TY - JOUR
T1 - Early administration of carvedilol protected against doxorubicin-induced cardiomyopathy
AU - Chen, Yung Lung
AU - Chung, Sheng Ying
AU - Chai, Han Tan
AU - Chen, Chih Hung
AU - Liu, Chu Feng
AU - Chen, Yi Ling
AU - Huang, Tien Hung
AU - Zhen, Yen Yi
AU - Sung, Pei Hsun
AU - Sun, Cheuk Kwan
AU - Chua, Sarah
AU - Lu, Hung I.
AU - Lee, Fan Yen
AU - Sheu, Jiunn Jye
AU - Yip, Hon Kan
N1 - Publisher Copyright:
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2015/12
Y1 - 2015/12
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=84966332571&partnerID=8YFLogxK
U2 - 10.1124/jpet.115.225375
DO - 10.1124/jpet.115.225375
M3 - 文章
C2 - 26511374
AN - SCOPUS:84966332571
SN - 0022-3565
VL - 355
SP - 516
EP - 527
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -