Abstract
Pulmonary arterial hypertension (PAH) is characterised by remodelling of small pulmonary arteries leading to a progressive increase in pulmonary vascular resistance and right ventricular failure [1]. PAH can be idiopathic, familial, or associated with a number of conditions or diseases, such as connective tissue disease. Its prognosis is poor, less than 3 yr from diagnosis. The aetiology of severe unexplained pulmonary hypertension remained largely unknown until a few years ago. The gene underlying familial PAH was identified in 2000, the BMPR-2 gene. However its mutations are not always present, and it probably does not explained the full scope of the disease. PAH is associated with structural alterations in pulmonary arteries including intimal fibrosis, medial hypertrophy and adventitial changes, pointing towards extracellular matrix remodelling which have raised the question of involvement of the matrix degrading enzymes. Among them, serine proteases, such as plasmina and endogenous vascular elastase (EVE), and matrix metalloproteases have been studied. In experimental models, the three of them are increased. Accordingly, their inhibition has preventing and in some cases therapeutic effects. However it should be stressed that opposite consequence of protease inhibition on PAH can be observed depending on the experimental model, either chronic hypoxia-induced PAH (deleterious) or toxic moncrotalin-induced PAH (positive). In humans, only sparse reports exist, that found increase in the MMP inhibitor, TIMP-1, and MMP-2 expression and decreased collagenase (MMP-1). Inflammation is part of the PAH, and accordingly, protease production is a well known part of the inflammatory response. Answering the question whether protease inhibition might represent a therapeutic option in human PAH is however certainly too early.
Chapter PDF
Similar content being viewed by others
Keywords
- Pulmonary Hypertension
- Pulmonary Arterial Hypertension
- Idiopathic Pulmonary Arterial Hypertension
- Pulmonary Artery Smooth Muscle Cell
- Smooth Muscle Cell Migration
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension. N Engl J Med 351: 1655–1665
Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M et al (2004) Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43: 5S–12S
Gaine SP, Rubin LJ (1998) Primary pulmonary hypertension. Lancet 352: 719–725
Hoeper MM, Galie N, Simonneau G, Rubin LJ (2002) New treatments for pulmonary arterial hypertension. Am J Respir Crit Care Med 165: 1209–1216
Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M et al (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335: 609–616
Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse JH, Knowles JA (2000) Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med 161: 1055–1059
Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ et al (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
Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA 3rd, Loyd JE, Nichols WC, Trembath RC (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26: 81–84
Nichols WC, Koller DL, Slovis B, Foroud T, Terry VH, Arnold ND, Siemieniak DR, Wheeler L, Phillips JA 3rd, Newman JH et al (1997) Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31–32. Nat Genet 15: 277–280
Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W et al (2006) Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27: 121–132
Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P et al (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
Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S (2007) Pathology of pulmonary hypertension. Clin Chest Med 28: 23–42, vii
Cool CD, Kennedy D, Voelkel NF, Tuder RM (1997) Pathogenesis and evolution of plexiform lesions in pulmonary hypertension associated with scleroderma and human immunodeficiency virus infection. Hum Pathol 28: 434–442
Santos S, Peinado VI, Ramirez J, Melgosa T, Roca J, Rodriguez-Roisin R, Barbera JA (2002) Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD. Eur Respir J 19: 632–638
Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD, Olley PM, Cutz E (1986) Pulmonary artery endothelial abnormalities in patients with congenital heart defects and pulmonary hypertension. A correlation of light with scanning electron microscopy and transmission electron microscopy. Lab Invest 55: 632–653
Todorovitch-Hunter L, Johnson DJ, Ranger P, Keeley FW, Rabinovitsh M (1988) Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline: a biochemical and ultrastructural study. Lab Invest 58: 184–195
LaBourene JI, Coles JG, Johnson DJ, Mehra A, Keeley FW, Rabinovitch M (1990) Alterations in elastin and collagen related to the mechanism of progressive pulmonary venous obstruction in a piglet model. A hemodynamic, ultrastructural, and biochemical study. Circ Res 66: 438–456
Cowan K, Jones P, Rabinovitch M (2000) Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin-C antisense prevents progression, of vascular disease. J Clin Invest 105: 21–34
Jones P, Cowan K, Rabinovitch M (1997) Tenascin-C, proliferation and subendothelial accumulation of fibronectin in progressive pulmonary vascular disease. Am J Pathol 150: 1349–1360
Jones P, Crack J, Rabinovitch M (1997) Regulation of Tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alphaVbeta3 integrin to promote EGF receptor phosphorylation and growth. J Cell Biol 139: 279–293
Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M (2006) Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 21: 134–145
Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B (1995) Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 146: 389–397
Todorovitch-Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M (1992) Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with non-progressive disease. Am Rev Respir Dis 146: 213–233
Ye CL, Rabinovitch M (1991) Inhibition of elastolysis by SC-37698 reduces development and progression of monocrotaline pulmonary hypertension. Am J Physiol 261: H1255–1267
Maruyama K, Ye CL, Woo M, Venkatacharya H, Lines LD, Silver MM, Rabinovitch M (1991) Chronic hypoxic pulmonary hypertension in rats and increased elastolytic activity. Am J Physiol 261: H1716–1726
Jacob MP, Bellon G, Robert L, Hornebeck W, Ayrault-Jarrier M, Burdin J, Polonovski J (1981) Elastase-type activity associated with high density lipoproteins in human serum. Biochem Biophys Res Commun 103: 311–318
Hornebeck W, Derouette JC, Robert L (1975) Isolation, purification and properties of aortic elastase. FEBS Lett 58: 66–70
Zhu L, Wigle D, Hinek A, Kobayashi J, Ye C, Zuker M, Dodo H, Keeley FW, Rabinovitch M (1994) The endogenous vascular elastase that governs development and progression of monocrotaline-induced pulmonary hypertension in rats is a novel enzyme related to the serine proteinase adipsin. J Clin Invest 94: 1163–1171
Rabinovitch M (1999) EVE and beyond, retro and prospective insights. Am J Physiol 277: L5–12
Thompson K, Rabinovitch M (1996) Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular-matrix bound basic fibroblast growth factor. J Cell Physiol 166: 495–505
Hinek A, Boyle J, Rabinovitch M (1992) Vascular smooth muscle cell detachment from elastin and migration through elastic laminae is promoted by chondroitin sulfate-induced „shedding“ of the 67-kDa cell surface elastin binding protein. Exp Cell Res 203: 344–353
Hinek A, Molossi S, Rabinovitch M (1996) Functional interplay between interleukin-1 receptor and elastin binding protein regulates fibronectin production in coronary artery smooth muscle cells. Exp Cell Res 225: 122–131
Fay WP, Garg N, Sunkar M (2007) Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol 27: 1231–1237
Zhang L, Seiffert D, Fowler BJ, Jenkins GR, Thinnes TC, Loskutoff DJ, Parmer RJ, Miles LA (2002) Plasminogen has a broad extrahepatic distribution. Thromb Haemost 87: 493–501
Kolev K, Machovich R (2003) Molecular and cellular modulation of fibrinolysis. Thromb Haemost 89: 610–621
Carmeliet P, Moons L, Ploplis V, Plow E, Collen D (1997) Impaired arterial neointima formation in mice with disruption of the plasminogen gene. J Clin Invest 99: 200–208
Carmeliet P, Moons L, Herbert JM, Crawley J, Lupu F, Lijnen R, Collen D (1997) Urokinase but not tissue plasminogen activator mediates arterial neointima formation in mice. Circ Res 81: 829–839
