactivates the pdgfbeta receptor in pulmonary artery smooth muscle cells. FASEB J 2007;21:2725-34.
165. Morecroft I, Heeley RP, Prentice HM, Kirk A, MacLean MR. 5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: Importance of the 5-ht1b receptor. Br J Pharmacol 1999;128:730-4.
166. Lawrie A, Spiekerkoetter E, Martinez EC, Ambartsumian N, Sheward WJ, MacLean MR, et al. Interdependent serotonin transporter and receptor pathways regulate s100a4/mts1, a gene associated with pulmonary vascular disease. Circ Res 2005;97:227-35.
167. Morecroft I, Pang L, Baranowska M, Nilsen M, Loughlin L, Dempsie Y, et al. In vivo effects of a combined 5-HT1B receptor/sert antagonist in experimental pulmonary hypertension. Cardiovasc Res 2010;85:593-603.
168. McGoon MD, Miller DP. REVEAL: A contemporary US pulmonary arterial hypertension registry. Eur Respir Rev 2012;21:8-18.
169. Fessel JP, Loyd JE, Austin ED. The genetics of pulmonary arterial hypertension in the post-bmpr2 era. Pulm Circ 2011;1:305-19.
170. Rabinovitch M, Gamble WJ, Miettinen OS, Reid L. Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Physiol 1981;240:H62-72.
171. Xu DQ, Luo Y, Liu Y, Wang J, Zhang B, Xu M, et al. Beta-estradiol attenuates hypoxic pulmonary hypertension by stabilizing the expression of p27kip1 in rats. Respir Res 2010;11:182.
172. White K, Dempsie Y, Nilsen M, Wright AF, Loughlin L, MacLean MR. The serotonin transporter, gender, and 17beta oestradiol in the development of pulmonary arterial hypertension. Cardiovasc Res 2011;90:373-82.
173. Dempsie Y, Nilsen M, White K, Mair KM, Loughlin L, Ambartsumian N, et al. Development of pulmonary arterial hypertension in mice over-expressing s100a4/mts1 is specific to females. Respir Res 2011;12:159.
174. Dempsie Y, Morecroft I, Nilsen M, Loughlin L, MacLean MR. The effects of gender on the development of dexfenfluramine-induced pulmonary arterial hypertension in mice. Am J Respir Crit Care Med 2009;179:A1808.
175. White K, Loughlin L, Maqbool Z, Nilsen M, McClure J, Dempsie Y, et al. Serotonin transporter, sex, and hypoxia: Microarray analysis in the pulmonary arteries of mice identifies genes with relevance to human PAH. Physiol Genomics 2011;43:417-37.
176. White K, Johansen AK, Nilsen M, Ciuclan L, Wallace E, Paton L, et al. Activity of the estrogen-metabolizing enzyme cytochrome p450 1b1 influences the development of pulmonary arterial hypertension. Circulation 2012;126:1087-98.
177. Carter KL, Cahir-McFarland E, Kieff E. Epstein-barr virus-induced changes in b-lymphocyte gene expression. J Virol 2002;76:10427-36.
178. Bandiera S, Weidlich S, Harth V, Broede P, Ko Y, Friedberg T. Proteasomal degradation of human CYP1B1: Effect of the asn453ser polymorphism on the post-translational regulation of cyp1b1 expression. Mol Pharmacol 2005;67:435-43.
179. Hanna IH, Dawling S, Roodi N, Guengerich FP, Parl FF. Cytochrome p450 1b1 (CYP1B1) pharmacogenetics: Association of polymorphisms with functional differences in estrogen hydroxylation activity. Cancer Res 2000;60:3440-4.
180. Simpson ER. Sources of estroge n and their importance. J Steroid Biochem Mol Biol 2003;86:225-30.
181. Misso ML, Jang C, Adams J, Tran J, Murata Y, Bell R, et al. Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy. Menopause 2005;12:210-5.
182. Badawi AF, Cavalieri EL, Rogan EG. Role of human cytochrome P450 1A1, 1A2, 1B1, and 3A4 in the 2-, 4-, and 16alpha-hydroxylation of 17betaestradiol. Metabolism 2001;50:1001-3.
183. Lee AJ, Cai MX, Thomas PE, Conney AH, Zhu BT. Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 2003;144:3382-98.
184. Meireles SI, Esteves GH, Hirata R, Peri S, Devarajan K, Slifker M, et al. Early changes in gene expression induced by tobacco smoke: Evidence for the importance of estrogen within lung tissue. Cancer Prev Res (Phila) 2010;3:707-17.
185. Conway DE, Sakurai Y, Weiss D, Vega JD, Taylor WR, Jo H, et al. Expression of CYP1A1 and CYP1B1 in human endothelial cells: Regulation by fluid shear stress. Cardiovasc Res 2009;81:669-77.
186. Tariq SH, Kamel H, Morley JE. Dehydroepiandrosterone and pregnenolone. In: Meikle AW, ed. Endocrine Replacement Therapy in Clinical Practice. Totowa, NJ; Humana Press; 2003: 307-368.
187. Johnson MD, Bebb RA, Sirrs SM. Uses of dhea in aging and other disease states. Ageing Res Rev 2002;1:29-41.
188. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551-5.
189. Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H. Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992;75:1002-4.
190. Baulieu EE. Dehydroepiandrosterone (DHEA): A fountain of youth? J Clin Endocrinol Metab 1996;81:3147-51.
191. Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: Intracrinology. Front Neuroendocrinol 2001;22:185-212.
192. MacDonald PC, Edman CD, Kerber IJ, Siiteri PK. Plasma precursors of estrogen. III. Conversion of plasma dehydroisoandrosterone to estrogen in young nonpregnant women. Gynecol Invest 1976;7:165-75.
