Molecular pathogenesis and current pathology of pulmonary hypertension

Heart Failure Reviews

Volumn 21, Issue 3, 2016, Pages 239-257

  de Jesus Perez, Vinicio A ^a  

^a STANFORD UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

Animal models of disease; BMPR2; Endothelial cells; Epigenetics; Genetics; Inflammation; Lung pathology; Pulmonary arterial hypertension; Right heart failure; Vascular biology; Vascular smooth muscle cells

Indexed keywords

BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CALCIUM CHANNEL CAV1.2; KI 67 ANTIGEN; POTASSIUM CHANNEL KCNK3; POTASSIUM CHANNEL KV1.2; POTASSIUM CHANNEL KV1.5; SMAD PROTEIN; SMAD9 PROTEIN; TRANSIENT RECEPTOR POTENTIAL CHANNEL; TRANSIENT RECEPTOR POTENTIAL CHANNEL C; UNCLASSIFIED DRUG; VOLTAGE GATED CALCIUM CHANNEL; VOLTAGE GATED POTASSIUM CHANNEL; MICRORNA;

APOPTOSIS; ARTICLE; CELL METABOLISM; CELL PROLIFERATION; ENVIRONMENTAL FACTOR; GENE EXPRESSION; GENE FUNCTION; GENE MUTATION; GENETIC VARIABILITY; HEREDITY; HISTOPATHOLOGY; HUMAN; MOLECULAR PATHOLOGY; NEXT GENERATION SEQUENCING; NONHUMAN; POTASSIUM TRANSPORT; PROTEIN EXPRESSION; PULMONARY HYPERTENSION; QUALITY OF LIFE; ANIMAL; DISEASE MODEL; ENVIRONMENTAL EXPOSURE; GENE EXPRESSION REGULATION; GENE THERAPY; GENETICS; HIGH THROUGHPUT SEQUENCING; MOUSE; PATHOPHYSIOLOGY; RAT; SEXUAL CHARACTERISTICS;

ANIMALS; DISEASE MODELS, ANIMAL; ENVIRONMENTAL EXPOSURE; GENE EXPRESSION REGULATION; GENETIC THERAPY; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; HYPERTENSION, PULMONARY; MICE; MICRORNAS; RATS; SEX CHARACTERISTICS;

EID: 84951738052     PISSN: 13824147     EISSN: 15737322     Source Type: Journal    
DOI: 10.1007/s10741-015-9519-2     Document Type: Article

References (172)

1. Hunter DJ (2005) Gene-environment interactions in human diseases. Nat Rev Genet 6:287–298
2. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J (2009) Accf/aha 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on expert consensus documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 53:1573–1619
3. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK et al (1987) Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107:216–223
4. Morrell NW (2006) Pulmonary hypertension due to bmpr2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3:680–686
5. Chin KM, Kim NH, Rubin LJ (2005) The right ventricle in pulmonary hypertension. Coron Artery Dis 16:13–18
6. Chin KM, Rubin LJ (2008) Pulmonary arterial hypertension. J Am Coll Cardiol 51:1527–1538
7. Rubin LJ (2006) Pulmonary arterial hypertension. Proc Am Thorac Soc 3:111–115
8. Tuder RM, Archer SL, Dorfmuller P, Erzurum SC, Guignabert C, Michelakis E, Rabinovitch M, Schermuly R, Stenmark KR, Morrell NW (2013) Relevant issues in the pathology and pathobiology of pulmonary hypertension. J Am Coll Cardiol 62:D4–12
9. Tuder RM (2014) How do we measure pathology in PAH (lung and RV) and what does it tell us about the disease. Drug Discov Today 19:1257–1263
10. Rabinovitch M (2001) Pathobiology of pulmonary hypertension Extracellular matrix. Clin Chest Med 22:433–449 viii
11. Heath D, Edwards JE (1958) The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18:533–547
12. Heath D, Helmholz HF Jr, Burchell HB, Dushane JW, Edwards JE (1958) Graded pulmonary vascular changes and hemodynamic findings in cases of atrial and ventricular septal defect and patent ductus arteriosus. Circulation 18:1155–1166
13. Rabinovitch M, Haworth SG, Vance Z, Vawter G, Castaneda AR, Nadas AS, Reid LM (1980) Early pulmonary vascular changes in congenital heart disease studied in biopsy tissue. Hum Pathol 11:499–509
14. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM (2012) Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186:261–272
15. Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99:675–691
16. Stenmark KR, Frid MG (1998) Smooth muscle cell heterogeneity: role of specific smooth muscle cell subpopulations in pulmonary vascular disease. Chest 114:82S–90S
17. Coflesky JT, Adler KB, Woodcock-Mitchell J, Mitchell J, Evans JN (1988) Proliferative changes in the pulmonary arterial wall during short-term hyperoxic injury to the lung. Am J Pathol 132:563–573
18. Ivy DD, McMurtry IF, Colvin K, Imamura M, Oka M, Lee DS, Gebb S, Jones PL (2005) Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: a new model of severe pulmonary arterial hypertension. Circulation 111:2988–2996
