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Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy.
J Pharmacol Exp Ther 2015; 355(3):516-27JP

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 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.

Authors+Show Affiliations

Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.).Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.) han.gung@msa.hinet.net cvsjjs@gmail.com.Division of Cardiology, Department of Internal Medicine (Y.-L.C., S.-Y.C., H.-T.C., Y.-L.C., T.-H.H., Y.-Y.Z., P.-H.S., S.C., H.-K.Y.); Division of General Medicine, Department of Internal Medicine (C.-H.C.); Department of Emergency Medicine (C.-F.L.); Division of Thoracic and Cardiovascular Surgery, Department of Surgery (H.-I.L., F.-Y.L., J.-J.S.); Institute for Translational Research in Biomedine (S.C., H.-K.Y.); and Center for Shockwave Medicine and Tissue Engineering (H.-K.Y.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung, Taiwan (C.-K.S.); and Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (H.-K.Y.) han.gung@msa.hinet.net cvsjjs@gmail.com.

Pub Type(s)

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

Language

eng

PubMed ID

26511374

Citation

Chen, Yung-Lung, et al. "Early Administration of Carvedilol Protected Against Doxorubicin-Induced Cardiomyopathy." The Journal of Pharmacology and Experimental Therapeutics, vol. 355, no. 3, 2015, pp. 516-27.
Chen YL, Chung SY, Chai HT, et al. Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy. J Pharmacol Exp Ther. 2015;355(3):516-27.
Chen, Y. L., Chung, S. Y., Chai, H. T., Chen, C. H., Liu, C. F., Chen, Y. L., ... Yip, H. K. (2015). Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy. The Journal of Pharmacology and Experimental Therapeutics, 355(3), pp. 516-27. doi:10.1124/jpet.115.225375.
Chen YL, et al. Early Administration of Carvedilol Protected Against Doxorubicin-Induced Cardiomyopathy. J Pharmacol Exp Ther. 2015;355(3):516-27. PubMed PMID: 26511374.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2015/10/28/ PY - 2015/05/05/received PY - 2015/10/07/accepted PY - 2015/10/30/entrez PY - 2015/10/30/pubmed PY - 2016/2/10/medline SP - 516 EP - 27 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 355 IS - 3 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 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/26511374/Early_Administration_of_Carvedilol_Protected_against_Doxorubicin_Induced_Cardiomyopathy_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=26511374 DB - PRIME DP - Unbound Medicine ER -