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Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity.

Dose-dependent oxidative stress by the anthracycline doxorubicin (Dox) and other chemotherapeutic agents causes irreversible cardiac damage, restricting their clinical effectiveness. We hypothesized that the resultant protein oxidation could be monitored and correlated with physiological functional... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 4, 2014, Vol.111(5), pp.2011-2016
Main Author: Aryal, Baikuntha
Other Authors: Jeong, Jinsook , Rao, V Ashutosh
Format: Electronic Article Electronic Article
Language: English
Subjects:
Ros
ID: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1321783111
Link: http://search.proquest.com/docview/1499115561/?pq-origsite=primo
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title: Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity.
format: Article
creator:
  • Aryal, Baikuntha
  • Jeong, Jinsook
  • Rao, V Ashutosh
subjects:
  • Actins–Metabolism
  • Animals–Toxicity
  • Cardiotoxins–Metabolism
  • Carrier Proteins–Toxicity
  • Doxorubicin–Pharmacology
  • Female–Metabolism
  • Metals–Pathology
  • Mice–Drug Effects
  • Myocardium–Drug Effects
  • Oxidation-Reduction–Drug Effects
  • Protein Binding–Drug Effects
  • Protein Carbonylation–Metabolism
  • Proteolysis–Metabolism
  • Rats–Metabolism
  • Rats, Inbred Shr–Metabolism
  • Recombinant Proteins–Metabolism
  • Actins
  • Cardiotoxins
  • Carrier Proteins
  • Metals
  • Recombinant Proteins
  • Myosin-Binding Protein C
  • Doxorubicin
  • Ros
  • Cancer
  • Cardioprotection
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 4, 2014, Vol.111(5), pp.2011-2016
description: Dose-dependent oxidative stress by the anthracycline doxorubicin (Dox) and other chemotherapeutic agents causes irreversible cardiac damage, restricting their clinical effectiveness. We hypothesized that the resultant protein oxidation could be monitored and correlated with physiological functional impairment. We focused on protein carbonylation as an indicator of severe oxidative damage because it is irreversible and results in proteasomal degradation. We identified and investigated a specific high-molecular weight cardiac protein that showed a significant increase in carbonylation under Dox-induced cardiotoxic conditions in a spontaneously hypertensive rat model. We confirmed carbonylation and degradation of this protein under oxidative stress and prevention of such effect in the presence of the iron chelator dexrazoxane. Using MS, the Dox-induced carbonylated protein was identified as the 140-kDa cardiac myosin binding protein C (MyBPC). We confirmed the carbonylation and degradation of MyBPC using HL-1 cardiomyocytes and a purified recombinant untagged cardiac MyBPC under metal-catalyzed oxidative stress conditions. The carbonylation and degradation of MyBPC were time- and drug concentration-dependent. We demonstrated that carbonylated MyBPC undergoes proteasome-mediated degradation under Dox-induced oxidative stress. Cosedimentation, immunoprecipitation, and actin binding assays were used to study the functional consequences of carbonylated MyBPC. Carbonylation of MyBPC showed significant functional impairment associated with its actin binding properties. The dissociation constant of carbonylated recombinant MyBPC for actin was 7.35 [+ or -] 1.9 [micro]M compared with 2.7 [+ or -] 0.6 [micro]M for native MyBPC. Overall, our findings indicate that MyBPC carbonylation serves as a critical determinant of cardiotoxicity and could serve as a mechanistic indicator for Dox-induced cardiotoxicity. cancer | ROS | cardioprotection www.pnas.org/cgi/doi/10.1073/pnas.1321783111
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 1091-6490 ; DOI: 10.1073/pnas.1321783111
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleDoxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity.
creatorAryal, Baikuntha ; Jeong, Jinsook ; Rao, V Ashutosh
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subjectActins–Metabolism ; Animals–Toxicity ; Cardiotoxins–Metabolism ; Carrier Proteins–Toxicity ; Doxorubicin–Pharmacology ; Female–Metabolism ; Metals–Pathology ; Mice–Drug Effects ; Myocardium–Drug Effects ; Oxidation-Reduction–Drug Effects ; Protein Binding–Drug Effects ; Protein Carbonylation–Metabolism ; Proteolysis–Metabolism ; Rats–Metabolism ; Rats, Inbred Shr–Metabolism ; Recombinant Proteins–Metabolism ; Actins ; Cardiotoxins ; Carrier Proteins ; Metals ; Recombinant Proteins ; Myosin-Binding Protein C ; Doxorubicin ; Ros ; Cancer ; Cardioprotection
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descriptionDose-dependent oxidative stress by the anthracycline doxorubicin (Dox) and other chemotherapeutic agents causes irreversible cardiac damage, restricting their clinical effectiveness. We hypothesized that the resultant protein oxidation could be monitored and correlated with physiological functional impairment. We focused on protein carbonylation as an indicator of severe oxidative damage because it is irreversible and results in proteasomal degradation. We identified and investigated a specific high-molecular weight cardiac protein that showed a significant increase in carbonylation under Dox-induced cardiotoxic conditions in a spontaneously hypertensive rat model. We confirmed carbonylation and degradation of this protein under oxidative stress and prevention of such effect in the presence of the iron chelator dexrazoxane. Using MS, the Dox-induced carbonylated protein was identified as the 140-kDa cardiac myosin binding protein C (MyBPC). We confirmed the carbonylation and degradation of MyBPC using HL-1 cardiomyocytes and a purified recombinant untagged cardiac MyBPC under metal-catalyzed oxidative stress conditions. The carbonylation and degradation of MyBPC were time- and drug concentration-dependent. We demonstrated that carbonylated MyBPC undergoes proteasome-mediated degradation under Dox-induced oxidative stress. Cosedimentation, immunoprecipitation, and actin binding assays were used to study the functional consequences of carbonylated MyBPC. Carbonylation of MyBPC showed significant functional impairment associated with its actin binding properties. The dissociation constant of carbonylated recombinant MyBPC for actin was 7.35 [+ or -] 1.9 [micro]M compared with 2.7 [+ or -] 0.6 [micro]M for native MyBPC. Overall, our findings indicate that MyBPC carbonylation serves as a critical determinant of cardiotoxicity and could serve as a mechanistic indicator for Dox-induced cardiotoxicity. cancer | ROS | cardioprotection www.pnas.org/cgi/doi/10.1073/pnas.1321783111
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