19. Montani D, Chaumais MC, Guignabert C, Gunther S, Girerd B, Jais X, Algalarrondo V, Price LC, Savale L, Sitbon O, Simonneau G, Humbert M (2014) Targeted therapies in pulmonary arterial hypertension. Pharmacol Ther 141:172–191
20. Boutet K, Montani D, Jais X, Yaici A, Sitbon O, Simonneau G, Humbert M (2008) Therapeutic advances in pulmonary arterial hypertension. Ther Adv Respir Dis 2:249–265
21. Zaidi SH, You XM, Ciura S, Husain M, Rabinovitch M (2002) Overexpression of the serine elastase inhibitor elafin protects transgenic mice from hypoxic pulmonary hypertension. Circulation 105:516–521
22. Nickel NP, Spiekerkoetter E, Gu M, Li CG, Li H, Kaschwich M, Diebold I, Hennigs JK, Kim KY, Miyagawa K, Wang L, Cao A, Sa S, Jiang X, Stockstill RW, Nicolls MR, Zamanian RT, Bland RD, Rabinovitch M (2015) Elafin reverses pulmonary hypertension via caveolin-1-dependent bone morphogenetic protein signaling. Am J Respir Crit Care Med 191:1273–1286
23. Rabinovitch M (1999) Eve and beyond, retro and prospective insights. Am J Physiol 277:L5–12
24. Rabinovitch M (2012) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 122:4306–4313
25. Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF (2001) The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 22:405–418
26. Tuder RM, Groves B, Badesch DB, Voelkel NF (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 144:275–285
27. Yeager ME, Golpon HA, Voelkel NF, Tuder RM (2002) Microsatellite mutational analysis of endothelial cells within plexiform lesions from patients with familial, pediatric, and sporadic pulmonary hypertension. Chest 121:61S
28. Tuder RM, Voelkel NF (2002) Angiogenesis and pulmonary hypertension: a unique process in a unique disease. Antioxid Redox Signal 4:833–843
29. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM (1998) Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 101:927–934
30. Rai PR, Cool CD, King JA, Stevens T, Burns N, Winn RA, Kasper M, Voelkel NF (2008) The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 178:558–564
31. van Dijk CG, Nieuweboer FE, Pei JY, Xu YJ, Burgisser P, van Mulligen E, El Azzouzi H, Duncker DJ, Verhaar MC, Cheng C (2015) The complex mural cell: pericyte function in health and disease. Int J Cardiol 190:75–89
32. Birbrair A, Zhang T, Wang ZM, Messi ML, Mintz A, Delbono O (2014) Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Front Aging Neurosci 6:245
33. Dore-Duffy P (2014) Pericytes and adaptive angioplasticity: the role of tumor necrosis factor-like weak inducer of apoptosis (tweak). Methods Mol Biol 1135:35–52
34. El-Bizri N, Wang L, Merklinger SL, Guignabert C, Desai T, Urashima T, Sheikh AY, Knutsen RH, Mecham RP, Mishina Y, Rabinovitch M (2008) Smooth muscle protein 22alpha-mediated patchy deletion of bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling. Circ Res 102:380–388
35. Ricard N, Tu L, Le Hiress M, Huertas A, Phan C, Thuillet R, Sattler C, Fadel E, Seferian A, Montani D, Dorfmuller P, Humbert M, Guignabert C (2014) Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. Circulation 129:1586–1597
36. Yuan K, Orcholski ME, Panaroni C, Shuffle EM, Huang NF, Jiang X, Tian W, Vladar EK, Wang L, Nicolls MR, Wu JY, de Jesus Perez VA (2015) Activation of the wnt/planar cell polarity pathway is required for pericyte recruitment during pulmonary angiogenesis. Am J Pathol 185:69–84
37. Durmowicz AG, Stenmark KR (1999) Mechanisms of structural remodeling in chronic pulmonary hypertension. Pediatr Rev 20:e91–e102
38. Stenmark KR, Frid MG, Yeager M, Li M, Riddle S, McKinsey T, El Kasmi KC (2012) Targeting the adventitial microenvironment in pulmonary hypertension: a potential approach to therapy that considers epigenetic change. Pulm Circ 2:3–14
39. Wang Z, Chesler NC (2011) Pulmonary vascular wall stiffness: an important contributor to the increased right ventricular afterload with pulmonary hypertension. Pulm Circ 1:212–223
40. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115:165–175
41. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA (2000) Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744
42. International PPH Consortium, Lane KB, Machado RD, Pauciulo MW, Thomson JR, 3rd Phillips JA, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26:81–84
43. Machado RD, Pauciulo MW, Thomson JR, Lane KB, Morgan NV, Wheeler L, Phillips JA 3rd, Newman J, Williams D, Galie N, Manes A, McNeil K, Yacoub M, Mikhail G, Rogers P, Corris P, Humbert M, Donnai D, Martensson G, Tranebjaerg L, Loyd JE, Trembath RC, Nichols WC (2001) BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 68:92–102
44. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 37:741–745
45. Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, Koskenvuo M, Wang L, Freeman BA, Chang HY, Rabinovitch M (2011) Disruption of PPAR gamma/beta-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial ec survival. J Clin Invest 121:3735–3746
46. de Jesus Perez VA, de Alastalo TP, Wu JC, Axelrod JD, Cooke JP, Amieva M, Rabinovitch M (2009) Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-Rhoa-Rac1 pathways. J Cell Biol 184:83–99
47. Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, Haghighat L, de Jesus Perez V, Wang L, Reddy S, Zhao M, Bernstein D, Solow-Cordero DE, Beachy PA, Wandless TJ, Ten Dijke P, Rabinovitch M (2013) Fk506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 123:3600–3613
48. Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X, Tregouet D, Reis A, Drouin-Garraud V, Fraisse A, Sitbon O, O’Callaghan DS, Simonneau G, Soubrier F, Humbert M (2010) Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 181:851–861
49. Sankelo M, Flanagan JA, Machado R, Harrison R, Rudarakanchana N, Morrell N, Dixon M, Halme M, Puolijoki H, Kere J, Elomaa O, Kupari M, Raisanen-Sokolowski A, Trembath RC, Laitinen T (2005) BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum Mutat 26:119–124
50. Sztrymf B, Coulet F, Girerd B, Yaici A, Jais X, Sitbon O, Montani D, Souza R, Simonneau G, Soubrier F, Humbert M (2008) Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 177:1377–1383
51. Best DH, Austin ED, Chung WK, Elliott CG (2014) Genetics of pulmonary hypertension. Curr Opin Cardiol 29:520–527
52. Drake KM, Dunmore BJ, McNelly LN, Morrell NW, Aldred MA (2013) Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 49:403–409
53. Ryan JJ (2013) Chloroquine in pulmonary arterial hypertension: a new role for an old drug? Circ Cardiovasc Genet 6:310–311
54. Yang J, Li X, Al-Lamki RS, Wu C, Weiss A, Berk J, Schermuly RT, Morrell NW (2013) Sildenafil potentiates bone morphogenetic protein signaling in pulmonary arterial smooth muscle cells and in experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol 33:34–42
55. Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, Erzurum SC, Aldred MA (2011) Altered microRNA processing in heritable pulmonary arterial hypertension: an important role for SMAD-8. Am J Respir Crit Care Med 184:1400–1408
56. Nasim MT, Ogo T, Ahmed M, Randall R, Chowdhury HM, Snape KM, Bradshaw TY, Southgate L, Lee GJ, Jackson I, Lord GM, Gibbs JS, Wilkins MR, Ohta-Ogo K, Nakamura K, Girerd B, Coulet F, Soubrier F, Humbert M, Morrell NW, Trembath RC, Machado RD (2011) Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 32:1385–1389
57. Lenato GM, Guanti G (2006) Hereditary haemorrhagic telangiectasia (HHT): genetic and molecular aspects. Curr Pharm Des 12:1173–1193
58. Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, Coccolo F, Ventura C, Phillips JA 3rd, Knowles JA, Janssen B, Eickelberg O, Eddahibi S, Herve P, Nichols WC, Elliott G (2004) Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol 43:33S–39S
59. Pousada G, Baloira A, Vilarino C, Cifrian JM, Valverde D (2014) Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension. PLoS One 9:e100261
60. de Jesus Perez VA, Yuan K, Lyuksyutova MA, Dewey F, Orcholski ME, Shuffle EM, Mathur M, Jr. Yancy L, Rojas V, Li CG, Cao A, Alastalo TP, Khazeni N, Cimprich KA, Butte AJ, Ashley E, Zamanian RT (2014) Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 189:1260–1272
61. Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Tregouet DA, Borczuk A, Rosenzweig EB, Girerd B, Montani D, Humbert M, Loyd JE, Kass RS, Chung WK (2013) A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 369:351–361
62. Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JA 3rd, Palomero T, Sumazin P, Kim HR, Talati MH, West J, Loyd JE, Chung WK (2012) Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 5:336–343
63. Austin ED, Cogan JD, West JD, Hedges LK, Hamid R, Dawson EP, Wheeler LA, Parl FF, Loyd JE, Phillips JA 3rd (2009) Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females. Eur Respir J 34:1093–1099
64. West J, Cogan J, Geraci M, Robinson L, Newman J, Phillips JA, Lane K, Meyrick B, Loyd J (2008) Gene expression in BMPR2 mutation carriers with and without evidence of pulmonary arterial hypertension suggests pathways relevant to disease penetrance. BMC Med Genomics 1:45
