Circulation Research. 2003;93:192-200
Published online before print July 10, 2003, doi: 10.1161/01.RES.0000085581.60197.4D
Published online before print July 10, 2003, doi: 10.1161/01.RES.0000085581.60197.4D
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2003 American Heart Association, Inc.
Molecular Medicine |
Uncoupling Protein-2 Overexpression Inhibits Mitochondrial Death Pathway in Cardiomyocytes
From the Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, Md.
Correspondence to Eduardo Marbán, MD, PhD, FACC, Institute of Molecular Cardiobiology, The Johns Hopkins University, 720 Rutland Ave, 844 Ross Building, Baltimore, MD 21205. E-mail marban{at}jhmi.edu
Uncoupling proteins (UCPs) are located in the mitochondrial inner membrane and partially dissipate the transmembrane proton electrochemical gradient. UCP2 is expressed in various human and rodent tissues, including the heart, where its functional role is unknown. In the present study, we tested the hypothesis that UCP2 overexpression could protect cardiomyocytes from oxidative stress–induced cell death by reducing reactive oxygen species (ROS) production in mitochondria. Using an adenoviral vector containing human UCP2, we investigated the effects of UCP2 overexpression on the mitochondrial death pathway induced by oxidative stress (100 µmol/L H2O2) in cultured neonatal cardiomyocytes. UCP2 overexpression significantly suppressed markers of cell death, including TUNEL positivity, phosphatidylserine exposure, propidium iodide uptake, and caspase-3 cleavage. Furthermore, UCP2 remarkably prevented the catastrophic loss of mitochondrial inner membrane potential induced by H2O2, which is a critical early event in cell death. Ca2+ overload and the production of ROS in mitochondria, both of which contribute to mitochondrial inner membrane potential loss, were dramatically attenuated by UCP2 overexpression. Thus, overexpression of UCP2 attenuates ROS generation and prevents mitochondrial Ca2+ overload, revealing a novel mechanism of cardioprotection.
Key Words: heart • mitochondria • membrane potential • calcium • reactive oxygen species
This article has been cited by other articles:
 |
|
 |
|
  N. Cheurfa, D. Dubois-Laforgue, D. A.F. Ferrarezi, A. F. Reis, G. M. Brenner, C. Bouche, C. Le Feuvre, F. Fumeron, J. Timsit, M. Marre, et al. The Common -866G>A Variant in the Promoter of UCP2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men Diabetes, April 1, 2008; 57(4): 1063 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. P. Evans, J. D. Ellett, M. G. Schmidt, R. G. Schnellmann, and K. D. Chavin Mitochondrial Uncoupling Protein-2 Mediates Steatotic Liver Injury following Ischemia/Reperfusion J. Biol. Chem., March 28, 2008; 283(13): 8573 - 8579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Jones, N. E. Zachara, G. A. Ngoh, B. G. Hill, Y. Teshima, A. Bhatnagar, G. W. Hart, and E. Marban Cardioprotection by N-Acetylglucosamine Linkage to Cellular Proteins Circulation, March 4, 2008; 117(9): 1172 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yan, B. M. Barnes, F. Kohl, and T. G. Marr Modulation of gene expression in hibernating arctic ground squirrels Physiol Genomics, January 17, 2008; 32(2): 170 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zungu, M. P. Alcolea, F. J. Garcia-Palmer, M. E. Young, and M. F. Essop Genomic modulation of mitochondrial respiratory genes in the hypertrophied heart reflects adaptive changes in mitochondrial and contractile function Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2819 - H2825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Tanaka-Esposito, Q. Chen, S. Moghaddas, and E. J. Lesnefsky Ischemic preconditioning does not protect via blockade of electron transport J Appl Physiol, August 1, 2007; 103(2): 623 - 628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Bodyak, D. L. Rigor, Y.-S. Chen, Y. Han, E. Bisping, W. T. Pu, and P. M. Kang Uncoupling protein 2 modulates cell viability in adult rat cardiomyocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H829 - H835. