File
vp100_41.pdf 3.62 MB
Authors
Leong, Zi Ping The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University
Okida, Ayumi Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University
Higuchi, Masashi The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Biochemistry, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University Researchers DB KAKEN
Yamano, Yoshiaki The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Biochemistry, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University Researchers DB KAKEN
Hikasa, Yoshiaki The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University Researchers DB KAKEN
Keywords
Cardiopulmonary remodeling
Imatinib
Sunitinib
Pulmonary arterial hypertension
Abstract
High-dose imatinib reverses cardiopulmonary remodeling but adverse effects limit its clinical use. Efficacy of the multi-kinase inhibitor sunitinib remains questionable. We compared anti-remodeling effects of imatinib with sunitinib on monocrotaline-induced right ventricular (RV) hypertrophy and pulmonary arterial remodeling in rats, focusing on a lower dose. Fourteen days after monocrotaline injection, oral gavage of imatinib (5, 15, or 50mg/kg), sunitinib (0.3, 1, 3, or 10mg/kg), or water for 14days was started. RV hypertrophy and b-type natriuretic peptide mRNA levels were significantly and dose-dependently reduced, much greater in imatinib- than sunitinib-treated groups. Imatinib normalized muscularization of 20–50μm intra-acinar pulmonary arteries more significantly than sunitinib. At transcript levels, sunitinib significantly upregulated pulmonary nestin, and downregulated platelet-derived growth factor receptor beta (PDGFR-β), fibroblast growth factor receptor 1, vascular endothelial growth factor receptor-2 and vascular endothelial growth factor (VEGF)-A, but not Raf-1 proto-oncogene serine/threonine kinase mRNAs. Sunitinib also suppressed VEGF-A, but not phosphorylated extra-cellular-signal-related kinase (ERK)-1/2 protein expression. The sole PDGFR-β antagonism of imatinib resulted in significant Raf-1 mRNA and phosphorylated ERK-1/2 protein downregulation, suggesting that the equivocal reversal effect of sunitinib may be due to its VEGF signaling inhibition in the lung. Imatinib's greater dose-dependent reversal on cardiopulmonary remodeling may make a low dose suitable for PAH treatment.
Publisher
Elsevier
Content Type
Journal Article
Link
ISSN
15371891
Journal Title
Vascular Pharmacology
Volume
100
Start Page
41
End Page
50
Published Date
2018-01-31
Publisher-DOI
Text Version
Author
Rights
(C) 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
Citation
Leong, Zi Ping. Okida, Ayumi. Higuchi, Masahi. et al. Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats. Vascular Pharmacology. 100. 41-50. 2018. doi:10.1016/j.vph.2017.10.006
Department
Faculty of Agriculture/Graduate School of Agriculture
Language
English
pii
S1537-1891(17)30214-8