Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation
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.
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.
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).
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.
KeywordsCardiotoxicity Mitochondria Reactive oxygen species Energetics
- 1.Ascensao A, Magalhaes J, Soares JM, Ferreira R, Neuparth MJ, Marques F, Oliveira PJ, Duarte JA (2005) Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis. Am J Physiol Heart Circ Physiol 289:H722–H731PubMedCrossRefGoogle Scholar
- 3.Bézaire V, Hofmann W, Kramer JKG, Kozak LP, Harper M-E (2001) Effects of fasting on muscle mitochondrial energetics and fatty acid metabolism in UCP3(−/−) and wild-type mice. Am J Physiol 281:E975–E982Google Scholar
- 8.Cadenas S, Echtay KS, Harper JA, Jekabsons MB, Buckingham JA, Grau E, Abuin A, Chapman H, Clapham JC, Brand MD (2002) The basal proton conductance of skeletal muscle mitochondria from transgenic mice overexpressing or lacking uncoupling protein-3. J Biol Chem 277:2773–2778PubMedCrossRefGoogle Scholar
- 11.Darley-Usmar V, Rickwood D, Wilson M (1987) Mitochondria: a practical approach. IRL Press, Ltd, OxfordGoogle Scholar
- 17.Halsall DJ, Luan J, Saker P, Huxtable S, Farooqi IS, Keogh J, Wareham NJ, O’Rahilly S (2001) Uncoupling protein 3 genetic variants in human obesity: the c-55t promoter polymorphism is negatively correlated with body mass index in a UK Caucasian population. Int J Obesity 25:472–477CrossRefGoogle Scholar
- 29.Liu J, Wang C, Murakami Y, Gong G, Ishibashi Y, Prody C, Ochiai K, Bache RJ, Godinot C, Zhang J (2001) Mitochondrial ATPase and high-energy phosphates in failing hearts. Am J Physiol 281:H1319–H1326Google Scholar
- 36.Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES, Jassal DS, Furutani E, Perez-Sanz TM, Graveline A, Janssens SP, Picard MH, Scherrer-Crosbie M, Bloch KD (2007) Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 116:506–514PubMedCrossRefGoogle Scholar
- 44.Sreekumar R, Unnikrishnan J, Fu A, Nygren J, Short KR, Schimke J, Barazzoni R, Nair KS (2002) Impact of high-fat diet and antioxidant supplement on mitochondrial functions and gene transcripts in rat muscle. Am J Physiol 282:E1055–E1061Google Scholar
- 46.Thompson KL, Rosenzweig BA, Zhang J, Knapton AD, Honchel R, Lipshultz SE, Retief J, Sistare FD, Herman EH (2009) Early alterations in heart gene expression profiles associated with doxorubicin cardiotoxicity in rats. Cancer Chemother Pharmacol. doi: 10.1007/s00280-009-1164-9
- 49.Walder K, Norman RA, Hanson RL, Schrauwen P, Neverova M, Jenkinson CP, Easlick J, Warden CH, Pecqueur C, Raimbault S, Ricquier D, Silver MHK, Shuldiner AR, Solanes G, Lowell BB, Chung WK, Leibel RL, Pratley R, Ravussin E (1998) Association between uncoupling protein polymorphisms (UCP2-UCP3) and energy metabolism/obesity in Pima indians. Hum Mol Genet 7:1431–1435PubMedCrossRefGoogle Scholar