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PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension

Venkatrao Medarametla, Stephen Festin, Chuluunbaatar Sugarragchaa, Alexander Eng, Amir Naqwi, Timothy Wiedmann and Lawrence S. Zisman
Pulmonary Circulation
Vol. 4, No. 1 (March 2014), pp. 82-102
DOI: 10.1086/674881
Stable URL:
Page Count: 21
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AbstractThe platelet-derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)- and 8 (D8)-minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4 ± 2.6 mmHg in the vehicle MCT group (n = 6), 44.4 ± 5.8 mmHg in the D4 MCT group (n = 6), and 37.1 ± 4.5 mmHg in the D8 MCT group (n = 5; P < 0.001 vs. vehicle); RVSP was 75.7 ± 7.1 mmHg in the vehicle MCT+PN group (n = 9), 40.4 ± 2.7 mmHg in the D4 MCT+PN group (n = 10), and 43.0 ± 3.0 mmHg in the D8 MCT+PN group (n = 8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGFβ receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGFα receptor, whereas PK10453 has a lower half-maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGFα and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGFα and PDGFβ receptors may have a therapeutic advantage over selective PDGFα receptor inhibition in PAH.

Notes and References

This item contains 30 references.

  • 1.
    ['1. Perros F, Montani D, Dorfmüller P, Durand-Gasselin I, Tcherakian C, Le Pavec J, Mazmanian M, et al. Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;178:81–88.']
  • 2.
    ['2. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 2005;115:2811–2821.']
  • 3.
    ['3. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, Peacock AJ, Barst RJ, Shapiro S, et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010;182:1171–1177.']
  • 4.
    ['4. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension. N Engl J Med 2005;353:1412–1413.']
  • 5.
    ['5. Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galiè N, Gómez-Sánchez MA, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013;127:1128–1138.']
  • 6.
    ['6. Paniagua RT, Robinson WH. Imatinib for the treatment of rheumatic diseases. Nat Clin Pract Rheumatol 2007;3:190–191.']
  • 7.
    ['7. Fujita H, Fukumoto Y, Saji K, Sugimura K, Demachi J, Nawata J, Shimokawa H. Acute vasodilator effects of inhaled fasudil, a specific Rho-kinase inhibitor, in patients with pulmonary arterial hypertension. Heart Vessels 2010;25:144–149.']
  • 8.
    ['8. Nagaoka T, Fagan KA, Gebb SA, Morris KG, Suzuki T, Shimokawa H, McMurtry IF, Oka M. Inhaled Rho kinase inhibitors are potent and selective vasodilators in rat pulmonary hypertension. Am J Respir Crit Care Med 2005;171:494–499.']
  • 9.
    ['9. Chen H, Kovar J, Sissons S, Cox K, Matter W, Chadwell F, Luan P, Vlahos CJ, Schutz-Geschwender A, Olive DM. A cell-based immunocytochemical assay for monitoring kinase signaling pathways and drug efficacy. Anal Biochem 2005;338:136–142.']
  • 10.
    ['10. Sakagami M. In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery. Adv Drug Deliv Rev 2006;58:1030–1060.']
  • 11.
    ['11. White RJ, Meoli DF, Swarthout RF, Kallop DY, Galaria II, Harvey JL, Miller CM, et al. Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:L583–L590.']
  • 12.
    ['12. Homma N, Nagaoka T, Karoor V, Imamura M, Taraseviciene-Stewart L, Walker LA, Fagan KA, McMurtry IF, Oka M. Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone. Am J Physiol Lung Cell Mol Physiol 2008;295:L71–L78.']
  • 13.
    ['13. Iacovides DC, Johnson AB, Wang N, Boddapati S, Korkola J, Gray JW. Identification and quantification of AKT isoforms and phosphoforms in breast cancer using a novel nanofluidic immunoassay. Mol Cell Proteomics 2013;12:3210–3220.']
  • 14.
    ['14. Fan AC, Deb-Basu D, Orban MW, Gotlib JR, Natkunam Y, O’Neill R, Padua R-A, et al. Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens. Nat Med 2009;15:566–571.']
  • 15.
    ['15. Hitzman CJ, Wattenberg LW, Wiedmann TS. Pharmacokinetics of 5-fluorouracil in the hamster following inhalation delivery of lipid-coated nanoparticles. J Pharm Sci 2006;95:1196–1211.']
  • 16.
    ['16. Zhang G, David A, Wiedmann TS. Performance of the vibrating membrane aerosol generation device: Aeroneb Micropump Nebulizer. J Aerosol Med 2007;20:408–416.']
  • 17.
    ['17. Panzhinskiy E, Zawada WM, Stenmark KR, Das M. Hypoxia induces unique proliferative response in adventitial fibroblasts by activating PDGFβ receptor-JNK1 signalling. Cardiovasc Res 2012;95:356–365.']
  • 18.
    ['18. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ, Lydon NB. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000;295:139–145.']
  • 19.
    ['19. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005;105:2640–2653.']
  • 20.
    ['20. Ciuclan L, Hussey MJ, Burton V, Good R, Duggan N, Beach S, Jones P, et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. Am J Respir Crit Care Med 2013;187:78–89.']
  • 21.
    ['21. Wu E, Palmer N, Tian Z, Moseman AP, Galdzicki M, Wang X, Berger B, Zhang H, Kohane IS. Comprehensive dissection of PDGF-PDGFR signaling pathways in PDGFR genetically defined cells. PLoS ONE 2008;3:e3794.']
  • 22.
    ['22. Nakamura K, Akagi S, Ogawa A, Kusano KF, Matsubara H, Miura D, Fuke S, et al. Pro-apoptotic effects of imatinib on PDGF-stimulated pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. Int J Cardiol 2011;159:100–106.']
  • 23.
    ['23. Ogawa A, Firth AL, Smith KA, Maliakal MV, Yuan JX. PDGF enhances store-operated Ca2+ entry by upregulating STIM1/Orai1 via activation of Akt/mTOR in human pulmonary arterial smooth muscle cells. Am J Physiol Cell Physiol 2012;302:C405–C411.']
  • 24.
    ['24. Ogawa A, Firth AL, Yao W, Madani MM, Kerr KM, Auger WR, Jamieson SW, Thistlethwaite PA, Yuan JX. Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2009;297:L666–L676.']
  • 25.
    ['25. Houssaini A, Abid S, Mouraret N, Wan F, Rideau D, Saker M, Marcos E, et al. Rapamycin reverses pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. Am J Respir Cell Mol Biol 2013;48:568–577.']
  • 26.
    ['26. Jasmin JF, Mercier I, Dupuis J, Tanowitz HB, Lisanti MP. Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy. Circulation 2006;114:912–920.']
  • 27.
    ['27. Masri FA, Xu W, Comhair SAA, Asosingh K, Koo M, Vasanji A, Drazba J, Anand-Apte B, Erzurum SC. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:L548–L554.']
  • 28.
    ['28. Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (endoMT) in the pathogenesis of fibrotic disorders. Am J Pathol 2011;179:1074–1080.']
  • 29.
    ['29. Yeager ME, Frid MG, Stenmark KR. Progenitor cells in pulmonary vascular remodeling. Pulm Circ 2011;1:3–16.']
  • 30.
    ['30. Sakao S, Tatsumi K, Voelkel NF. Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2010;43:629–634.']