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ljubkovic, Y. Mio, J. Marinovic, A. Stadnicka, D. C. Warltier, Z. J. Bosnjak, and M. Bienengraeber Isoflurane preconditioning uncouples mitochondria and protects against hypoxia-reoxygenation Am J Physiol Cell Physiol, May 1, 2007; 292(5): C1583 - C1590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. R. Madamanchi and M. S. Runge Mitochondrial Dysfunction in Atherosclerosis Circ. Res., March 2, 2007; 100(4): 460 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Minamiyama, Y. Bito, S. Takemura, Y. Takahashi, S. Kodai, S. Mizuguchi, Y. Nishikawa, S. Suehiro, and S. Okada Calorie Restriction Improves Cardiovascular Risk Factors via Reduction of Mitochondrial Reactive Oxygen Species in Type II Diabetic Rats J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 535 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Chen, A. K. S. Camara, D. F. Stowe, C. L. Hoppel, and E. J. Lesnefsky Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion Am J Physiol Cell Physiol, January 1, 2007; 292(1): C137 - C147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. N. Sack Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance Cardiovasc Res, November 1, 2006; 72(2): 210 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gutierrez, S. W. Ballinger, V. M. Darley-Usmar, and A. Landar Free Radicals, Mitochondria, and Oxidized Lipids: The Emerging Role in Signal Transduction in Vascular Cells Circ. Res., October 27, 2006; 99(9): 924 - 932. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Jo, C. Yang, Q. Miao, M. Marzec, M. A. Wasik, P. Lu, and Y. L. Wang Peroxisome Proliferator-Activated Receptor {gamma} Promotes Lymphocyte Survival through Its Actions on Cellular Metabolic Activities J. Immunol., September 15, 2006; 177(6): 3737 - 3745. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Takeda, M. Akao, M. Matsumoto-Ida, M. Kato, H. Takenaka, Y. Kihara, T. Kume, A. Akaike, and T. Kita Serofendic Acid, a Novel Substance Extracted From Fetal Calf Serum, Protects Against Oxidative Stress in Neonatal Rat Cardiac Myocytes J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1882 - 1890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Derdak, P. Fulop, E. Sabo, R. Tavares, E. P. Berthiaume, M. B. Resnick, G. Paragh, J. R. Wands, and G. Baffy Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-{kappa}B activation and oxidative stress Carcinogenesis, May 1, 2006; 27(5): 956 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yamasaki, H. Sasaki, K. Ogawa, T. Shono, S. Tamura, A. Doi, M. Sasahara, H. Kawashima, T. Nakao, H. Furuta, et al. Uncoupling Protein 2 Promoter Polymorphism -866G/A Affects Peripheral Nerve Dysfunction in Japanese Type 2 Diabetic Patients Diabetes Care, April 1, 2006; 29(4): 888 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ardehali, B. O'Rourke, and E. Marban Cardioprotective Role of the Mitochondrial ATP-Binding Cassette Protein 1 Circ. Res., October 14, 2005; 97(8): 740 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. McLeod, A. Aziz, R. F. Hoyt Jr., J. P. McCoy Jr., and M. N. Sack Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia J. Biol. Chem., September 30, 2005; 280(39): 33470 - 33476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Prabhakaran, L. Li, E. M. Mills, J. L. Borowitz, and G. E. Isom Up-Regulation of Uncoupling Protein 2 by Cyanide Is Linked with Cytotoxicity in Mesencephalic Cells J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1338 - 1345. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Li, K. Prabhakaran, E. M. Mills, J. L. Borowitz, and G. E. Isom Enhancement of Cyanide-Induced Mitochondrial Dysfunction and Cortical Cell Necrosis by Uncoupling Protein-2 Toxicol. Sci., July 1, 2005; 86(1): 116 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-U. Lee, I. K. Lee, J. Han, D.-K. Song, Y. M. Kim, H. S. Song, H. S. Kim, W. J. Lee, E. H. Koh, K.-H. Song, et al. Effects of Recombinant Adenovirus-Mediated Uncoupling Protein 2 Overexpression on Endothelial Function and Apoptosis Circ. Res., June 10, 2005; 96(11): 1200 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. da Silva, E. Lucchinetti, T. Pasch, M. C. Schaub, and M. Zaugg Ischemic but not pharmacological preconditioning elicits a gene expression profile similar to unprotected myocardium Physiol Genomics, December 15, 2004; 20(1): 117 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Brookes, Y. Yoon, J. L. Robotham, M. W. Anders, and S.-S. Sheu Calcium, ATP, and ROS: a mitochondrial love-hate triangle Am J Physiol Cell Physiol, October 1, 2004; 287(4): C817 - C833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Horimoto, M. B. Resnick, T. A. Konkin, J. Routhier, J. R. Wands, and G. Baffy Expression of Uncoupling Protein-2 in Human Colon Cancer Clin. Cancer Res., September 15, 2004; 10(18): 6203 - 6207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hoerter, M.-d.-M. Gonzalez-Barroso, E. Couplan, P. Mateo, C. Gelly, A.-M. Cassard-Doulcier, P. Diolez, and F. Bouillaud Mitochondrial Uncoupling Protein 1 Expressed in the Heart of Transgenic Mice Protects Against Ischemic-Reperfusion Damage Circulation, August 3, 2004; 110(5): 528 - 533. [Abstract] [Full Text] [PDF]
|
|