65. Frump AL, Goss KN, Vayl A, Albrecht M, Fisher A, Tursunova R, Fierst J, Whitson J, Cucci AR, Brown MB, Lahm T (2015) Estradiol improves right ventricular function in rats with severe angioproliferative pulmonary hypertension: effects of endogenous and exogenous sex hormones. Am J Physiol Lung Cell Mol Physiol 308:L873–L890
66. Lahm T, Crisostomo PR, Markel TA, Wang M, Weil BR, Novotny NM, Meldrum DR (2008) The effects of estrogen on pulmonary artery vasoreactivity and hypoxic pulmonary vasoconstriction: potential new clinical implications for an old hormone. Crit Care Med 36:2174–2183
67. Burg ED, Remillard CV, Yuan JX (2008) Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: pharmacotherapeutic implications. Br J Pharmacol 153(Suppl 1):S99–S111
68. Fantozzi I, Platoshyn O, Wong AH, Zhang S, Remillard CV, Furtado MR, Petrauskene OV, Yuan JX (2006) Bone morphogenetic protein-2 upregulates expression and function of voltage-gated k+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 291:L993–1004
69. Ko EA, Burg ED, Platoshyn O, Msefya J, Firth AL, Yuan JX (2007) Functional characterization of voltage-gated k+ channels in mouse pulmonary artery smooth muscle cells. Am J Physiol Cell Physiol 293:C928–C937
70. Mandegar M, Remillard CV, Yuan JX (2002) Ion channels in pulmonary arterial hypertension. Prog Cardiovasc Dis 45:81–114
71. Mandegar M, Yuan JX (2002) Role of k + channels in pulmonary hypertension. Vasc Pharmacol 38:25–33
72. Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM, Wilhelm J, Morty RE, Brau ME, Weir EK, Kwapiszewska G, Klepetko W, Seeger W, Olschewski H (2006) Impact of task-1 in human pulmonary artery smooth muscle cells. Circ Res 98:1072–1080
73. Gurney A, Manoury B (2009) Two-pore potassium channels in the cardiovascular system. Eur Biophys J 38:305–318
74. Tang B, Li Y, Nagaraj C, Morty RE, Gabor S, Stacher E, Voswinckel R, Weissmann N, Leithner K, Olschewski H, Olschewski A (2009) Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 41:476–483
75. Manoury B, Lamalle C, Oliveira R, Reid J, Gurney AM (2011) Contractile and electrophysiological properties of pulmonary artery smooth muscle are not altered in TASK-1 knockout mice. J Physiol 589:3231–3246
76. Fernandez RA, Wan J, Song S, Smith KA, Gu Y, Tauseef M, Tang H, Makino A, Mehta D, Yuan JX (2015) Upregulated expression of STIM2, TRPC6, and Orai2 contributes to the transition of pulmonary arterial smooth muscle cells from a contractile to proliferative phenotype. Am J Physiol Cell Physiol 308:C581–C593
77. Smith KA, Voiriot G, Tang H, Fraidenburg DR, Song S, Yamamura H, Yamamura A, Guo Q, Wan J, Pohl NM, Tauseef M, Bodmer R, Ocorr K, Thistlethwaite PA, Haddad GG, Powell FL, Makino A, Mehta D, Yuan JX (2015) Notch activation of ca signaling mediates hypoxic pulmonary vasoconstriction and pulmonary hypertension. Am J Respir Cell Mol Biol 53(3):355–367
78. Liu XR, Zhang MF, Yang N, Liu Q, Wang RX, Cao YN, Yang XR, Sham JS, Lin MJ (2012) Enhanced store-operated ca(2)+ entry and trpc channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats. Am J Physiol Cell Physiol 302:C77–C87
79. Wang C, Li JF, Zhao L, Liu J, Wan J, Wang YX, Wang J, Wang C (2009) Inhibition of SOC/Ca2+/Nfat pathway is involved in the anti-proliferative effect of sildenafil on pulmonary artery smooth muscle cells. Respir Res 10:123
80. Xu L, Chen Y, Yang K, Wang Y, Tian L, Zhang J, Wang EW, Sun D, Lu W, Wang J (2014) Chronic hypoxia increases TRPC6 expression and basal intracellular ca2+ concentration in rat distal pulmonary venous smooth muscle. PLoS One 9:e112007
81. Leblanc N, Forrest AS, Ayon RJ, Wiwchar M, Angermann JE, Pritchard HA, Singer CA, Valencik ML, Britton F, Greenwood IA (2015) Molecular and functional significance of ca(2+)-activated cl(−) channels in pulmonary arterial smooth muscle. Pulm Circ 5:244–268
82. Zhu S, White RE, Barman SA (2008) Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle. Ther Adv Respir Dis 2:119–127
83. Barman SA, Zhu S, Han G, White RE (2003) Camp activates bkca channels in pulmonary arterial smooth muscle via cgmp-dependent protein kinase. Am J Physiol Lung Cell Mol Physiol. 284:L1004–L1011
84. Dai ZK, Liu YW, Hsu JH, Yeh JL, Chen IJ, Wu JR, Wu BN (2015) The xanthine derivative KMUP-1 attenuates serotonin-induced vasoconstriction and k(+)-channel inhibitory activity via the PKC pathway in pulmonary arteries. Int J Biol Sci 11:633–642
