Inflammation and pulmonary hypertension

Cardiology in Review

Volumn 18, Issue 2, 2010, Pages 67-72

  Mathew, Rajamma ^a  

^a NEW YORK MEDICAL COLLEGE   (United States)

Author keywords

Caveolin 1; Cytokines; Inflammation; Pulmonary hypertension

Indexed keywords

ANTIINFLAMMATORY AGENT; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CAVEOLIN 1; INTERLEUKIN 6; PYRROLIDINE DITHIOCARBAMATE; STAT3 PROTEIN;

CELL INFILTRATION; CELL PROLIFERATION; CYTOKINE PRODUCTION; CYTOKINE RELEASE; ENDOTHELIAL DYSFUNCTION; ENDOTHELIUM CELL; GENE ACTIVATION; GENE EXPRESSION REGULATION; GENE MUTATION; HUMAN; IMMUNOPATHOGENESIS; IMMUNOSTIMULATION; INFLAMMATION; LUNG INFILTRATE; MORTALITY; NONHUMAN; PROTEIN EXPRESSION; PROTEIN SYNTHESIS INHIBITION; PULMONARY HYPERTENSION; REVIEW; SIGNAL TRANSDUCTION; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; UPREGULATION;

APOPTOSIS; BONE MORPHOGENETIC PROTEIN RECEPTORS, TYPE II; CAVEOLIN 1; ENDOTHELIUM, VASCULAR; HUMANS; HYPERTENSION, PULMONARY; INFLAMMATION; INTERLEUKIN-6; PREVALENCE; RISK FACTORS; STAT3 TRANSCRIPTION FACTOR; VASOCONSTRICTION;

EID: 77149164131     PISSN: 10615377     EISSN: None     Source Type: Journal    
DOI: 10.1097/CRD.0b013e3181cd612f     Document Type: Review

References (123)

1. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54:543-554.
2. Mathew R, Gewitz MH. Pulmonary hypertension in infancy and childhood. Heart Dis. 2002;2:362-368.
3. Sanchez O, Humbert M, Sitbon O, et al. Treatment of pulmonary hypertension secondary to connective tissue disease. Thorax. 1999;54:273-277.
4. Guillevin L. Vasculopathies and pulmonary arterial hypertension. Rheumatology. 2009;48(suppl 3):iii54-iii57.
5. Lane KB, Machado RD, Paucuilo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial pulmonary hypertension. Nat Genet. 2000;26:81-84.
6. Michelakis E, Wilkins MR, Rabinovitch M. Emerging concepts and translational priorities in pulmonary arterial hypertension. Circulation. 2008;118: 1486-1495.
7. Dorfmuller P, Perros F, Balabanian K, et al. Inflammation in pulmonary arterial hypertension. Eur Respir J. 2003;22:8-363.
8. Marchesi C, Paradis P, Schiffrin EL. Role of the renin-angiotensin system in vascular inflammation. Trends Pharmacol Sci. 2008;29:367-374.
9. Gurubhagavatula I, Palevsky HI. Pulmonary hypertension in systemic autoimmune disease. Rheum Dis Clin North Am. 1997;23:365-394.
10. Lesprit P, Godeau B, Authier FJ, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med. 1996;157:907-911.
11. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension. A case control study, Swiss HIV cohort study. Am J Respir Crit Care Med. 1997;155:990-995.
12. Humbert M, Monti G, Brenot F, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med. 1995;151:1628-1631.
13. 3C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165: 1419-1425.
14. Itoh T, Nagaya N, Ishibashi-Ueda H, et al. Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension. Respirology. 2006;11:158-163.
15. Sanchez O, Marcus E, Perros E, et al. Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Resp Crit Care Med. 2007;176:1041-1047.
16. Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144:275-285.
17. Dorfmüller P, Zarka V, Durand-Gasselin J, et al. Cytokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 2002;165:534-539.
18. Brun H, Holmstrøm H, Thaulow E, et al. Patients with pulmonary hypertension related to congenital systemic-to-pulmonary shunts are characterized by inflammation involving endothelial cell activation and platelet-mediated inflammation. Congenit Heart Dis. 2009;4:153-159.
19. Upton D, Morrell MW. TGF-β and BMPR-II pharmacology: implications for pulmonary vascular disease. Curr Opin Pharmacol. 2009;9:274-280.
20. Song Y, Coleman L, Shi J, et al. Inflammation, endothelial injury and persistent pulmonary hypertension in heterozygous BMPR2 mutant mice. Am J Physiol. 2009;295:H677-H690.
21. Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiologic roles: the signal orchestration model. Rev Physiol Biochem Pharmacol. 2003;149:1-38.
22. Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1-78.
23. Nabata T, Morimoto S, Koh E, et al. Interleukin-6 stimulates c-myc expression and proliferation of cultured vascular smooth muscle cells. Biochem Int. 1990;20:445-454.
24. Sellimovic N, Bergh CH, Andersson B, et al. Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension. Eur Respir J. 2009;34:662-668.
25. Chaouat A, Savale L, Chouaid C, et al. Role for interleukin-6 in COPD-related pulmonary hypertension. Chest. 2009;136:678-687.
26. Quarck R, Nawrot T, Myens B, et al. C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol. 2009;53:1211-1218.
27. Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515-581.
28. Bhargava A, Kumar A, Yuan N, et al. Monocrotaline induces interleukin-6 mRNA expression in rat lungs. Heart Dis. 1999;1:126-133.
29. Miyata M, Sakuma F, Yoshimura A, et al. Pulmonary hypertension in rats. 2. Role of interleukin-6. Int Arch Allergy Immunol. 1995;108:287-291.
30. Golembeski SM, West J, Tada T, et al. Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest. 2005;128:572S-573S.
31. Steiner MK, Sytkina OL, Kolliputi N, et al. Interleukin-6 over expression induces pulmonary hypertension. Circ Res. 2009;104:236-244.
32. Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res. 2009; 10:6.
33. Puthier D, Derenne S, Barille S, et al. Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J Hematol. 1999;107:192-195.
34. Lévy M, Maurey C, Celermajer DS, et al. Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease. J Am Coll Cardiol. 2007;49:803-810.
35. Huang J, Wolk J, Gewitz MH, et al. Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension. Expt Lung Res. In press.
