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Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats.
Vascul Pharmacol. 2018 01; 100:41-50.VP

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.

Authors+Show Affiliations

The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1, Yoshida, Yamaguchi 753-8515, Japan; Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8550, Japan.Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8550, Japan.The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1, Yoshida, Yamaguchi 753-8515, Japan; Laboratory of Veterinary Biochemistry, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8550, Japan.The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1, Yoshida, Yamaguchi 753-8515, Japan; Laboratory of Veterinary Biochemistry, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8550, Japan.The United Graduate School of Veterinary Science, Yamaguchi University, 1677-1, Yoshida, Yamaguchi 753-8515, Japan; Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori 680-8550, Japan. Electronic address: hikasa@muses.tottori-u.ac.jp.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29100963

Citation

Leong, Zi Ping, et al. "Reversal Effects of Low-dose Imatinib Compared With Sunitinib On Monocrotaline-induced Pulmonary and Right Ventricular Remodeling in Rats." Vascular Pharmacology, vol. 100, 2018, pp. 41-50.
Leong ZP, Okida A, Higuchi M, et al. Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats. Vascul Pharmacol. 2018;100:41-50.
Leong, Z. P., Okida, A., Higuchi, M., Yamano, Y., & Hikasa, Y. (2018). Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats. Vascular Pharmacology, 100, 41-50. https://doi.org/10.1016/j.vph.2017.10.006
Leong ZP, et al. Reversal Effects of Low-dose Imatinib Compared With Sunitinib On Monocrotaline-induced Pulmonary and Right Ventricular Remodeling in Rats. Vascul Pharmacol. 2018;100:41-50. PubMed PMID: 29100963.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats. AU - Leong,Zi Ping, AU - Okida,Ayumi, AU - Higuchi,Masahi, AU - Yamano,Yoshiaki, AU - Hikasa,Yoshiaki, Y1 - 2017/10/31/ PY - 2017/08/05/received PY - 2017/10/21/revised PY - 2017/10/29/accepted PY - 2017/11/5/pubmed PY - 2018/9/5/medline PY - 2017/11/5/entrez KW - Cardiopulmonary remodeling KW - Imatinib KW - Pulmonary arterial hypertension KW - Sunitinib SP - 41 EP - 50 JF - Vascular pharmacology JO - Vascul Pharmacol VL - 100 N2 - 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. SN - 1879-3649 UR - https://www.unboundmedicine.com/medline/citation/29100963/Reversal_effects_of_low_dose_imatinib_compared_with_sunitinib_on_monocrotaline_induced_pulmonary_and_right_ventricular_remodeling_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1537-1891(17)30214-8 DB - PRIME DP - Unbound Medicine ER -