85. Dubuis E, Potier M, Wang R, Vandier C (2005) Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCA channels. Cardiovasc Res 65:751–761
86. Gai XY, Wei YH, Zhang W, Wuren TN, Wang YP, Li ZQ, Liu S, Ma L, Lu DX, Zhou Y, Ge RL (2015) Echinacoside induces rat pulmonary artery vasorelaxation by opening the NO-cGMP-PKG-BKCa channels and reducing intracellular ca2+ levels. Acta Pharmacol Sin 36:587–596
87. Bonnet S, Dumas-de-La-Roque E, Begueret H, Marthan R, Fayon M, Dos Santos P, Savineau JP, Baulieu EE (2003) Dehydroepiandrosterone (dhea) prevents and reverses chronic hypoxic pulmonary hypertension. Proc Natl Acad Sci USA 100:9488–9493
88. Rehman J, Archer SL (2010) A proposed mitochondrial-metabolic mechanism for initiation and maintenance of pulmonary arterial hypertension in fawn-hooded rats: the warburg model of pulmonary arterial hypertension. Adv Exp Med Biol 661:171–185
89. Tuder RM, Davis LA, Graham BB (2012) Targeting energetic metabolism: a new frontier in the pathogenesis and treatment of pulmonary hypertension. Am J Respir Crit Care Med 185:260–266
90. Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thebaud B, Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry MS, Weir EK, Archer SL (2006) An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation 113:2630–2641
91. Fijalkowska I, Xu W, Comhair SA, Janocha AJ, Mavrakis LA, Krishnamachary B, Zhen L, Mao T, Richter A, Erzurum SC, Tuder RM (2010) Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol 176:1130–1138
92. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-k+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51
93. Dromparis P, Sutendra G, Michelakis ED (2010) The role of mitochondria in pulmonary vascular remodeling. J Mol Med 88:1003–1010
94. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED (2005) Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Investig 115:1479–1491
95. McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED (2004) Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res 95:830–840
96. Dromparis P, Paulin R, Stenson TH, Haromy A, Sutendra G, Michelakis ED (2013) Attenuating endoplasmic reticulum stress as a novel therapeutic strategy in pulmonary hypertension. Circulation 127:115–125
97. Ryter SW, Nakahira K, Haspel JA, Choi AM (2012) Autophagy in pulmonary diseases. Annu Rev Physiol 74:377–401
98. Sutendra G, Dromparis P, Wright P, Bonnet S, Haromy A, Hao Z, McMurtry MS, Michalak M, Vance JE, Sessa WC, Michelakis ED (2011) The role of nogo and the mitochondria-endoplasmic reticulum unit in pulmonary hypertension. Sci Transl Med 3:88ra55
99. Long L, Yang X, Southwood M, Lu J, Marciniak SJ, Dunmore BJ, Morrell NW (2013) Chloroquine prevents progression of experimental pulmonary hypertension via inhibition of autophagy and lysosomal bone morphogenetic protein type ii receptor degradation. Circ Res 112:1159–1170
100. Lahm T, Petrache I (2012) LC3 as a potential therapeutic target in hypoxia-induced pulmonary hypertension. Autophagy 8:1146–1147
101. Lee SJ, Smith A, Guo L, Alastalo TP, Li M, Sawada H, Liu X, Chen ZH, Ifedigbo E, Jin Y, Feghali-Bostwick C, Ryter SW, Kim HP, Rabinovitch M, Choi AM (2011) Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med 183:649–658
102. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Kumar RK, Landzberg M, Machado RF, Olschewski H, Robbins IM, Souza R (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 62:D34–D41
103. de Jesus Perez V, Kudelko K, Snook S, Zamanian RT (2011) Drugs and toxins-associated pulmonary arterial hypertension: lessons learned and challenges ahead. Int J Clin Pract Suppl (169):8–10
104. Montani D, Seferian A, Savale L, Simonneau G, Humbert M (2013) Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev 22:244–250
105. Gross SB (1999) Appetite suppressants and cardiac valvulopathy. Current clinical perspectives. Adv Nurse Pract 7:36–40
106. Seiler KU, Wassermann O, Wensky H (1976) On the role of serotonin in the pathogenesis of pulmonary hypertension induced by anorectic drugs; an experimental study in the isolated perfused rat lung, II. Fenfluramine, mazindol, mefenorex, phentermine and R 800. Clin. Exp Pharmacol Physiol. 3:323–330
107. Wang Y, Liu M, Wang HM, Bai Y, Zhang XH, Sun YX, Wang HL (2013) Involvement of serotonin mechanism in methamphetamine-induced chronic pulmonary toxicity in rats. Hum Exp Toxicol 32:736–746