36. Bromberg J. STAT proteins and oncogenesis. J Clin Invest. 2002;109:1139-1142.
37. Darnell JE Jr. STATs and gene regulation. Science. 1997;272:1630-1645.
38. Jenkins BJ, Roberts AW, Najdovska M, et al. The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis. Blood. 2005;105:3512-3520.
39. McLoughlin RM, Jenkins BJ, Grail D, et al. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc Natl Acad Sci U S A. 2005;102:9589-9594.
40. Yu H, Jove R. The STATs of cancer - new molecular targets come of age. Nat Rev Cancer. 2004;4:97-105.
41. Garcia R, Bowman TL, Niu G, et al. Constitutive activation of Stat3 by the Src and JAK tyrosine kinase participates in growth regulation of human breast carcinoma cells. Oncogene. 2001;20:2499-2513.
42. Simeone-Penney MC, Severgnini M, Takahashi RL, et al. PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1. Am J Physiol. 2008;294:L698-L704.
43. Vignais ML, Sadowski HB, Watling D, et al. Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol Cell Biol. 1996;16:1759-1769.
44. Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264:95-98.
45. Gillespie MN, Rippetoe PE, Haven CA, et al. Polyamines and epidermal growth factor in monocrotaline-induced pulmonary hypertension. Am Rev Respir Dis. 1989;140:1463-1466.
46. Perros F, Montani D, Dorfmüller P, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;178:81-88.
47. Dauer DJ, Ferraro B, Song L, et al. STAT3 regulates genes common to both wound healing and cancer. Oncogene. 2005;24:3397-3408.
48. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. STAT3 as an oncogene. Cell. 1999;98:295-303.
49. Gritsko T, Williams A, Turkson J, et al. Persistent activation of STAT3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res. 2006;12:11-19.
50. Seki Y, Kai H, Shibata R, et al. Role of JAK/STAT pathway in rat carotid artery remodeling after vascular injury. Circ Res. 2000;87:12-18.
51. Shibata R, Kai H, Seki Y, et al. Inhibition of STAT3 prevents neointima formation by inhibiting proliferation and promoting apoptosis of neointimal smooth muscle cells. Hum Gene Ther. 2003;14:601-610.
52. Mathew R, Huang J, Shah M, et al. Disruption of endothelial-cell caveolin-1α/raft scaffolding during development of monocrotaline-induced pulmonary hypertension. Circulation. 2004;110:1499-1506.
53. Jasmin JF, Mercier I, Dupuis J, et al. Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Circulation. 2006;114:912-920.
54. Huang J, Kaminski PM, Edwards JG, et al. Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotalineinduced pulmonary artery hypertension. Am J Physiol. 2008;294:L1250-L1259.
55. Mathew R, Huang J, Zhao X, et al. Activation of signal transducer and activator of transcription (STAT) 3 in hypoxia-induced pulmonary hypertension. FASEB J. 2007,21:A1435.
56. Masri FA, Xu W, Combair SA, et al. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary artery hypertension. Am J Physiol. 2007;293:L548-L554.
57. McMurtry MS, Archer SL, Altieri DC, et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverse pulmonary arterial hypertension. J Clin Invest. 2005;115:1479-1491.
58. Gao LF, Wen LJ, Yu H, et al. Knockdown of Stat3 expression using RNAi inhibits growth of laryngeal tumor. Acta Pharmacol Sin. 2006;27:347-352.
59. Lin MT, Lin BR, Chang CC, et al. IL-6 induced AGS gastric cancer cell invasion via activation of the c-Src/RhoA/ROCK signaling pathway. Int J Cancer. 2007;120:2600-2609.
60. Abe K, Shimokova H, Morikawa K, et al. Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats. Circ Res. 2004;94:385-393.
61. Abe K, Tawara S, Oi K, et al. Long-term inhibition of Rho kinase ameliorates hypoxia-induced pulmonary hypertension in mice. J Cardiovasc Pharmacol. 2006;48:280-285.
62. Oka M, Fagan KA, Jones PL, et al. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Phamacol. 2008;155: 444-454.
63. Sawada N, Itoh H, Ueyama K, et al. Inhibition of Rho-associated kinase results in suppression of neointimal formation of balloon-injured arteries. Circulation. 2000;101:2030-2033.
64. Debidda M, Wang L, Zang H, et al. A role for STAT3 in Rho GTPaseregulated cell migration and proliferation. J Biol Chem. 2000;280:17275-12785.
65. Jumg JE, Lee HG, Cho IH, et al. STAT3 is a potential modulator of HIF 1α-mediated VEGF expression in human renal carcinoma cells. FASEB J. 2005;19:1296-1298.
66. Tuder RM, Chacon M, Alger L, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 2001;195:367-374.
67. Xu Q, Briggs J, Park S, et al. Targeting STAT3 blocks HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene. 2005;24:5552-5560.
