Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension

Csilla Fazakas, Chandran Nagaraj, Diana Zabini, Attila G. Végh, Leigh M. Marsh, I. Wilhelm, I. Krizbai, Horst Olschewski, Andrea Olschewski, Zoltán Bálint

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The multi-kinase inhibitor dasatinib is used for treatment of imatinib-resistant chronic myeloid leukemia, but is prone to induce microvascular dysfunction. In lung this can manifest as capillary leakage with pleural effusion, pulmonary edema or even pulmonary arterial hypertension. To understand how dasatinib causes endothelial dysfunction we examined the effects of clinically relevant concentrations of dasatinib on both human pulmonary arterial macro- and microvascular endothelial cells (ECs). The effects of dasatinib was compared to imatinib and nilotinib, two other clinically used BCR/Abl kinase inhibitors that do not inhibit Src. Real three-dimensional morphology and high resolution stiffness mapping revealed softening of both macro- and microvascular ECs upon dasatinib treatment, which was not observed in response to imatinib. In a dose-dependent manner, dasatinib decreased transendothelial electrical resistance/impedance and caused a permeability increase as well as disruption of tight adherens junctions in both cell types. In isolated perfused and ventilated rat lungs, dasatinib increased mean pulmonary arterial pressure, which was accompanied by a gain in lung weight. The Rho-kinase inhibitor Y27632 partly reversed the dasatinib-induced changes in vitro and ex vivo, presumably by acting downstream of Src. Co-administration of the Rho-kinase inhibitor Y27632 completely blunted the increased pulmonary pressure in response to dasatinib. In conclusion, a dasatinib-induced permeability increase in human pulmonary arterial macro- and microvascular ECs might explain many of the adverse effects of dasatinib in patients. Rho-kinase inhibition might be suitable to ameliorate these effects.

Original languageEnglish
Article number537
JournalFrontiers in Physiology
Volume9
Issue numberMAY
DOIs
Publication statusPublished - May 15 2018

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rho-Associated Kinases
Pulmonary Hypertension
Lung
Endothelial Cells
Electric Impedance
Permeability
Dasatinib
Phosphotransferases
Adherens Junctions
Tight Junctions
Pulmonary Edema
Pleural Effusion
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Arterial Pressure

Keywords

  • Dasatinib
  • Endothelial cells
  • Endothelial elasticity
  • Paracellular permeability
  • Pulmonary arterial hypertension
  • Rho-kinase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. / Fazakas, Csilla; Nagaraj, Chandran; Zabini, Diana; Végh, Attila G.; Marsh, Leigh M.; Wilhelm, I.; Krizbai, I.; Olschewski, Horst; Olschewski, Andrea; Bálint, Zoltán.

In: Frontiers in Physiology, Vol. 9, No. MAY, 537, 15.05.2018.

Research output: Contribution to journalArticle

Fazakas, C, Nagaraj, C, Zabini, D, Végh, AG, Marsh, LM, Wilhelm, I, Krizbai, I, Olschewski, H, Olschewski, A & Bálint, Z 2018, 'Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension', Frontiers in Physiology, vol. 9, no. MAY, 537. https://doi.org/10.3389/fphys.2018.00537
Fazakas, Csilla ; Nagaraj, Chandran ; Zabini, Diana ; Végh, Attila G. ; Marsh, Leigh M. ; Wilhelm, I. ; Krizbai, I. ; Olschewski, Horst ; Olschewski, Andrea ; Bálint, Zoltán. / Rho-kinase inhibition ameliorates dasatinib-induced endothelial dysfunction and pulmonary hypertension. In: Frontiers in Physiology. 2018 ; Vol. 9, No. MAY.
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