108. Dempsie Y, Morecroft I, Welsh DJ, MacRitchie NA, Herold N, Loughlin L, Nilsen M, Peacock AJ, Harmar A, Bader M, MacLean MR (2008) Converging evidence in support of the serotonin hypothesis of dexfenfluramine-induced pulmonary hypertension with novel transgenic mice. Circulation 117:2928–2937
109. Lawrie A, Spiekerkoetter E, Martinez EC, Ambartsumian N, Sheward WJ, MacLean MR, Harmar AJ, Schmidt AM, Lukanidin E, Rabinovitch M (2005) Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 97:227–235
110. Dempsie Y, Nilsen M, White K, Mair KM, Loughlin L, Ambartsumian N, Rabinovitch M, Maclean MR (2011) Development of pulmonary arterial hypertension in mice over-expressing S100A4/Mts1 is specific to females. Respir Res 12:159
111. Spiekerkoetter E, Alvira CM, Kim YM, Bruneau A, Pricola KL, Wang L, Ambartsumian N, Rabinovitch M (2008) Reactivation of gamma hv 68 induces neointimal lesions in pulmonary arteries of S100A4/Mts1-overexpressing mice in association with degradation of elastin. Am J Physiol Lung Cell Mol Physiol 294:L276–L289
112. Meloche J, Courchesne A, Barrier M, Carter S, Bisserier M, Paulin R, Lauzon-Joset JF, Breuils-Bonnet S, Tremblay E, Biardel S, Racine C, Courture C, Bonnet P, Majka SM, Deshaies Y, Picard F, Provencher S, Bonnet S (2013) Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology. J Am Heart Assoc 2:e005157
113. Schaiberger PH, Kennedy TC, Miller FC, Gal J, Petty TL (1993) Pulmonary hypertension associated with long-term inhalation of “crank” methamphetamine. Chest 104:614–616
114. Thompson CA (2008) Pulmonary arterial hypertension seen in methamphetamine abusers. Am J Health Syst Pharm 65:1109–1110
115. Perros F, Gunther S, Ranchoux B, Godinas L, Antigny F, Chaumais MC, Dorfmuller P, Hautefort A, Raymond N, Savale L, Jais X, Girerd B, Cottin V, Sitbon O, Simonneau G, Humbert M, Montani D (2015) Mitomycin-induced pulmonary veno-occlusive disease: evidence from human disease and animal models. Circulation 132:834–847
116. Ryan JJ, Marsboom G, Archer SL (2013) Rodent models of group 1 pulmonary hypertension. Handb Exp Pharmacol 218:105–149
117. Roth RA, Reindel JF (1991) Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolite. Adv Exp Med Biol 283:477–487
118. Schultze AE, Roth RA (1998) Chronic pulmonary hypertension—the monocrotaline model and involvement of the hemostatic system. J Toxicol Environ Health B Crit Rev. 1:271–346
119. Wilson DW, Segall HJ, Pan LC, Lame MW, Estep JE, Morin D (1992) Mechanisms and pathology of monocrotaline pulmonary toxicity. Crit Rev Toxicol 22:307–325
120. Campbell AI, Kuliszewski MA, Stewart DJ (1999) Cell-based gene transfer to the pulmonary vasculature: endothelial nitric oxide synthase overexpression inhibits monocrotaline-induced pulmonary hypertension. Am J Respir Cell Mol Biol 21:567–575
121. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ (2005) Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 96:442–450
122. Gomez-Arroyo JG, Farkas L, Alhussaini AA, Farkas D, Kraskauskas D, Voelkel NF, Bogaard HJ (2012) The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol. 302:L363–L369
123. Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA, Botney MD (1997) Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. Am J Pathol 151:1019–1025
124. Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, Scerbavicius R, Burns N, Cool C, Wood K, Parr JE, Boackle SA, Voelkel NF (2007) Absence of t cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med 175:1280–1289
125. Abe K, Toba M, Alzoubi A, Ito M, Fagan KA, Cool CD, Voelkel NF, McMurtry IF, Oka M (2010) Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 121:2747–2754
126. Vitali SH, Hansmann G, Rose C, Fernandez-Gonzalez A, Scheid A, Mitsialis SA, Kourembanas S (2014) The sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up. Pulm Circ 4:619–629
127. Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, Miyazono K, Li E, Bloch KD (2004) BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol 287:L1241–L1247
128. Beppu H, Lei H, Bloch KD, Li E (2005) Generation of a floxed allele of the mouse BMP type II receptor gene. Genesis 41:133–137
129. West J, Harral J, Lane K, Deng Y, Ickes B, Crona D, Albu S, Stewart D, Fagan K (2008) Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295:L744–L755