Quax PH, Lamfers ML, Lardenoye JH, Grimbergen JM, de Vries MR, Slomp J, de Ruiter MC, Kockx MM, Verheijen JH, van Hinsbergh VW (2001) Adenoviral expression of a urokinase receptor-targeted protease inhibitor inhibits neointima formation in murine and human blood vessels. Circulation 103: 562–569
Schafer K, Konstantinides S, Riedel C, Thinnes T, Muller K, Dellas C, Hasenfuss G, Loskutoff DJ (2002) Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase-or tissue-type plasminogen activator. Circulation 106: 1847–1852
Bansal DD, Klein MR, Hausmann EHS, MacGregor RR (1997) Secretion of cardiac plasminogen activator during hypoxia-induced right ventricular hypertrophy. J Mol Cell Cardiol 29: 310563114
Graham CH, Fitzpatrick TE, McCrae KR (1998) Hypoxia stimulates urokinase receptor expression through a heme protein-dependent pathway. Blood 91: 3300–3307
Pinsky DJ, Liao H, Lawson CA, Yan SF, Chen J, Carmeliet P, Loskutoff DJ, Stern DM (1998) Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 102: 919–928
Saksela O, Rifkin DB (1990) Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 110: 767–775
Overall CM, Lopez-Otin C (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2: 657–672
Nagase H (1997) Activation mechanisms of matrix metalloproteinases. Biol Chem 378: 151–160
Okada Y, Nakanishi I (1989) Activation of matrix metalloproteinase 3 (stromelysin) and matrix metalloproteinase 2 (‘gelatinase’) by human neutrophil elastase and cathepsin G. FEBS Lett 249: 353–356
Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d’Ortho M-P, Murphy G (1998) The TIMP-2-MT1 MMP ‘receptor’ regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem 273: 871–880
Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477: 267–283
Hoegy SE, Oh HR, Corcoran ML, Stetler-Stevenson WG (2001) Tissue inhibitor of metalloproteinases-2 (TIMP-2) suppresses TKR-growth factor signaling independent of metalloproteinase inhibition. J Biol Chem 276: 3203–3214
Frisdal E, Gest V, Vieillard-Baron A, Levame M, Lepetit H, Eddahibi S, Lafuma C, Harf A, Adnot S, Dortho MP (2001) Gelatinase expression in pulmonary arteries during experimental pulmonary hypertension. Eur Respir J 18: 838–845
Thakker-Varia S, Tozzi CA, Poiani GJ, Barbiaz JP, Tatem L, Wilson FJ, Riley DJ (1998) Expression of matrix degrading enzymes in pulmonary vascular remodeling in the rat. Am J Physiol (Lung Cell Mol Physiol 19) 275: L398–L406
Tozzi CA, Thakker-Varia S, Shiu YY, Bannett RF, Peng BW, Poiani GJ, Wilson FJ, Riley DJ (1998) Mast cell colagenase correlates with regression of pulmonary vascular remodeling in the rat. Am J Respir Cell Mol Biol 18: 497–510
Vieillard-Baron A, Frisdal E, Eddahibi S, Deprez I, Baker AH, Newby AC, Berger P, Levame M, Raffestin B, Adnot S et al (2000) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 87: 418–425
Levi M, Moons L, Bouche A, Shapiro SD, Collen D, Carmeliet P (2001) Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice. Circulation 103: 2014–2020
Partovian C, Adnot S, Eddahibi S, Teiger E, Levame M, Dreyfus P, Raffestin B, Frelin C (1998) Heart and lung VEGF mRNA expression in rats with monocrotaline-or hypoxia-induced pulmonary hypertension. Am J Physiol 275: H1948–1956
Partovian C, Adnot S, Raffestin B, Louzier V, Levame M, Mavier IM, Lemarchand P, Eddahibi S (2000) Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 23: 762–771
Cowan K, Heilbut A, Humpl T, Lam C, Ito S, Rabinovitch M (2000) Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med 6: 698–702
Vieillard-Baron A, Frisdal E, Raffestin B, Baker AH, Eddahibi S, Adnot S, D’Ortho MP (2003) Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats. Hum Gene Ther 14: 861–869
Miyazono K, Maeda S, Imamura T (2005) BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16: 251–263
Massague J, Chen YG (2000) Controlling TGF-beta signaling. Genes Dev 14: 627–644
Rosenzweig BL, Imamura T, Okadome T, Cox GN, Yamashita H, ten Dijke P, Heldin CH, Miyazono K (1995) Cloning and characterization of a human type II receptor for bone morphogenetic proteins. Proc Natl Acad Sci USA 92: 7632–7636
Takahashi H, Goto N, Kojima Y, Tsuda Y, Morio Y, Muramatsu M, Fukuchi Y (2006) Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290: L450–458
