Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension

Nina Rol, Michiel A. de Raaf, Xiaoqing Q. Sun, Vincent P. Kuiper, Denielli da Silva Gonçalves Bos, Chris Happé, Kondababu Kurakula, Chris Dickhoff, Raphael Thuillet, Ly Tu, Christophe Guignabert, Ingrid Schalij, Kirsten Lodder, Xiaoke Pan, Franziska E. Herrmann, Geerten P. van Nieuw Amerongen, Pieter Koolwijk, Anton Vonk-Noordegraaf, Frances S. de Man, Lutz Wollin & 3 others Marie-José Goumans, Robert Szulcek, Harm J. Bogaard

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.
Original languageEnglish
Pages (from-to)432-439
JournalCardiovascular Research
Volume115
Issue number2
Early online date18 Jul 2018
DOIs
Publication statusPublished - 2019

Cite this

Rol, Nina ; de Raaf, Michiel A. ; Sun, Xiaoqing Q. ; Kuiper, Vincent P. ; da Silva Gonçalves Bos, Denielli ; Happé, Chris ; Kurakula, Kondababu ; Dickhoff, Chris ; Thuillet, Raphael ; Tu, Ly ; Guignabert, Christophe ; Schalij, Ingrid ; Lodder, Kirsten ; Pan, Xiaoke ; Herrmann, Franziska E. ; van Nieuw Amerongen, Geerten P. ; Koolwijk, Pieter ; Vonk-Noordegraaf, Anton ; de Man, Frances S. ; Wollin, Lutz ; Goumans, Marie-José ; Szulcek, Robert ; Bogaard, Harm J. / Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension. In: Cardiovascular Research. 2019 ; Vol. 115, No. 2. pp. 432-439.
@article{e90150bc84e7418eba45f9ec4ed4dbf4,
title = "Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension",
abstract = "Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10{\%} hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.",
author = "Nina Rol and {de Raaf}, {Michiel A.} and Sun, {Xiaoqing Q.} and Kuiper, {Vincent P.} and {da Silva Gon{\cc}alves Bos}, Denielli and Chris Happ{\'e} and Kondababu Kurakula and Chris Dickhoff and Raphael Thuillet and Ly Tu and Christophe Guignabert and Ingrid Schalij and Kirsten Lodder and Xiaoke Pan and Herrmann, {Franziska E.} and {van Nieuw Amerongen}, {Geerten P.} and Pieter Koolwijk and Anton Vonk-Noordegraaf and {de Man}, {Frances S.} and Lutz Wollin and Marie-Jos{\'e} Goumans and Robert Szulcek and Bogaard, {Harm J.}",
year = "2019",
doi = "10.1093/cvr/cvy186",
language = "English",
volume = "115",
pages = "432--439",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "2",

}

Rol, N, de Raaf, MA, Sun, XQ, Kuiper, VP, da Silva Gonçalves Bos, D, Happé, C, Kurakula, K, Dickhoff, C, Thuillet, R, Tu, L, Guignabert, C, Schalij, I, Lodder, K, Pan, X, Herrmann, FE, van Nieuw Amerongen, GP, Koolwijk, P, Vonk-Noordegraaf, A, de Man, FS, Wollin, L, Goumans, M-J, Szulcek, R & Bogaard, HJ 2019, 'Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension' Cardiovascular Research, vol. 115, no. 2, pp. 432-439. https://doi.org/10.1093/cvr/cvy186, https://doi.org/10.1093/cvr/cvy186

Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension. / Rol, Nina; de Raaf, Michiel A.; Sun, Xiaoqing Q.; Kuiper, Vincent P.; da Silva Gonçalves Bos, Denielli; Happé, Chris; Kurakula, Kondababu; Dickhoff, Chris; Thuillet, Raphael; Tu, Ly; Guignabert, Christophe; Schalij, Ingrid; Lodder, Kirsten; Pan, Xiaoke; Herrmann, Franziska E.; van Nieuw Amerongen, Geerten P.; Koolwijk, Pieter; Vonk-Noordegraaf, Anton; de Man, Frances S.; Wollin, Lutz; Goumans, Marie-José; Szulcek, Robert; Bogaard, Harm J.

In: Cardiovascular Research, Vol. 115, No. 2, 2019, p. 432-439.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension

AU - Rol, Nina

AU - de Raaf, Michiel A.

AU - Sun, Xiaoqing Q.

AU - Kuiper, Vincent P.

AU - da Silva Gonçalves Bos, Denielli

AU - Happé, Chris

AU - Kurakula, Kondababu

AU - Dickhoff, Chris

AU - Thuillet, Raphael

AU - Tu, Ly

AU - Guignabert, Christophe

AU - Schalij, Ingrid

AU - Lodder, Kirsten

AU - Pan, Xiaoke

AU - Herrmann, Franziska E.

AU - van Nieuw Amerongen, Geerten P.

AU - Koolwijk, Pieter

AU - Vonk-Noordegraaf, Anton

AU - de Man, Frances S.

AU - Wollin, Lutz

AU - Goumans, Marie-José

AU - Szulcek, Robert

AU - Bogaard, Harm J.

PY - 2019

Y1 - 2019

N2 - Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.

AB - Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Methods and results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30032282

U2 - 10.1093/cvr/cvy186

DO - 10.1093/cvr/cvy186

M3 - Article

VL - 115

SP - 432

EP - 439

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

ER -