Volume 10 Supplement 1

2nd Cross Company Respiratory Symposium

Open Access

Effects of Multikinase inhibitors on pressure overload-induced right ventricular remodelling

  • Baktybek Kojonazarov1,
  • Akylbek Sydykov1,
  • Soni Savai Pullamsetti1, 2,
  • Himal Luitel1,
  • Bhola K Dahal1,
  • Djuro Kosanovic1,
  • Xia Tian1,
  • Matthaeus Majewski1,
  • Christin Baumann1,
  • Steve Evans3,
  • Peter Phillips3,
  • David Fairman3,
  • Neil Davie3,
  • Chris Wayman3,
  • Iain Kilty3,
  • Norbert Weissmann1,
  • Friedrich Grimminger1,
  • Werner Seeger1, 2,
  • Hossein Ardeschir Ghofrani1 and
  • Ralph Theo Schermuly1
Journal of Inflammation201310(Suppl 1):P37

https://doi.org/10.1186/1476-9255-10-S1-P37

Published: 14 August 2013

Little is known about the effects of current PAH therapies and receptor tyrosine kinase inhibitors on heart remodelling. We sought to investigate the effects of the multikinase inhibitors sunitinib (PDGFR-, VEGFR- and KIT-inhibitor) and sorafenib (raf1/b-, VEGFR-, PDGFR-inhibitor) on pressure overload induced right ventricular (RV) remodelling. We investigated the effects of the kinase inhibitors on hemodynamics and remodelling in rats subjected either to monocrotaline (MCT)-induced PH or to surgical pulmonary artery banding (PAB). MCT rats were treated from day 21 to 35 with either vehicle, sunitinib (1 mg/kg, 5 mg/kg and 10 mg/kg/day) or sorafenib (10 mg/kg/day). PAB rats were treated with vehicle, sunitinib (10 mg/kg/day) or sorafenib (10mg/kg/day) from day 7 to 21. RV function and remodelling were determined using echocardiography, invasive hemodynamic measurement and histomorphometry. Treatment with both sorafenib and sunitinib decreased right ventricular systolic pressure, pulmonary vascular remodelling, RV hypertrophy and fibrosis in MCT rats. This was associated with an improvement of RV function. Importantly, after PAB, both compounds reversed RV chamber and cellular hypertrophy, reduced RV interstitial and perivascular fibrosis, and improved RV function. We demonstrated that sunitinib and sorafenib reversed RV remodelling and significantly improved RV function measured via a range of invasive and non-invasive cardiopulmonary endpoints in experimental models of RV hypertrophy.

Authors’ Affiliations

(1)
Universities of Giessen and Marburg Lung Centre (UGMLC)
(2)
Department of Lung Development and Remodelling, Max-Planck Institute for Heart and Lung Research
(3)
Inflammation and Remodeling Research, Pfizer Cambridge

Copyright

© Kojonazarov et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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