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Cross Talk Between Smad, MAPK, and Actin in the Etiology of Pulmonary Arterial Hypertension

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Membrane Receptors, Channels and Transporters in Pulmonary Circulation

Part of the book series: Advances in Experimental Medicine and Biology ((volume 661))

Abstract

The gene for the type 2 receptor for the bone morphogenic pathway, BMPR2, is mutated in a large majority of familial pulmonary arterial hypertension (PAH),. However, the mechanisms linking BMPR2 mutation to disease remain obscure. BMPR2 potentially signals through multiple immediate downstream pathways, including Smad, MAPK, LIM domain kinase 1 (LIMK) and dynein, light chain, Tctex-type 1 (TCTEX), v-src sarcoma viral oncogene homolog (SRC), and nuclear factor kappa-B (NFkB). Functional consequences of BMPR2 mutation, largely ascertained from animal models, include a shift from contractile to synthetic phenotype in smooth muscle, probably downstream of Smad signal; alterations in expression of actin organization related genes, possibly related to focal adhesions; alterations in cytokines and inflammatory cell recruitment; increased proliferation and apoptosis; and increased collagen and matrix. A synthesis of the available data suggests that the normal role of BMPR2 in adult animals is to assist in injury repair. BMPR2 is suppressed in injured tissue, which facilitates inflammatory response, shift to a synthetic cellular phenotype, and alterations in migration or permeability of cells in the vascular wall. We thus hypothesize that BMPR2 mutation thus leads to an impaired ability to terminate the injury repair process, leading to strong predisposition to PAH.

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References

  1. Deng Z, Morse JH, Slager SL 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

    Article  PubMed  CAS  Google Scholar 

  2. Lane KB, Machado RD, Pauciulo MW et al (2000) Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26:81-84

    Article  PubMed  CAS  Google Scholar 

  3. Thomson JR, Machado RD, Pauciulo MW et al (2000) Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-β family. J Med Genet 37:741-745

    Article  PubMed  CAS  Google Scholar 

  4. Tiedemann H, Asashima M, Grunz H, Knochel W (2001) Pluripotent cells (stem cells) and their determination and differentiation in early vertebrate embryogenesis. Dev Growth Differ 43:469-502

    Article  PubMed  CAS  Google Scholar 

  5. Herpin A, Cunningham C (2007) Cross-talk between the bone morphogenetic protein pathway and other major signaling pathways results in tightly regulated cell-specific outcomes. FEBS J 274:2977-2985

    Article  PubMed  CAS  Google Scholar 

  6. Nohe A, Keating E, Underhill TM, Knaus P, Petersen NO (2003) Effect of the distribution and clustering of the type I A BMP receptor (ALK3) with the type II BMP receptor on the activation of signalling pathways. J Cell Sci 116:3277-3284

    Article  PubMed  CAS  Google Scholar 

  7. Nishihara A, Watabe T, Imamura T, Miyazono K (2002) Functional heterogeneity of bone morphogenetic protein receptor-II mutants found in patients with primary pulmonary hypertension. Mol Biol Cell 13:3055-3063

    Article  PubMed  CAS  Google Scholar 

  8. Jeffery TK, Upton PD, Trembath RC, Morrell NW (2005) BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. Am J Physiol Lung Cell Mol Physiol 288:L370-L378

    Article  PubMed  CAS  Google Scholar 

  9. Rudarakanchana N, Flanagan JA, Chen H et al (2002) Functional analysis of bone morphogenetic protein type II receptor mutations underlying primary pulmonary hypertension. Hum Mol Genet 11:1517-1525

    Article  PubMed  CAS  Google Scholar 

  10. Foletta VC, Lim MA, Soosairajah J et al (2003) Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1. J Cell Biol 162:1089-1098

    Article  PubMed  CAS  Google Scholar 

  11. Machado RD, Rudarakanchana N, Atkinson C et al (2003) Functional interaction between BMPR-II and Tctex-1, a light chain of dynein, is isoform-specific and disrupted by mutations underlying primary pulmonary hypertension. Hum Mol Genet 12:3277-3286

