Circulation. 2001;104:790-795
doi: 10.1161/hc3201.094152
doi: 10.1161/hc3201.094152
(Circulation. 2001;104:790.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Altered Growth Responses of Pulmonary Artery Smooth Muscle Cells From Patients With Primary Pulmonary Hypertension to Transforming Growth Factor-ß1 and Bone Morphogenetic Proteins
From the Department of Medicine (N.W.M., X.Y., P.D.U., K.B.J., N.M., K.K.S.), University of Cambridge, Addenbrooke’s and Papworth Hospitals, Cambridge, United Kingdom; and Division of Clinical Genetics (R.C.T.), University of Leicester, Leicester, United Kingdom.
Correspondence to Dr Nicholas W. Morrell, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Box 157, Hills Rd, Cambridge CB2 2QQ, UK. E-mail nwm23{at}cam.ac.uk
Background— Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-ß (TGF-ß) superfamily, underlie many cases of familial and sporadic primary pulmonary hypertension (PPH). We postulated that pulmonary artery smooth muscle cells (PASMCs) from patients with PPH might demonstrate abnormal growth responses to TGF-ß superfamily members.
Methods and Results— For studies of 3H-thymidine incorporation or cell proliferation, PASMCs (passages 4 to 8) were derived from main pulmonary arteries. In control cells, 24-hour incubation with TGF-ß1 (10 ng/mL) or bone morphogenetic protein (BMP)-2, -4, and -7 (100 ng/mL) inhibited basal and serum-stimulated 3H-thymidine incorporation, and TGF-ß1 and BMPs inhibited the proliferation of serum-stimulated PASMCs. In contrast, TGF-ß1 stimulated 3H-thymidine incorporation (200%; P<0.001) and cell proliferation in PASMCs from PPH but not from patients with secondary pulmonary hypertension. In addition, BMPs failed to suppress DNA synthesis and proliferation in PASMCs from PPH patients. Reverse transcription–polymerase chain reaction of PASMC mRNA detected transcripts for type I (TGF-ßRI, Alk-1, ActRI, and BMPRIB) and type II (TGF-ßRII, BMPR-II, ActRII, ActRIIB) receptors. Receptor binding and cross-linking studies with 125I-TGF-ß1 confirmed that the abnormal responses in PPH cells were not due to differences in TGF-ß receptor binding. Mutation analysis of PASMC DNA failed to detect mutations in TGF-ßRII and Alk-1 but confirmed the presence of a mutation in BMPR-II in 1 of 5 PPH isolates.
Conclusions— We conclude that PASMCs from patients with PPH exhibit abnormal growth responses to TGF-ß1 and BMPs and that altered integration of TGF-ß superfamily growth signals may contribute to the pathogenesis of PPH.
Key Words: hypertension, pulmonary • muscle, smooth • growth substances • proteins
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M. Humbert, N. W. Morrell, S. L. Archer, K. R. Stenmark, M. R. MacLean, I. M. Lang, B. W. Christman, E. K. Weir, O. Eickelberg, N. F. Voelkel, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 13S - 24S. [Abstract] [Full Text] [PDF]
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J. H. Newman, R. C. Trembath, J. A. Morse, E. Grunig, J. E. Loyd, S. Adnot, F. Coccolo, C. Ventura, J. A. Phillips III, J. A. Knowles, et al. Genetic basis of pulmonary arterial hypertension: Current understanding and future directions J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 33S - 39S. [Abstract] [Full Text] [PDF]
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M. Rabinovitch The Mouse Through the Looking Glass: A New Door Into the Pathophysiology of Pulmonary Hypertension Circ. Res., April 30, 2004; 94(8): 1001 - 1004. [Full Text] [PDF]
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J. West, K. Fagan, W. Steudel, B. Fouty, K. Lane, J. Harral, M. Hoedt-Miller, Y. Tada, J. Ozimek, R. Tuder, et al. Pulmonary Hypertension in Transgenic Mice Expressing a Dominant-Negative BMPRII Gene in Smooth Muscle Circ. Res., April 30, 2004; 94(8): 1109 - 1114. [Abstract] [Full Text] [PDF]
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H. El-Haroun, D. Bradbury, A. Clayton, and A. J. Knox Interleukin-1{beta}, Transforming Growth Factor-{beta}1, and Bradykinin Attenuate Cyclic AMP Production by Human Pulmonary Artery Smooth Muscle Cells in Response to Prostacyclin Analogues and Prostaglandin E2 by Cyclooxygenase-2 Induction and Downregulation of Adenylyl Cyclase Isoforms 1, 2, and 4 Circ. Res., February 20, 2004; 94(3): 353 - 361. [Abstract] [Full Text] [PDF]
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I. M. Robbins Advancing Therapy for Pulmonary Arterial Hypertension: Can Animal Models Help? Am. J. Respir. Crit. Care Med., January 1, 2004; 169(1): 5 - 6. [Full Text] [PDF]
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C. V. Remillard and J. X.-J. Yuan Activation of K+ channels: an essential pathway in programmed cell death Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L49 - L67. [Abstract] [Full Text] [PDF]
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C. Blanpain, E. Le Poul, J. Parma, C. Knoop, M. Detheux, M. Parmentier, G. Vassart, and M. J Abramowicz Serotonin 5-HT2B receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension Cardiovasc Res, December 1, 2003; 60(3): 518 - 528. [Abstract] [Full Text] [PDF]
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S. Zhang, I. Fantozzi, D. D. Tigno, E. S. Yi, O. Platoshyn, P. A. Thistlethwaite, J. M. Kriett, G. Yung, L. J. Rubin, and J. X.-J. Yuan Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L740 - L754. [Abstract] [Full Text] [PDF]
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S. Sharma Treatment of Pulmonary Arterial Hypertension: A Step Forward Chest, July 1, 2003; 124(1): 8 - 11. [Full Text] [PDF]
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C. P. Denton, B. Zheng, L. A. Evans, X. Shi-wen, V. H. Ong, I. Fisher, K. Lazaridis, D. J. Abraham, C. M. Black, and B. de Crombrugghe Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor {beta} (TGF{beta}) Receptor Leads to Paradoxical Activation of TGF{beta} Signaling Pathways with Fibrosis in Transgenic Mice J. Biol. Chem., June 27, 2003; 278(27): 25109 - 25119. [Abstract] [Full Text] [PDF]
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S. Eddahibi, N. Morrell, M-P. d'Ortho, R. Naeije, and S. Adnot Pathobiology of pulmonary arterial hypertension Eur. Respir. J., December 1, 2002; 20(6): 1559 - 1572. [Abstract] [Full Text] [PDF]
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M. Humbert, Z. Deng, G. Simonneau, R.J. Barst, O. Sitbon, M. Wolf, N. Cuervo, K.J. Moore, S.E. Hodge, J.A. Knowles, et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives Eur. Respir. J., September 1, 2002; 20(3): 518 - 523. [Abstract] [Full Text] [PDF]
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M. Humbert and R.C. Trembath Genetics of pulmonary hypertension: from bench to bedside Eur. Respir. J., September 1, 2002; 20(3): 741 - 749. [Abstract] [Full Text] [PDF]
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N. Rudarakanchana, J. A. Flanagan, H. Chen, P. D. Upton, R. Machado, D. Patel, R. C. Trembath, and N. W. Morrell Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension Hum. Mol. Genet., June 15, 2002; 11(13): 1517 - 1525. [Abstract] [Full Text] [PDF]
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M. M. Hoeper, N. Galie, G. Simonneau, and L. J. Rubin New Treatments for Pulmonary Arterial Hypertension Am. J. Respir. Crit. Care Med., May 1, 2002; 165(9): 1209 - 1216. [Full Text] [PDF]
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M.M. Hoeper Pulmonary hypertension in collagen vascular disease Eur. Respir. J., March 1, 2002; 19(3): 571 - 576. [Abstract] [Full Text] [PDF]
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N Rudarakanchana, R C Trembath, and N W Morrell New insights into the pathogenesis and treatment of primary pulmonary hypertension Thorax, November 1, 2001; 56(11): 888 - 890. [Full Text] [PDF]
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C. Atkinson, S. Stewart, P. D. Upton, R. Machado, J. R. Thomson, R. C. Trembath, and N. W. Morrell Primary Pulmonary Hypertension Is Associated With Reduced Pulmonary Vascular Expression of Type II Bone Morphogenetic Protein Receptor Circulation, April 9, 2002; 105(14): 1672 - 1678. [Abstract] [Full Text] [PDF]
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