130. Ranchoux B, Antigny F, Rucker-Martin C, Hautefort A, Pechoux C, Bogaard HJ, Dorfmuller P, Remy S, Lecerf F, Plante S, Chat S, Fadel E, Houssaini A, Anegon I, Adnot S, Simonneau G, Humbert M, Cohen-Kaminsky S, Perros F (2015) Endothelial-to-mesenchymal transition in pulmonary hypertension. Circulation 131:1006–1018
131. Yuan K, Orcholski M, Tian X, Liao X, de Jesus Perez VA (2013) Micrornas: promising therapeutic targets for the treatment of pulmonary arterial hypertension. Expert Opin Ther Targets 17:557–564
132. Bienertova-Vasku J, Novak J, Vasku A (2015) Micrornas in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment. J Am Soc Hypertens 9:221–234
133. Sarkar J, Gou D, Turaka P, Viktorova E, Ramchandran R, Raj JU (2010) Microrna-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration. Am J Physiol Lung Cell Mol Physiol 299:L861–L871
134. Yang S, Banerjee S, Freitas A, Cui H, Xie N, Abraham E, Liu G (2012) miR-21 regulates chronic hypoxia-induced pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 302:L521–L529
135. Bockmeyer CL, Maegel L, Janciauskiene S, Rische J, Lehmann U, Maus UA, Nickel N, Haverich A, Hoeper MM, Golpon HA, Kreipe H, Laenger F, Jonigk D (2012) Plexiform vasculopathy of severe pulmonary arterial hypertension and microrna expression. J Heart Lung Transplant 31:764–772
136. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB (2009) Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 104:236–244, 228p following 244
137. Pullamsetti SS, Doebele C, Fischer A, Savai R, Kojonazarov B, Dahal BK, Ghofrani HA, Weissmann N, Grimminger F, Bonauer A, Seeger W, Zeiher AM, Dimmeler S, Schermuly RT (2012) Inhibition of microrna-17 improves lung and heart function in experimental pulmonary hypertension. Am J Respir Crit Care Med 185:409–419
138. Courboulin A, Paulin R, Giguere NJ, Saksouk N, Perreault T, Meloche J, Paquet ER, Biardel S, Provencher S, Cote J, Simard MJ, Bonnet S (2011) Role for miR-204 in human pulmonary arterial hypertension. J Exp Med 208:535–548
139. Meloche J, Le Guen M, Potus F, Vinck J, Ranchoux B, Johnson I, Antigny F, Tremblay E, Breuils-Bonnet S, Perros F, Provencher S, Bonnet S (2015) miR-223 reverses experimental pulmonary arterial hypertension. Am J Physiol Cell Physiol 309:C363–C372
140. Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, McClure JD, Grant J, Thomas M, Frid M, Stenmark K, White K, Seto AG, Morrell NW, Bradshaw AC, MacLean MR, Baker AH (2015) MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ Res 117:870–883
141. Caruso P, Dempsie Y, Stevens HC, McDonald RA, Long L, Lu R, White K, Mair KM, McClure JD, Southwood M, Upton P, Xin M, van Rooij E, Olson EN, Morrell NW, MacLean MR, Baker AH (2012) A role for miR-145 in pulmonary arterial hypertension: evidence from mouse models and patient samples. Circ Res 111:290–300
142. Bertero T, Cottrill K, Krauszman A, Lu Y, Annis S, Hale A, Bhat B, Waxman AB, Chau BN, Kuebler WM, Chan SY (2015) The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. J Biol Chem 290:2069–2085
143. Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, Graham BB, Kumar R, Black SM, Fratz S, Fineman JR, West JD, Haley KJ, Waxman AB, Chau BN, Cottrill KA, Chan SY (2014) Systems-level regulation of microrna networks by miR-130/301 promotes pulmonary hypertension. J Clin Invest 124:3514–3528
144. White K, Loscalzo J, Chan SY (2012) Holding our breath: the emerging and anticipated roles of microrna in pulmonary hypertension. Pulm Circ 2:278–290
145. Kim GH, Ryan JJ, Marsboom G, Archer SL (2011) Epigenetic mechanisms of pulmonary hypertension. Pulm Circ 1:347–356
146. Zhao L, Chen CN, Hajji N, Oliver E, Cotroneo E, Wharton J, Wang D, Li M, McKinsey TA, Stenmark KR, Wilkins MR (2012) Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. Circulation 126:455–467
147. Lan B, Hayama E, Kawaguchi N, Furutani Y, Nakanishi T (2015) Therapeutic efficacy of valproic acid in a combined monocrotaline and chronic hypoxia rat model of severe pulmonary hypertension. PLoS One 10:e0117211
148. Bogaard HJ, Mizuno S, Hussaini AA, Toldo S, Abbate A, Kraskauskas D, Kasper M, Natarajan R, Voelkel NF (2011) Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats. Am J Respir Crit Care Med 183:1402–1410
149. Archer SL, Marsboom G, Kim GH, Zhang HJ, Toth PT, Svensson EC, Dyck JR, Gomberg-Maitland M, Thebaud B, Husain AN, Cipriani N, Rehman J (2010) Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. Circulation 121:2661–2671
