Early administration of carvedilol protected against doxorubicin-induced cardiomyopathy

Yung Lung Chen, Sheng Ying Chung, Han Tan Chai, Chih Hung Chen, Chu Feng Liu, Yi Ling Chen, Tien Hung Huang, Yen Yi Zhen, Pei Hsun Sung, Cheuk Kwan Sun, Sarah Chua, Hung I. Lu, Fan Yen Lee, Jiunn Jye Sheu, Hon Kan Yip*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

36 Scopus citations

Abstract

This study tested for the benefits of early administration of carvedilol as protection against doxorubicin (DOX)-induced cardiomyopathy. Thirty male, adult B6 mice were categorized into group 1 (untreated control), group 2 [DOX treatment (15 mg/every other day for 2 weeks, i.p.], and group 3 [carvedilol (15 mg/kg/d, from day 7 after DOX treatment for 28 days)], and euthanized by day 35 after DOX treatment. By day 35, the left ventricular ejection fraction (LVEF) was significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 3 than in group 1, whereas the left ventricular (LV) end-diastolic and LV endsystolic dimensions showed an opposite pattern to the LVEF among the three groups. The protein expressions of fibrotic (Smad3, TGF-β), apoptotic (BAX, cleaved caspase 3, PARP), DNA damage (γ-H2AX), oxidative stress (oxidized protein), mitochondrial damage (cytosolic cytochrome-C), heart failure (brain natriuretic peptide), and hypertrophic (β-MHC) biomarkers of the LV myocardium showed an opposite pattern to the LVEF among the three groups. The protein expressions of antifibrotic (BMP-2, Smad1/5), α-MHC, and phosphorylated-Akt showed an identical pattern to the LVEF among the three groups. The microscopic findings of fibrotic and collagen-deposition areas and the numbers of γ-H2AX+ and 53BP1+ cells in the LV myocardium exhibited an opposite pattern, whereas the numbers of endothelial cell (CD31+, vWF+) markers showed an identical pattern to the LVEF among the three groups. Cardiac stem cell markers (C-kit+ and Sca-1+ cells) were significantly and progressively increased from group 1 to group 3. Additionally, the in vitro study showed carvedilol treatment significantly inhibited DOX-induced cardiomyoblast DNA (CD90/ XRCC1+, CD90/53BP1+, and r-H2AX+ cells) damage. Early carvedilol therapy protected against DOX-induced DNA damage and cardiomyopathy.

Original languageEnglish
Pages (from-to)516-527
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume355
Issue number3
DOIs
StatePublished - 12 2015

Bibliographical note

Publisher Copyright:
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

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