    Article  PubMed  CAS  Google Scholar 

  12. Lu M, Lin SC, Huang Y et al (2007) XIAP induces NF-κB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Mol Cell 26:689-702

    Article  PubMed  CAS  Google Scholar 

  13. Wong WK, Knowles JA, Morse JH (2005) Bone morphogenetic protein receptor type II C-terminus interacts with c-Src: implication for a role in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 33:438-446

    Article  PubMed  CAS  Google Scholar 

  14. Newman JH, Phillips JA III, Loyd JE (2008) Narrative review: the enigma of pulmonary arterial hypertension: new insights from genetic studies. Ann Intern Med 148:278-283

    PubMed  Google Scholar 

  15. Lu MM, Yang H, Zhang L, Shu W, Blair DG, Morrisey EE (2001) The bone morphogenic protein antagonist gremlin regulates proximal-distal patterning of the lung. Dev Dyn 222:667-680

    Article  PubMed  CAS  Google Scholar 

  16. Morrell NW (2006) Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3:680-686

    Article  PubMed  CAS  Google Scholar 

  17. Rajan P, Panchision DM, Newell LF, McKay RD (2003) BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells. J Cell Biol 161:911-921

    Article  PubMed  CAS  Google Scholar 

  18. Yanagisawa M, Nakashima K, Takizawa T, Ochiai W, Arakawa H, Taga T (2001) Signaling crosstalk underlying synergistic induction of astrocyte differentiation by BMPs and IL-6 family of cytokines. FEBS Lett 489:139-143

    Article  PubMed  CAS  Google Scholar 

  19. Yamaguchi K, Nagai S, Ninomiya-Tsuji J et al (1999) XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J 18:179-187

    Article  PubMed  CAS  Google Scholar 

  20. Fuentealba LC, Eivers E, Ikeda A et al (2007) Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 131:980-993

    Article  PubMed  CAS  Google Scholar 

  21. Winter-Vann AM, Johnson GL (2007) Integrated activation of MAP3Ks balances cell fate in response to stress. J Cell Biochem 102:848-858

    Article  PubMed  CAS  Google Scholar 

  22. Li MG, Serr M, Newman EA, Hays TS (2004) The Drosophila tctex-1 light chain is dispensable for essential cytoplasmic dynein functions but is required during spermatid differentiation. Mol Biol Cell 15:3005-3014

    Article  PubMed  CAS  Google Scholar 

  23. Sachdev P, Menon S, Kastner DB et al (2007) G protein βγ subunit interaction with the dynein light-chain component Tctex-1 regulates neurite outgrowth. EMBO J 26:2621-2632

    Article  PubMed  CAS  Google Scholar 

  24. Chuang JZ, Yeh TY, Bollati F et al (2005) The dynein light chain Tctex-1 has a dynein-independent role in actin remodeling during neurite outgrowth. Dev Cell 9:75-86

    Article  PubMed  CAS  Google Scholar 

  25. Baruzzi A, Caveggion E, Berton G (2008) Regulation of phagocyte migration and recruitment by Src-family kinases. Cell Mol Life Sci 65:2175-2190

    Article  PubMed  CAS  Google Scholar 

  26. Kuramochi Y, Guo X, Sawyer DB (2006) Neuregulin activates erbB2-dependent src/FAK signaling and cytoskeletal remodeling in isolated adult rat cardiac myocytes. J Mol Cell Cardiol 41:228-235

    Article  PubMed  CAS  Google Scholar 

  27. Ghosh S, Hayden MS (2008) New regulators of NF-κB in inflammation. Nat Rev Immunol 8:837-848

    Article  PubMed  CAS  Google Scholar 

  28. West J, Harral J, Lane K et al (2008) Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions. Am J Physiol Lung Cell Mol Physiol 295:L744-L755

    Article  PubMed  CAS  Google Scholar 

  29. West J, Fagan K, Steudel W et al (2004) Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res 94:1109-1114

    Article  PubMed  CAS  Google Scholar 

  30. Tada Y, Majka S, Carr M et al (2007) Molecular effects of loss of BMPR2 signaling in smooth muscle in a transgenic mouse model of PAH. Am J Physiol Lung Cell Mol Physiol 292:L1556-L1563

