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

Rol, Nina; Raaf, Michiel Alexander de; Sun, Xuerong; Kuiper, Vincent P; Bós, Denielli da Silva Gonçalves; Happé, Chris; Kurakula, Kondababu; Dickhoff, Chris; Thuillet, Raphaël; Tu, Ly; Guignabert, Christophe; Schalij, Ingrid; Lodder, Kirsten; Pan, Xiaoke; Herrmann, Franziska; Amerongen, Geerten P. van Nieuw; Koolwijk, Pieter; Vonk‐Noordegraaf, Anton; Man, Frances S. de; Wollin, Lutz; Goumans, Marie–José; Szulcek, Robert; Bogaard, Harm Jan

doi:10.1093/cvr/cvy186

Cited by 42 publications

(37 citation statements)

References 40 publications

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“…Additionally, it has been reported that BIBF1000, a structural precursor of nintedanib, did not disturb RV function in rats subjected to mechanical pressure overload by pulmonary artery-banding (42). Another recent study also showed that less dilatation, decreased fibrosis and hypertrophy of right ventricle after chronic treatment with nintedanib in Su/Hx-PAH rat by echocardiography and histological analysis (43), suggesting no cardiac toxicity of nintedanib.…”

Section: Discussionmentioning

confidence: 94%

“…In contrast, Huang et al reported that chronic treatment with nintedanib reduced pulmonary vascular remodeling in the Fos-related antigen-2 mouse model of systemic sclerosis (46), which was supportive of our results. On the other hand, another more recent study showed that chronic treatment with nintedanib of established late-phase PAH, from 8 to 11 weeks, did not improved pulmonary hemodynamics and vascular remodeling in SuHx rats (43). The results of these recent studies of established animal and human PAH suggest that the therapeutic power of nintedanib may be limited at least in advanced stages of PAH.…”

Section: Discussionmentioning

confidence: 97%

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Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. The inhibitory effects of nintedanib were evaluated both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and pulmonary hemodynamics and PAs pathology were evaluated. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented both in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Tsutsumi

Nagaoka

Yoshida

et al. 2019

Preprint

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“…The beneficial effects of carvedilol (β-blocker), iloprost (prostacyclin) and losartan (angiotensin receptor blocker) on RV function in animals are partly ascribed to attenuated TGF-β-mediated fibrosis [ 53 , 54 , 129 ]. Furthermore, nintedanib, a tyrosine kinase inhibitor known to inhibit TGF-β-mediated fibrosis, attenuated cardiac fibrosis in experimental pulmonary hypertension [ 130 , 131 ]…”

Section: Tgf-β Signaling In the Heart In Pulmonary Arterial Hypertmentioning

confidence: 99%

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Rol

Kurakula

Happé

et al. 2018

IJMS

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Knowledge pertaining to the involvement of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in pulmonary arterial hypertension (PAH) is continuously increasing. There is a growing understanding of the function of individual components involved in the pathway, but a clear synthesis of how these interact in PAH is currently lacking. Most of the focus has been on signaling downstream of BMPR2, but it is imperative to include the role of TGF-β signaling in PAH. This review gives a state of the art overview of disturbed signaling through the receptors of the TGF-β family with respect to vascular remodeling and cardiac effects as observed in PAH. Recent (pre)-clinical studies in which these two pathways were targeted will be discussed with an extended view on cardiovascular research fields outside of PAH, indicating novel future perspectives.

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“…A recent experiment in rats showed that nintedanib reduced fibrosis and improved RV function, despite having no significant effects on the pulmonary vasculature. 18 Lastly, for advanced PAH, novel interventional techniques such as RV assist devices, devices to improve pulmonary arterial compliance, and advances in balloon septostomy are being explored as options for bridging to transplantation.…”

Section: Novel Therapies Targeting the Right Ventriclementioning

confidence: 99%

Basic Science and Clinical Trials: Accelerating the Future

Halliday

Brittain

2018

Advances in Pulmonary Hypertension

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The Scientific Sessions at the 2018 Pulmonary Hypertension Association International Conference began with presentations on the theme of “Basic Science and Clinical Trials: Accelerating the Future.” These presentations, by leading pulmonary hypertension researchers, focused on recent breakthroughs in understanding the pathobiology of the disease, preclinical models of new treatments, early-phase clinical trials, and future directions for the treatment of pulmonary arterial hypertension.

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

Abstract: 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 favorable effects on right ventricular remodeling.

Cited by 42 publications

References 40 publications

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

Nintedanib ameliorates experimental pulmonary arterial hypertension via inhibition of endothelial mesenchymal transition and smooth muscle cell proliferation

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

Basic Science and Clinical Trials: Accelerating the Future

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