193. Barrett-Connor E, Goodman-Gruen D. The epidemiology of dheas and cardiovascular disease. Ann N Y Acad Sci 1995;774:259-70.
194. Williams JR. The effects of dehydroepiandrosterone on carcinogenesis, obesity, the immune system, and aging. Lipids 2000;35:325-31.
195. Levy HR. Glucose-6-phosphate dehydrogenases. Adv Enzymol Relat Areas Mol Biol 1979;48:97-192.
196. Schwartz AG, Pashko LL. Dehydroepiandrosterone, glucose-6-phosphate dehydrogenase, and longevity. Ageing Res Rev 2004;3:171-87.
197. Tian WN, Braunstein LD, Pang J, Stuhlmeier KM, Xi QC, Tian X, et al. Importance of glucose-6-phosphate dehydrogenase activity for cell growth. J Biol Chem 1998;273:10609-17.
198. Gupte SA, Li KX, Okada T, Sato K, Oka M. Inhibitors of pentose phosphate pathway cause vasodilation: Involvement of voltage-gated potassium channels. J Pharmacol Exp Ther 2002;301:299-305.
199. Simoncini T, Mannella P, Fornari L, Varone G, Caruso A, Genazzani AR. Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms. Endocrinology 2003;144:3449-55.
200. Liu D, Dillon JS. Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to G alpha(i2,3). J Biol Chem 2002;277:21379-88.
201. Bhuiyan MS, Tagashira H, Fukunaga K. Dehydroepiandrosteronemediated stimulation of sigma-1 receptor activates akt-enos signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding. Cardiovasc Ther 2011;29:219-30.
202. Karbowska J, Kochan Z. Effect of dhea on endocrine functions of adipose tissue, the involvement of ppar gamma. Biochem Pharmacol 2005;70:249-57.
203. Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factorkappab signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 1998;273:32833-41.
204. Schulz S, Nyce JW. Inhibition of protein isoprenylation and p21ras membrane association by dehydroepiandrosterone in human colonic adenocarcinoma cells in vitro. Cancer Res 1991;51:6563-7.
205. Williams MR, Ling S, Dawood T, Hashimura K, Dai A, Li H, et al. Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ars and ers. J Clin Endocrinol Metab 2002;87:176-81.
206. Farrukh IS, Peng W, Orlinska U, Hoidal JR. Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: A Ca(2+)-activated K(+)-channel opener. Am J Physiol 1998;274:L186-95.
207. Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA, Botney MD. Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. Am J Pathol 1997;151:1019-25.
208. Hampl V, Bibova J, Povysilova V, Herget J. Dehydroepiandrosterone sulphate reduces chronic hypoxic pulmonary hypertension in rats. Eur Respir J 2003;21:862-5.
209. Bonnet S, Dumas-de-La-Roque E, Begueret H, Marthan R, Fayon M, Dos Santos P, et al. Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension. Proc Natl Acad Sci USA 2003;100:9488-93.
210. Oka M, Karoor V, Homma N, Nagaoka T, Sakao E, Golembeski SM, et al. Dehydroepiandrosterone upregulates soluble guanylate cyclase and inhibits hypoxic pulmonary hypertension. Cardiovasc Res 2007;74:377-87.
211. Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, et al. Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: The possible role of nitric oxide. Arterioscler Thromb Vasc Biol 2000;20:782-92.
212. Kawano H, Yasue H, Kitagawa A, Hirai N, Yoshida T, Soejima H, et al. Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men. J Clin Endocrinol Metab 2003;88:3190-5.
213. Debonneuil EH, Quillard J, Baulieu EE. Hypoxia and dehydroepiandrosterone in old age: A mouse survival study. Respir Res 2006;7:144.
214. Dessouroux A, Akwa Y, Baulieu EE. DHEA decreases HIF-1alpha accumulation under hypoxia in human pulmonary artery cells: Potential role in the treatment of pulmonary arterial hypertension. J Steroid Biochem Mol Biol 2008;109:81-9.
215. Dumas de La Roque E, Savineau JP, Metivier AC, Billes MA, Kraemer JP, Doutreleau S, et al. Dehydroepiandrosterone (DHEA) improves pulmonary hypertension in chronic obstructive pulmonary disease (COPD): A pilot study. Ann Endocrinol (Paris) 2012;73:20-5.
216. Homma N, Nagaoka T, Karoor V, Imamura M, Taraseviciene-Stewart L, Walker LA, et al. Involvement of RHOA/RHO kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone. Am J Physiol Lung Cell Mol Physiol 2008;295:L71-8.
217. Paulin R, Meloche J, Jacob MH, Bisserier M, Courboulin A, Bonnet S. Dehydroepiandrosterone inhibits the src/stat3 constitutive activation in pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2011;301:H1798-809.
218. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, et al. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010;121:2747-54.
219. Bogaard HJ, Natarajan R, Henderson SC, Long CS, Kraskauskas D, Smithson L, et al. Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure. Circulation 2009;120:1951-60.
220. Alzoubi A, Toba M, Abe K, O’Neill KD, Rocic P, Fagan KA, et al. Dehydroepiandrosterone restores right ventricular structure and function in rats with severe pulmonary arterial hypertension. Am J Physiol Heart Circ Physiol 2013 Apr 12. [Epub ahead of print]
221. Ahlem C, Auci D, Mangano K, Reading C, Frincke J, Stickney D, et al. HE3286: A novel synthetic steroid as an oral treatment for autoimmune disease. Ann N Y Acad Sci 2009;1173:781-90.
222. Gabler NB, French B, Strom BL, Liu Z, Palevsky HI, Taichman DB, et al. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest 2012;141:20-6.