Abstract
Pulmonary hypertension (PH) is a disorder characterized by vascular remodeling and proliferation, a phenotype dependent upon unimpeded growth factor and kinase pathway activation with strong similarities to malignant tumors. This chapter details our novel application of the multikinase inhibitor, sorafenib, in rodent models of PH to improved hemodynamic parameters and attenuates PH structural changes1. Sorafenib is a Raf kinase inhibitor and our biochemical and genomic evidence supported the potential involvement of the MAPK cascade system and TGFB3 in PH development and the response to therapy. Integration of expression genomic analyses coupled with intense bioinformatics identified gene expression and ontology signatures in the development of PH and implicated the role of cytoskeletal protein such as caldesmon or nmMLCK as potentially key participants in PH-induced vascular remodeling and proliferation. Our studies suggest the PKI sorafenib as a potentially novel treatment for severe PH with the MAPK cascade a potential canonical target profoundly effecting vascular cytoskeletal rearrangements and remodeling1.
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Moreno-Vinasco L, Gomberg-Maitland M, Maitland ML et al (2008) Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension. Physiol Genomics 33:278-291
Higenbottam T, Cremona G (1993) Acute and chronic hypoxic pulmonary hypertension. Eur Respir J 6:1207-1212
Moudgil R, Michelakis ED, Archer SL (2005) Hypoxic pulmonary vasoconstriction. J Appl Physiol 98:390-403
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
Raiesdana A, Loscalzo J (2006) Pulmonary arterial hypertension. Ann Med 38:95-110
Rhodes CJ, Davidson A, Gibbs JS, Wharton J, Wilkins MR (2009) Therapeutic targets in pulmonary arterial hypertension. Pharmacol Ther 121:69-88
Adatia I (2002) Recent advances in pulmonary vascular disease. Curr Opin Pediatr 14:292-297
Bull TM, Coldren CD, Nana-Sinkam P et al (2005) Microarray analysis of peripheral blood cells in pulmonary arterial hypertension, surrogate to biopsy. Chest 128:584S
Geraci MW, Gao B, Hoshikawa Y, Yeager ME, Tuder RM, Voelkel NF (2001) Genomic approaches to research in pulmonary hypertension. Respir Res 2:210-215
Girgis RE, Li D, Zhan X et al (2003) Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 285:H938-H945
Girgis RE, Ma SF, Ye S et al (2005) Differential gene expression in chronic hypoxic pulmonary hypertension: effect of simvastatin treatment. Chest 128:579S
Bull TM, Coldren CD, Moore M et al (2004) Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med 170:911-919
Budhiraja R, Tuder RM, Hassoun PM (2004) Endothelial dysfunction in pulmonary hypertension. Circulation 109:159-165
Archer SL, Michelakis ED (2006) An evidence-based approach to the management of pulmonary arterial hypertension. Curr Opin Cardiol 21:385-392
Grant SK (2009) Therapeutic protein kinase inhibitors. Cell Mol Life Sci 66:1163-1177
McLaughlin VV, McGoon MD (2006) Pulmonary arterial hypertension. Circulation 114:1417-1431
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
Wilhelm SM, Carter C, Tang L et al (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099-7109
Rahmani M, Davis EM, Bauer C, Dent P, Grant S (2005) Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem 280:35217-35227
Rahmani M, Davis EM, Crabtree TR et al (2007) The kinase inhibitor sorafenib induces cell death through a process involving induction of endoplasmic reticulum stress. Mol Cell Biol 27:5499-5513
Rahmani M, Nguyen TK, Dent P, Grant S (2007) The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation. Mol Pharmacol 72:788-795
Grant S (2008) Cotargeting survival signaling pathways in cancer. J Clin Invest 118:3003-3006
Gharib SA, Luchtel DL, Madtes DK, Glenny RW (2005) Global gene annotation analysis and transcriptional profiling identify key biological modules in hypoxic pulmonary hypertension. Physiol Genomics 22:14-23
Malek RL, Wang HY, Kwitek AE et al (2006) Physiogenomic resources for rat models of heart, lung and blood disorders. Nat Genet 38:234-239
Mirzapoiazova T, Kolosova IA, Romer L, Garcia JG, Verin AD (2005) The role of caldesmon in the regulation of endothelial cytoskeleton and migration. J Cell Physiol 203:520-528
Dudek SM, Garcia JG (2001) Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol 91:1487-1500
Phillips PG (1994) Thrombin-induced alterations in endothelial cell cytoarchitectural and functional properties. Semin Thromb Hemost 20:417-425
Phillips PG, Lum H, Malik AB, Tsan MF (1989) Phallacidin prevents thrombin-induced increases in endothelial permeability to albumin. Am J Physiol 257:C562-C567
Acknowledgments
This work was supported by NIH-NHLBI (JGNG P01 HL58064, RO1 HL090860-01) and K22 (LMV 008308-01) awards.
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Moreno-Vinasco, L., Garcia, J.G.N. (2010). Receptor Tyrosine Kinase Inhibitors in Rodent Pulmonary 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_27
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DOI: https://doi.org/10.1007/978-1-60761-500-2_27
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