Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation.
OBJECTIVE
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.
Bugger
Heiko
H
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, FMP 3, New Haven, CT 06520, USA.
Guzman
Cinthia
C
Zechner
Christoph
C
Palmeri
Monica
M
Russell
Kerry S
KS
Russell
Raymond R
RR
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D015536:Down-Regulation; D004317:Doxorubicin / Q000633:toxicity*; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D007473:Ion Channels / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; C000604391:Ucp2 protein, rat; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D004317:Doxorubicin; D000255:Adenosine Triphosphate
J Biol Chem. 2000 May 26;275(21):16258-66
10748196
Circulation. 2007 Jul 31;116(5):506-14
17638931
J Biol Chem. 1998 Jan 23;273(4):2015-23
9442038
Am J Physiol Heart Circ Physiol. 2001 Sep;281(3):H1319-26
11514303
J Biol Chem. 2000 Oct 27;275(43):33585-92
10899161
J Biol Chem. 2001 Mar 23;276(12):8705-12
11098051
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6880-4
10823916
J Pharmacol Exp Ther. 2001 Aug;298(2):461-8
11454906
Biophys Chem. 1990 Apr;35(2-3):247-57
2204444
J Clin Invest. 1992 Mar;89(3):968-73
1541685
Eur Heart J. 1993 Nov;14(11):1493-8
8299631
Circulation. 2004 Aug 3;110(5):528-33
15262832
Int J Obes Relat Metab Disord. 1999 Dec;23(12):1242-5
10643679
Exp Mol Pathol. 1987 Feb;46(1):123-35
2879739
Cardiovasc Res. 2002 Mar;53(4):936-43
11922903
Mol Cell Biochem. 2002 Mar;232(1-2):19-26
12030376
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H722-31
15792986
J Appl Physiol (1985). 1992 Nov;73(5):2004-10
1474078
Circulation. 2005 Oct 25;112(17):2686-95
16246967
J Biol Chem. 2002 Jan 25;277(4):2773-8
11707458
Ann N Y Acad Sci. 2002 Apr;959:199-213
11976197
J Mol Cell Cardiol. 2003 Jul;35(7):861-5
12818577
J Biol Chem. 2001 Jun 8;276(23):20240-4
11274222
Am J Physiol Endocrinol Metab. 2002 May;282(5):E1055-61
11934670
FASEB J. 2001 Sep;15(11):2033-5
11511517
Biochim Biophys Acta. 1983 Jan 13;722(1):43-50
6218826
Biochim Biophys Acta. 2005 Jan 7;1706(1-2):1-11
15620362
Hum Mol Genet. 1998 Sep;7(9):1431-5
9700198
Mol Cell Biochem. 2003 Jun;248(1-2):203-8
12870675
Br Heart J. 1991 May;65(5):245-8
2039668
J Bioenerg Biomembr. 1999 Aug;31(4):367-76
10665526
Biosci Rep. 1997 Jun;17(3):259-72
9337481
Circ Res. 1999 Aug 20;85(4):357-63
10455064
Cancer Res. 2002 Aug 15;62(16):4592-8
12183413
Cardiology. 2002;97(4):203-9
12145475
Biochem J. 1989 Apr 1;259(1):181-9
2719642
Biochim Biophys Acta. 1987 Jul 22;892(3):320-30
3036220
Am J Physiol Endocrinol Metab. 2001 Nov;281(5):E975-82
11595653
J Physiol. 2003 Sep 1;551(Pt 2):491-501
12824444
J Mol Cell Cardiol. 2001 Jun;33(6):1065-89
11444914
Biochem Pharmacol. 1990 Oct 1;40(7):1441-8
2222502
FASEB J. 2001 Mar;15(3):833-45
11259402
Diabetes. 2000 Feb;49(2):143-56
10868929
Circ Res. 2003 Aug 8;93(3):192-200
12855674
J Mol Cell Cardiol. 2006 Sep;41(3):389-405
16879835
Cancer Chemother Pharmacol. 2010 Jul;66(2):303-14
19915844
FASEB J. 1997 Aug;11(10):809-15
9271366
Free Radic Biol Med. 1994 Aug;17(2):117-26
7959172
Am J Physiol. 1998 Oct;275(4):E558-67
9755073
Am J Physiol. 1990 Aug;259(2 Pt 1):E204-9
2382713
Int J Obes Relat Metab Disord. 2001 Apr;25(4):472-7
11319649
Biochim Biophys Acta. 2009 Feb;1793(2):427-38
19038292