68. Deng Z, Morse JH, Slager SL, et al. Familial pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphohenic protein receptor II gene. Am J Hum Genet. 2000;67:734-744.
69. Rudarakanchana N, Flanagan JA, Chen H, et al. Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet. 2002;11:1517-1535.
70. Cogan JD, Pauciulo MW, Batchman AP, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:590-598.
71. Morrell NW. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling. Proc Am Thorac Soc. 2006;3:680-686.
72. Thomson J, Machado M, Pauciulo M, et al. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor membrane of the TGF-β family. J Med Genet. 2000;37:741-745.
73. Roberts KE, McElroy JJ, Wong WP, et al. BMPR2 mutation in pulmonary arterial hypertension with congenital heart disease. Eur Respir J. 2004;24: 371-374.
74. Morty RE, Nejman B, Kwapiszewska G, et al. Dysregulated bone morphogenic protein signaling in monocrotaline-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2007;27:1072-1078.
75. Takahashi K, Kogaki S, Matsushita T, et al. Hypoxia induces alteration of bone morphogenic protein receptor signaling in pulmonary artery endothelial cell. Pediatr Res. 2007;61:392-397.
76. Ramos M, Lamé MW, Segall HJ, et al. Monocrotaline pyrrole induces Smad nuclear accumulation and altered signaling expression in human pulmonary arterial endothelial cells. Vascul Pharmacol. 2007;46:439-448.
77. Miyazono K. Signal transduction by bone morphogenetic protein receptors: functional roles of Smad proteins. Bone. 1999;25:91-93.
78. Nohe A, Hassel S, Ehrlich M, et al. The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways. J Biol Chem. 2002;277:5330-5338.
79. Hogan BL. Bone morphogenic protein: multifunctional regulators of vertebrate development. Genes Dev. 1996;10:1589-1594.
80. Yokouchi Y, Sakiyama J, Kameda T, et al. BMP- 2/4 mediate programmed cell death in chicken limb buds. Development. 1996;122:3725-3734.
81. Iwasaki S, Iguchi M, Watanabe K, et al. Specific activation of the p38 mitogen-activated protein kinase signaling pathway and induction of neurite outgrowth in PC12 cells by bone morphogenic protein 2. J Biol Chem. 1999;274:26503-26510.
82. Bhatia M, Bonnet D, Wu D, et al. Bone morphogenic proteins regulate the developmental program of human hematopoitic stem cells. J Exp Med. 1999;189:1139-1147.
83. Nakaoka T, Gonda K, Ogita T, et al. Inhibition of rat vascular smooth cell proliferation in vitro and in vivo by bone morphogenic protein-2. J Clin Invest. 1997;100:2824-2832.
84. Reynolds AM, Xia W, Holmes M, et al. Bone morphogenic protein type 2 receptor gene therapy attenuates hypoxic pulmonary hypertension. Am J Physiol. 2007;292:L1183-L1192.
85. Yu PB, Deng DY, Beppu H, et al. Bone morphogenic protein (BMP) type II receptor is required for BMP-mediated growth arrest and differentiation in pulmonary artery smooth muscle cells. J Biol Chem. 2008;283:3877-3888.
86. Kawamura C, Kizaki M, Yamato K, et al. Bone morphogenic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3. Blood. 2000;96:2005-2011.
87. Brock M, Trenkmann M, Gay RE, et al. Interleukin-6 modulates the expression of the bone morphogenic protein receptor type II through a novel STAT3-microRNA cluster 17/92 pathway. Circ Res. 2009;104:1184-1191.
88. Newman JH, Wheeler L, Lane KB, et al. Mutations in the gene for bone morphogenic protein receptor II as a cause of pulmonary hypertension. N Engl J Med. 2001;345:367-371.
89. West J, Harral J, Lane K, et al. Mice expressing BMPR2R899X transgene in smooth muscle developing pulmonary vascular lesions. Am J Physiol. 2008;295:L744-L755.
90. Hagen M, Fagan K, Steudel W, et al. Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol. 2007;292: L1473-L1479.
91. Cohen AW, Hnasko R, Schubert W, et al. Role of caveolae and caveolins in health and disease. Physiol Rev. 2004;84:1342-1379.
92. Okamato T, Schlegel PE, Scherer PE, et al. Caveolins, a family of scaffolding proteins for organizing "preassembled signaling complexes" at the plasma membrane. J Biol Chem. 1998;273:54119-54122.
93. Quest AF, Leyton L, Párraga M. Caveolins, caveolae, and lipid rafts in cellular transport, signaling and disease. Biochem Cell Biol. 2004;82:129-144.
94. Rehman A, Swärd K. The role of caveolin-1 in cardiovascular regulation. Acta Physiol. 2009;195:231-245.
95. Liu P, Budick M, Anderson RG. Multiple functions of caveolin-1. J Biol Chem. 2002;277:41295-41298.
