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vp100_41.pdf 3.62 MB
著者
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
樋口 雅司 The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Biochemistry, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University 研究者総覧 KAKEN
山野 好章 The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Biochemistry, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University 研究者総覧 KAKEN
日笠 喜朗 The United Graduate School of Veterinary Science, Yamaguchi University / Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University 研究者総覧 KAKEN
キーワード
Cardiopulmonary remodeling
Imatinib
Sunitinib
Pulmonary arterial hypertension
抄録
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.
出版者
Elsevier
資料タイプ
学術雑誌論文
外部リンク
ISSN
15371891
掲載誌名
Vascular Pharmacology
100
開始ページ
41
終了ページ
50
発行日
2018-01-31
出版者DOI
著者版フラグ
著者版
著作権表記
(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/
掲載情報
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
部局名
農学部・農学研究科
言語
英語
pii
S1537-1891(17)30214-8