150. Wang Y, Kahaleh B (2013) Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. J Cell Mol Med 17:1291–1299
151. Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, Coldren CD (2010) Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 182:1153–1160
152. Machado RD, James V, Southwood M, Harrison RE, Atkinson C, Stewart S, Morrell NW, Trembath RC, Aldred MA (2005) Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation 111:607–613
153. Federici C, Drake KM, Rigelsky CM, McNelly LN, Meade SL, Comhair SA, Erzurum SC, Aldred MA (2015) Increased mutagen sensitivity and DNA damage in pulmonary arterial hypertension. Am J Respir Crit Care Med 192:219–228
154. Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, Koskenvuo JW, Alastalo TP (2014) Loss of bone morphogenetic protein receptor 2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 50:1118–1128
155. Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, Couture C, Michelakis ED, Provencher S, Bonnet S (2014) Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 129:786–797
156. Dib H, Tamby MC, Bussone G, Regent A, Berezne A, Lafine C, Broussard C, Simonneau G, Guillevin L, Witko-Sarsat V, Humbert M, Mouthon L (2012) Targets of anti-endothelial cell antibodies in pulmonary hypertension and scleroderma. Eur Respir J 39:1405–1414
157. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF (2005) Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 26:1110–1118
158. Hagen M, Fagan K, Steudel W, Carr M, Lane K, Rodman DM, West J (2007) Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 292:L1473–L1479
159. Courboulin A, Tremblay VL, Barrier M, Meloche J, Jacob MH, Chapolard M, Bisserier M, Paulin R, Lambert C, Provencher S, Bonnet S (2011) Kruppel-like factor 5 contributes to pulmonary artery smooth muscle proliferation and resistance to apoptosis in human pulmonary arterial hypertension. Respir Res 12:128
160. Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S (2009) Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 10:6
161. Golembeski SM, West J, Tada Y, Fagan KA (2005) Interleukin-6 causes mild pulmonary hypertension and augments hypoxia-induced pulmonary hypertension in mice. Chest 128:572S–573S
162. Good RB, Gilbane AJ, Trinder SL, Denton CP, Coghlan G, Abraham DJ, Holmes AM (2015) Endothelial to mesenchymal transition contributes to endothelial dysfunction in pulmonary arterial hypertension. Am J Pathol 185:1850–1858
163. Bonnet S, Rochefort G, Sutendra G, Archer SL, Haromy A, Webster L, Hashimoto K, Bonnet SN, Michelakis ED (2007) The nuclear factor of activated t cells in pulmonary arterial hypertension can be therapeutically targeted. Proc Natl Acad Sci USA 104:11418–11423
164. Macian F (2005) Nfat proteins: key regulators of t-cell development and function. Nat Rev Immunol 5:472–484
165. Heissmeyer V, Macian F, Varma R, Im SH, Garcia-Cozar F, Horton HF, Byrne MC, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A (2005) A molecular dissection of lymphocyte unresponsiveness induced by sustained calcium signalling. Novartis Found Symp 267:165–174 (discussion 174–169)
166. Thenappan T, Goel A, Marsboom G, Fang YH, Toth PT, Zhang HJ, Kajimoto H, Hong Z, Paul J, Wietholt C, Pogoriler J, Piao L, Rehman J, Archer SL (2011) A central role for cd68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med 183:1080–1091
167. Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, Gera L, Farkas L, Rabinovitch M, Zamanian RT, Inayathullah M, Fridlib M, Rajadas J, Peters-Golden M, Voelkel NF, Nicolls MR (2013) Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Science translational medicine. 5:200ra117
168. Kim YM, Haghighat L, Spiekerkoetter E, Sawada H, Alvira CM, Wang L, Acharya S, Rodriguez-Colon G, Orton A, Zhao M, Rabinovitch M (2011) Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions. Am J Pathol 179:1560–1572
169. Rabinovitch M (1995) Elastase and cell matrix interactions in the pathobiology of vascular disease. Acta Paediatr Jpn 37:657–666
170. Rabinovitch M (1998) Elastase and the pathobiology of unexplained pulmonary hypertension. Chest 114:213S–224S
171. Kobayashi J, Wigle D, Childs T, Zhu L, Keeley FW, Rabinovitch M (1994) Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling. J Cell Physiol 160:121–131
172. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M (2005) Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112:423–431