Abstract
Following its initial description over a century ago, pulmonary arterial hypertension (PAH) continues to challenge researchers committed to understanding its pathobiology and finding a cure. The last two decades have seen major developments in our understanding of the genetics and molecular basis of PAH that drive cells within the pulmonary vascular wall to produce obstructive vascular lesions; presently, the field of PAH research has taken numerous approaches to dissect the complex amalgam of genetic, molecular and inflammatory pathways that interact to initiate and drive disease progression. In this review, we discuss the current understanding of PAH pathology and the role that genetic factors and environmental influences share in the development of vascular lesions and abnormal cell function. We also discuss how animal models can assist in elucidating gene function and the study of novel therapeutics, while at the same time addressing the limitations of the most commonly used rodent models. Novel experimental approaches based on application of next generation sequencing, bioinformatics and epigenetics research are also discussed as these are now being actively used to facilitate the discovery of novel gene mutations and mechanisms that regulate gene expression in PAH. Finally, we touch on recent discoveries concerning the role of inflammation and immunity in PAH pathobiology and how they are being targeted with immunomodulatory agents. We conclude that the field of PAH research is actively expanding and the major challenge in the coming years is to develop a unified theory that incorporates genetic and mechanistic data to address viable areas for disease modifying drugs that can target key processes that regulate the evolution of vascular pathology of PAH.
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References
Hunter DJ (2005) Gene-environment interactions in human diseases. Nat Rev Genet 6:287–298
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
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
Morrell NW (2006) Pulmonary hypertension due to bmpr2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3:680–686
Chin KM, Kim NH, Rubin LJ (2005) The right ventricle in pulmonary hypertension. Coron Artery Dis 16:13–18
Chin KM, Rubin LJ (2008) Pulmonary arterial hypertension. J Am Coll Cardiol 51:1527–1538
Rubin LJ (2006) Pulmonary arterial hypertension. Proc Am Thorac Soc 3:111–115
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
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
Rabinovitch M (2001) Pathobiology of pulmonary hypertension Extracellular matrix. Clin Chest Med 22:433–449 viii
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
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
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
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
Stenmark KR, Fagan KA, Frid MG (2006) Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms. Circ Res 99:675–691
Stenmark KR, Frid MG (1998) Smooth muscle cell heterogeneity: role of specific smooth muscle cell subpopulations in pulmonary vascular disease. Chest 114:82S–90S
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
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
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
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
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
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
Rabinovitch M (1999) Eve and beyond, retro and prospective insights. Am J Physiol 277:L5–12
Rabinovitch M (2012) Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 122:4306–4313
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
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
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
Tuder RM, Voelkel NF (2002) Angiogenesis and pulmonary hypertension: a unique process in a unique disease. Antioxid Redox Signal 4:833–843
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
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
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
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
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
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
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
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
Durmowicz AG, Stenmark KR (1999) Mechanisms of structural remodeling in chronic pulmonary hypertension. Pediatr Rev 20:e91–e102
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
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
Rabinovitch M, Guignabert C, Humbert M, Nicolls MR (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115:165–175
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
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
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
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
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
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
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
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
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
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
Best DH, Austin ED, Chung WK, Elliott CG (2014) Genetics of pulmonary hypertension. Curr Opin Cardiol 29:520–527
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
Ryan JJ (2013) Chloroquine in pulmonary arterial hypertension: a new role for an old drug? Circ Cardiovasc Genet 6:310–311
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
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
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
Lenato GM, Guanti G (2006) Hereditary haemorrhagic telangiectasia (HHT): genetic and molecular aspects. Curr Pharm Des 12:1173–1193
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
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
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
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
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
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
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
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
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
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
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
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
Mandegar M, Remillard CV, Yuan JX (2002) Ion channels in pulmonary arterial hypertension. Prog Cardiovasc Dis 45:81–114
Mandegar M, Yuan JX (2002) Role of k + channels in pulmonary hypertension. Vasc Pharmacol 38:25–33
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
Gurney A, Manoury B (2009) Two-pore potassium channels in the cardiovascular system. Eur Biophys J 38:305–318
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Dromparis P, Sutendra G, Michelakis ED (2010) The role of mitochondria in pulmonary vascular remodeling. J Mol Med 88:1003–1010
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
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
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
Ryter SW, Nakahira K, Haspel JA, Choi AM (2012) Autophagy in pulmonary diseases. Annu Rev Physiol 74:377–401
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
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
Lahm T, Petrache I (2012) LC3 as a potential therapeutic target in hypoxia-induced pulmonary hypertension. Autophagy 8:1146–1147
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
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
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
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
Gross SB (1999) Appetite suppressants and cardiac valvulopathy. Current clinical perspectives. Adv Nurse Pract 7:36–40
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
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
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
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
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
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
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
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
Thompson CA (2008) Pulmonary arterial hypertension seen in methamphetamine abusers. Am J Health Syst Pharm 65:1109–1110
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
Ryan JJ, Marsboom G, Archer SL (2013) Rodent models of group 1 pulmonary hypertension. Handb Exp Pharmacol 218:105–149
Roth RA, Reindel JF (1991) Lung vascular injury from monocrotaline pyrrole, a putative hepatic metabolite. Adv Exp Med Biol 283:477–487
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Bienertova-Vasku J, Novak J, Vasku A (2015) Micrornas in pulmonary arterial hypertension: pathogenesis, diagnosis and treatment. J Am Soc Hypertens 9:221–234
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
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
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
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
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
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
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
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
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
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
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
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
Kim GH, Ryan JJ, Marsboom G, Archer SL (2011) Epigenetic mechanisms of pulmonary hypertension. Pulm Circ 1:347–356
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
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
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
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
Wang Y, Kahaleh B (2013) Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. J Cell Mol Med 17:1291–1299
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
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
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
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
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
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
Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF (2005) Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 26:1110–1118
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
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
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
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
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
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
Macian F (2005) Nfat proteins: key regulators of t-cell development and function. Nat Rev Immunol 5:472–484
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)
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
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
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
Rabinovitch M (1995) Elastase and cell matrix interactions in the pathobiology of vascular disease. Acta Paediatr Jpn 37:657–666
Rabinovitch M (1998) Elastase and the pathobiology of unexplained pulmonary hypertension. Chest 114:213S–224S
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
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
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de Jesus Perez, V.A. Molecular pathogenesis and current pathology of pulmonary hypertension. Heart Fail Rev 21, 239–257 (2016). https://doi.org/10.1007/s10741-015-9519-2
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DOI: https://doi.org/10.1007/s10741-015-9519-2