RT Journal Article
SR Electronic
T1 Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 516
OP 527
DO 10.1124/jpet.115.225375
VO 355
IS 3
A1 Yung-Lung Chen
A1 Sheng-Ying Chung
A1 Han-Tan Chai
A1 Chih-Hung Chen
A1 Chu-Feng Liu
A1 Yi-Ling Chen
A1 Tien-Hung Huang
A1 Yen-Yi Zhen
A1 Pei-Hsun Sung
A1 Cheuk-Kwan Sun
A1 Sarah Chua
A1 Hung-I Lu
A1 Fan-Yen Lee
A1 Jiunn-Jye Sheu
A1 Hon-Kan Yip
YR 2015
UL http://jpet.aspetjournals.org/content/355/3/516.abstract
AB 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 end-systolic 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.