96. WAF1/cip1-dependent mechanism. Mol Biol Cell. 2001;12:2229-2244.
97. Garrean S, Gao XP, Brokovych V, et al. Caveolin-1 regulates NF-κB activation and lung inflammatory response to sepsis induced by lipopolysaccharide. J Immunol. 2006;177:4853-4860.
98. Wang XM, Kim HP, Song R, et al. Caveolin-1 confers anti-inflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. Am J Respir Cell Mol Biol. 2006;34:434-442.
99. Pike J. Lipid rafts: bringing order to chaos. J Lipid Res. 2003;44:655-667.
100. Mateev SV, Smart EJ. Heterologous desensitization of EGF receptors and PDGF receptors by sequestration in caveolae. Am J Physiol. 2002;282: C935-C948.
101. Peterson TE, Guicciardi ME, Gulati R, et al. Caveolin-1 can regulate vascular smooth muscle cell fate by switching platelet-derived growth factor signaling from a proliferative to an apoptotic pathway. Arterioscler Thromb Vasc Biol. 2003;23:1521-1527.
102. Shakirova Y, Bonnevier J, Albinsson S, et al. Increased Rho activation and PKC-mediated smooth muscle contractility in the absence of caveolin-1. Am J Physiol. 2006;291:C1326-C1335.
103. Ramos M, Lamé MW, Segall HJ, et al. The BMP type II receptor is located in lipid rafts, including caveolae of pulmonary endothelium in vivo and in vitro. Vasc Pharmacol. 2006;44:50-59.
104. Jasmin JF, Mercier I, Hnasko R, et al. Lung remodeling and pulmonary hypertension after myocardial infarction: pathogenic role of reduced caveolin expression. Cardiovasc Res. 2004;63:747-755.
105. Garaci MW, Moore M, Gesell T, et al. Gene expression pattern in the lungs of patients with primary pulmonary hypertension, a gene array microanalysis. Circ Res. 2001;88:555-562.
106. Mathew R, Huang J, Gewitz MH. Pulmonary artery hypertension: caveolin-1 and eNOS interrelationship, a new perspective. Cardiol Rev. 2007;15: 143-149.
107. Jasmin JF, Mercier I, Sotgia F, et al. SOCS proteins and caveolin-1 as negative regulators of endocrine signaling. Trends Endocrinol Metabol. 2006;17:150-158.
108. Hulit J, Bach T, Fu M, et al. The cyclin D1 gene is transcriptionally repressed by caveolin-1. J Biol Chem. 2000;21:203-209.
109. Zhao YY, Liu Y, Stan RV, et al. Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice. Proc Natl Acad Sci U S A. 2002;99:11375-11380.
110. Murata T, Lin MI, Huang Y, et al. Reexpression of caveolin-1 in endothelium rescues vascular, cardiac and pulmonary defects in global caveolin-1 knockout mice. J Expt Med. 2007;204:2373-2382.
111. Jirik FR, Podor TJ, Hirano T, et al. Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 secretion by human endothelial cells. J Immunol. 1989;142:144-147.
112. Marfaing-Koka A, Devergne O, Gorgone G, et al. Regulation of the production of the RANTES chemokine by endothelial cells. J Immunol. 1995;154:1870-1878.
113. Muller WA. Leukocyte-endothelial cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003;24:326-333.
114. Song L, Go S, Pachter JS. Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells. Blood. 2007; 109:1515-1523.
115. Montani D, Achouh L, Marcelin AG, et al. Reversibility of pulmonary arterial hypertension in HIV/HHV8-associated Castleman's disease. Eur Respir J. 2005;26:969-972.
116. Sanchez O, Sitbon O, Jais X, et al. Immunosuppressive therapy in connective tissue disease associated pulmonary hypertension. Chest. 2006;130: 182-189.
117. Sullivan CC, Du L, Chu D, et al. Induction of pulmonary hypertension by an angiopoietin1/Tie2/serotonin pathway. Proc Natl Acad Sci U S A. 2003;100: 12331-12336.
118. Ito T, Okada T, Miyashita H, Nomoto T, et al. Interleukin-10 expression mediated by an adeno-associated virus vector prevents monocrotaline-induced pulmonary arterial hypertension in rats. Circ Res. 2007;101:734-741.
119. Henriques-Coelho T, Oliveira SM, Moura RS, et al. Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway. Endocrinology. 2008;149:4367-4373.
120. Ikeda Y, Yonemitsu Y, Kataoka C, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats. Am J Physiol. 2002;283:H2021-H2028.
121. Suzuki C, Takahashi M, Morimoto H, et al. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats. Biochem Biophys Res Commun. 2006;349:781-788.
122. McMurtry MS, Bonnet S, Michelakis ED, et al. Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamycin-atorvastatin-simvastatin study. Am J Physiol. 2007;293: L933-L940.
123. Mayerl C, Lukasser M, Sedivy R, et al. Atherosclerosis research from past to present: on tack of two pathologists with opposing views, Carl Von Rokitansky and Rudolf Virchow. Virchows Arch. 2006;449: 96-103.