| Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation. | |
| | |
MedLine Citation:
|
PMID: 20809120 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
PURPOSE: Doxorubicin-based chemotherapy is limited by the development of dose-dependent left ventricular dysfunction and congestive heart failure caused by reactive oxygen species (ROS). Uncoupling proteins (UCP) can inhibit mitochondrial ROS production as well as decrease myocyte damage from exogenous ROS. Prior studies have shown that cardiac UCP2 and UCP3 mRNA expression is decreased with acute doxorubicin treatment. However, the expression of UCP protein in hearts with doxorubicin cardiotoxicity and the resultant changes in mitochondrial function and oxidant stress have not been determined. METHODS: Heart failure was induced in Sprague-Dawley rats with intraperitoneal injections of doxorubicin (2 mg/kg t.i.w., total dose: 18 mg/kg). Mitochondria were isolated from mice receiving doxorubicin or saline injections for determination of UCP2 and UCP3 expression. In addition, mitochondrial respiration, ATP synthesis and ROS production were determined. RESULTS: Doxorubicin-induced heart failure was associated with significant decreases in UCP2 and UCP3 protein expression compared with nonfailing hearts (P < 0.05). While the rates of state 3 and state 4 respiration and ATP synthesis were lower in mitochondria isolated from failing hearts, the respiratory control ratio was 15% higher (P < 0.05), and the ratio of ATP production to oxygen consumption was 25% higher (P < 0.05) in mitochondria from failing hearts, indicating greater coupling between citric acid cycle flux and mitochondrial ATP synthesis. However, the decrease in UCP expression was associated with 50% greater mitochondrial ROS generation (P < 0.05). CONCLUSIONS: Downregulation of myocardial UCP2 and UCP3 in the setting of doxorubicin-induced heart failure is associated with improved efficiency of ATP synthesis, which might compensate for abnormal energy metabolism. However, this beneficial effect is counterbalanced by greater oxidant stress. |
| | |
Authors:
|
Heiko Bugger; Cinthia Guzman; Christoph Zechner; Monica Palmeri; Kerry S Russell; Raymond R Russell |
Publication Detail:
|
Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2010-08-31 |
Journal Detail:
|
Title: Cancer chemotherapy and pharmacology Volume: 67 ISSN: 1432-0843 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2011 Jun |
Date Detail:
|
Created Date: 2011-05-26 Completed Date: 2011-07-22 Revised Date: 2012-09-19 |
Medline Journal Info:
|
Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
|
Languages: eng Pagination: 1381-8 Citation Subset: IM |
Affiliation:
|
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, FMP 3, New Haven, CT 06520, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adenosine Triphosphate
/
biosynthesis Animals Antibiotics, Antineoplastic / toxicity* Down-Regulation Doxorubicin / toxicity* Heart Failure / chemically induced, metabolism*, physiopathology Ion Channels / biosynthesis* Male Mice Mitochondria, Heart / drug effects*, metabolism Mitochondrial Proteins / biosynthesis* Myocardium / metabolism, pathology Rats Rats, Sprague-Dawley Reactive Oxygen Species / metabolism* Ventricular Function, Left / drug effects |
| Grant Support | |
ID/Acronym/Agency:
|
R01 HL077310/HL/NHLBI NIH HHS; R01 HL077310-05/HL/NHLBI NIH HHS; R01 HL080176-05/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Antibiotics, Antineoplastic; 0/Ion Channels; 0/Mitochondrial Proteins; 0/Reactive Oxygen Species; 0/mitochondrial uncoupling protein 2; 0/mitochondrial uncoupling protein 3; 23214-92-8/Doxorubicin; 56-65-5/Adenosine Triphosphate |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Cell cycle and apoptosis regulatory protein (CARP)-1 is a novel, adriamycin-inducible, diffuse large...
Next Document: Corticorelin acetate, a synthetic corticotropin-releasing factor with preclinical antitumor activity...