    Article  PubMed  CAS  Google Scholar 

  31. Hagen M, Fagan K, Steudel W et al (2007) Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. Am J Physiol Lung Cell Mol Physiol 292:L1473-L1479

    Article  PubMed  CAS  Google Scholar 

  32. Taraseviciene-Stewart L, Kasahara Y, Alger L et al (2001) Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 15:427-438

    Article  PubMed  CAS  Google Scholar 

  33. Tada Y, Laudi S, Harral J et al (2008) Murine pulmonary response to chronic hypoxia is strain specific. Exp Lung Res 34:313-323

    Article  PubMed  CAS  Google Scholar 

  34. Dorfmuller P, Perros F, Balabanian K, Humbert M (2003) Inflammation in pulmonary arterial hypertension. Eur Respir J 22:358-363

    Article  PubMed  CAS  Google Scholar 

  35. Shimzu K, Takahashi T, Iwasaki T et al (2008) Hemin treatment abrogates monocrotaline-induced pulmonary hypertension. Med Chem 4:572-576

    Article  PubMed  CAS  Google Scholar 

  36. Klein M, Schermuly RT, Ellinghaus P et al (2008) Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 118:2081-2090

    Article  PubMed  CAS  Google Scholar 

  37. Huang J, Kaminski PM, Edwards JG et al (2008) Pyrrolidine dithiocarbamate restores endothelial cell membrane integrity and attenuates monocrotaline-induced pulmonary artery hypertension. Am J Physiol Lung Cell Mol Physiol 294:L1250-L1259

    Article  PubMed  CAS  Google Scholar 

  38. West J, Cogan J, Geraci M et al (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

    Article  PubMed  Google Scholar 

  39. MacLean MR (2007) Pulmonary hypertension and the serotonin hypothesis: where are we now. Int J Clin Pract Suppl 156:27-31

    Article  PubMed  CAS  Google Scholar 

  40. Phillips JA III, Poling JS, Phillips CA et al (2008) Synergistic heterozygosity for TGFβ1 SNPs and BMPR2 mutations modulates the age at diagnosis and penetrance of familial pulmonary arterial hypertension. Genet Med 10:359-365

    Article  PubMed  CAS  Google Scholar 

  41. Remillard CV, Tigno DD, Platoshyn O et al (2007) Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol 292:C1837-C1853

    Article  PubMed  CAS  Google Scholar 

  42. Wigley FM, Lima JA, Mayes M, McLain D, Chapin JL, Ward-Able C (2005) The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 52:2125-2132

    Article  PubMed  Google Scholar 

  43. Ihn H (2008) Autocrine TGF-β signaling in the pathogenesis of systemic sclerosis. J Dermatol Sci 49:103-113

    Article  PubMed  CAS  Google Scholar 

  44. Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28:521-574

    Article  PubMed  CAS  Google Scholar 

  45. Wagenvoort CA, Wagenvoort N, Draulans-Noe Y (1984) Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery. J Thorac Cardiovasc Surg 87:876-886

    PubMed  CAS  Google Scholar 

  46. Bellotto F, Chiavacci P, Laveder F, Angelini A, Thiene G, Marcolongo R (1999) Effective immunosuppressive therapy in a patient with primary pulmonary hypertension. Thorax 54:372-374

    Article  PubMed  CAS  Google Scholar 

  47. Sanchez O, Sitbon O, Jais X, Simonneau G, Humbert M (2006) Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 130:182-189

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University, School of Medicine, Nashville, TN, USA

    James West

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  1. James West
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Editors and Affiliations

  1. Departments of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, 60612, USA

    Jason X. -J. Yuan

  2. Guy’s Hospital Campus, Dept. Physiology, King’s College London, London, SE1 1UL, United Kingdom

    Jeremy P. T. Ward

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© 2010 Humana Press, a part of Springer Science+Business Media, LLC

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West, J. (2010). Cross Talk Between Smad, MAPK, and Actin in the Etiology of Pulmonary Arterial Hypertension. In: Yuan, JJ., Ward, J. (eds) Membrane Receptors, Channels and Transporters in Pulmonary Circulation. Advances in Experimental Medicine and Biology, vol 661. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-500-2_17

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