Early Administration of Carvedilol Protected against Doxorubicin-Induced Cardiomyopathy.
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.
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.).
Yung-Lung
YL
Chen
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.).
Sheng-Ying
SY
Chung
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-Tan
HT
Chai
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.).
Chih-Hung
CH
Chen
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.).
Chu-Feng
CF
Liu
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.).
Yi-Ling
YL
Chen
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.).
Tien-Hung
TH
Huang
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.).
Yen-Yi
YY
Zhen
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.).
Pei-Hsun
PH
Sung
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.).
Cheuk-Kwan
CK
Sun
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.).
Sarah
S
Chua
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.).
Hung-I
HI
Lu
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.).
Fan-Yen
FY
Lee
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.
Jiunn-Jye
JJ
Sheu
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.
Hon-Kan
HK
Yip
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000517:prevention & control*; D000077261:Carvedilol; D003094:Collagen / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects; D014463:Ultrasonography
D000319:Adrenergic beta-Antagonists; D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D004317:Doxorubicin; D003094:Collagen