Morty RE, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri FM, Peters DM, Dumitrascu R, Seeger W, Knaus P et al (2007) Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 27: 1072–1078
Deng H, Makizumi R, Ravikumar TS, Dong H, Yang W, Yang WL (2007) Bone morphogenetic protein-4 is overexpressed in colonic adenocarcinomas and promotes migration and invasion of HCT116 cells. Exp Cell Res 313: 1033–1044
Lepetit H, Eddahibi S, Fadel E, Frisdal E, Munaut C, Noel A, Humbert M, Adnot S, D’Ortho MP, Lafuma C (2005) Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 25: 834–842
Matsui K, Takano Y, Yu ZX, Hi JE, Stetler-Stevenson WG, Travis WD, Ferrans VJ (2002) Immunohistochemical study of endothelin-1 and matrix metalloproteinases in plexogenic pulmonary arteriopathy. Pathol Res Pract 198: 403–412
Delclaux C, d’Ortho M-P, Delacourt C, Lebargy F, Brun-Buisson C, Brochard L, Lemaire F, Lafuma C, Harf A (1997) Gelatinase in epithelial lining fluid of patients with adult respiratory distress syndrome. Am J Physiol (Lung Cell Mol Physiol 16) 272: L442–L451
Kondoh Y, Tanagushi H, Taki F, Takagi K, Satake T (1992) 7S collagen in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Chest 101: 1091–1094
Emonard H, Hornebeck W (1997) Binding of 92 kDa and 72 kDa progelatinases to insoluble elastin modulates their proteolytic activation. Biol Chem 378: 265–271
Uzui H, Lee JD, Shimizu H, Tsutani H, Ueda T (2000) The role of protein-tyrosine phosphorylation and gelatinase production in the migration and proliferation of smooth muscle cells. Atherosclerosis 149: 51–59
Dorfmuller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22: 358–363
Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR (2006) Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168: 659–669
Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Stenmark KR (2005) Circulating mononuclear cells with a dual, macrophage-fibroblast phenotype contribute robustly to hypoxia-induced pulmonary adventitial remodeling. Chest 128: 583S–584S
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
Barbera JA, Peinado VI, Santos S (2003) Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J 21: 892–905
Peinado VI, Barbera JA, Abate P, Ramirez J, Roca J, Santos S, Rodriguez-Roisin R (1999) Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159: 1605–1611
Peinado VI, Ramirez J, Roca J, Rodriguez-Roisin R, Barbera JA (2006) Identification of vascular progenitor cells in pulmonary arteries of patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 34: 257–263
Santos S, Peinado VI, Ramirez J, Morales-Blanhir J, Bastos R, Roca J, Rodriguez-Roisin R, Barbera JA (2003) Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 167: 1250–1256
Shapiro S (1994) Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med 150: S160–164
Weiss SJ, Peppin GJ (1986) Collagenolytic metalloenzymes of the human neutrophil: characteristics, regulation and potential function in vivo. Biochem Pharmacol 35: 3189–3197
Kazes I, Elalamy I, Sraer JD, Hatmi M, Nguyen G (2000) Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation. Blood 96: 3064–3069
Sawicki G, Salas E, Murat J, Miszta Lane H, Radomski MW (1997) Release of gelatinase A during platelet activation mediates aggregation. Nature 386: 616–619
Koolwijk P, Sidenius N, Peters E, Sier CF, Hanemaaijer R, Blasi F, van Hinsbergh VW (2001) Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: implication for angiogenesis in fibrin matrices. Blood 97: 3123–3131
Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA (1994) Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res 75: 539–545
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
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Birkhäuser Verlag Basel/Switzerland
About this chapter
Cite this chapter
d’Ortho, MP. (2008). MMPs, inflammation and pulmonary arterial hypertension. In: Lagente, V., Boichot, E. (eds) Matrix Metalloproteinases in Tissue Remodelling and Inflammation. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8585-9_6
Download citation
DOI: https://doi.org/10.1007/978-3-7643-8585-9_6
Publisher Name: Birkhäuser Basel
Print ISBN: 978-3-7643-8584-2
Online ISBN: 978-3-7643-8585-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)