© 2001 American Heart Association, Inc.
Integrative Physiology |
Mitochondrial DNA Damage and Dysfunction Associated With Oxidative Stress in Failing Hearts After Myocardial Infarction
From the Departments of Cardiovascular Medicine (H.T., T.I., S.H., N.S., A.T.), Clinical Chemistry and Laboratory Medicine (D.K., N.H.), and Developmental Molecular Anatomy (K.N.), Graduate School of Medical Sciences and the Department of Biophysics, Faculty of Pharmaceutical Sciences (H.U.), Kyushu University, Fukuoka, Japan.
Correspondence to Hiroyuki Tsutsui, MD, PhD, Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. E-mail prehiro{at}cardiol.med.kyushu-u.ac.jp
Abstract—Mitochondria are one of the enzymatic sources of reactive oxygen species (ROS) and could also be a major target for ROS-mediated damage. We hypothesized that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery ligation for 4 weeks, the LV was dilated and contractility was diminished. Hydroxyl radicals, which originated from the superoxide anion, and lipid peroxide formation in the mitochondria were both increased in the noninfarcted LV from MI mice. The mtDNA copy number relative to the nuclear gene (18S rRNA) preferentially decreased by 44% in MI by a Southern blot analysis, associated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gene transcripts, including the subunits of complex I (ND1, 2, 3, 4, 4L, and 5), complex III (cytochrome b), complex IV (cytochrome c oxidase), and rRNA (12S and 16S). Consistent with these molecular changes, the enzymatic activity of complexes I, III, and IV decreased in MI, whereas, in contrast, complex II and citrate synthase, encoded only by nuclear DNA, both remained at normal levels. An intimate link among ROS, mtDNA damage, and defects in the electron transport function, which may lead to an additional generation of ROS, might play an important role in the development and progression of LV remodeling and failure.
Key Words: mitochondria • free radicals • heart failure • myocardial infarction • remodeling
This article has been cited by other articles:
 |
|
 |
|
  S. K. Roy Chowdhury, G. V. Sangle, X. Xie, G. L. Stelmack, A. J. Halayko, and G. X. Shen Effects of extensively oxidized low-density lipoprotein on mitochondrial function and reactive oxygen species in porcine aortic endothelial cells Am J Physiol Endocrinol Metab, January 1, 2010; 298(1): E89 - E98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Wu, L. Yan, C. Depre, S. K. Dhar, Y.-T. Shen, J. Sadoshima, S. F. Vatner, and D. E. Vatner Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction Am J Physiol Cell Physiol, October 1, 2009; 297(4): C928 - C934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Bugger and E. D. Abel Rodent models of diabetic cardiomyopathy Dis. Model. Mech., September 1, 2009; 2(9-10): 454 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shimokawa and D. Heistad Akira Takeshita, MD, PhD: 1940-2009 Arterioscler Thromb Vasc Biol, June 1, 2009; 29(6): 787 - 788. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Vandermeers, P. Hubert, P. Delvenne, C. Mascaux, B. Grigoriu, A. Burny, A. Scherpereel, and L. Willems Valproate, in Combination with Pemetrexed and Cisplatin, Provides Additional Efficacy to the Treatment of Malignant Mesothelioma Clin. Cancer Res., April 15, 2009; 15(8): 2818 - 2828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Turer, R. D. Stevens, J. R. Bain, M. J. Muehlbauer, J. van der Westhuizen, J. P. Mathew, D. A. Schwinn, D. D. Glower, C. B. Newgard, and M. V. Podgoreanu Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion Circulation, April 7, 2009; 119(13): 1736 - 1746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hiraumi, E. Iwai-Kanai, S. Baba, Y. Yui, Y. Kamitsuji, Y. Mizushima, H. Matsubara, M. Watanabe, K.-i. Watanabe, S. Toyokuni, et al. Granulocyte colony-stimulating factor protects cardiac mitochondria in the early phase of cardiac injury Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H823 - H832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tsutsui, S. Kinugawa, and S. Matsushima Mitochondrial oxidative stress and dysfunction in myocardial remodelling Cardiovasc Res, February 15, 2009; 81(3): 449 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. van Bilsen, F. A. van Nieuwenhoven, and G. J. van der Vusse Metabolic remodelling of the failing heart: beneficial or detrimental? Cardiovasc Res, February 15, 2009; 81(3): 420 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Kellogg, K. Converso, T. Wiggin, M. Stevens, and R. Pop-Busui Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H453 - H461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ananthakrishnan, M. Kaneko, Y. C. Hwang, N. Quadri, T. Gomez, Q. Li, C. Caspersen, and R. Ramasamy Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H333 - H341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Urata, Y. Koga-Wada, Y. Kayamori, and D. Kang Platelet contamination causes large variation as well as overestimation of mitochondrial DNA content of peripheral blood mononuclear cells Ann Clin Biochem, September 1, 2008; 45(5): 513 - 514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Doughan, D. G. Harrison, and S. I. Dikalov Molecular Mechanisms of Angiotensin II-Mediated Mitochondrial Dysfunction: Linking Mitochondrial Oxidative Damage and Vascular Endothelial Dysfunction Circ. Res., February 29, 2008; 102(4): 488 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Gustafsson and R. A. Gottlieb Heart mitochondria: gates of life and death Cardiovasc Res, January 15, 2008; 77(2): 334 - 343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. George Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res, January 15, 2008; 77(2): 302 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Redout, M. J. Wagner, M. J. Zuidwijk, C. Boer, R. J.P. Musters, C. van Hardeveld, W. J. Paulus, and W. S. Simonides Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species Cardiovasc Res, September 1, 2007; 75(4): 770 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Seddon, Y. H Looi, and A. M Shah Oxidative stress and redox signalling in cardiac hypertrophy and heart failure Heart, August 1, 2007; 93(8): 903 - 907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Sparagna, A. J. Chicco, R. C. Murphy, M. R. Bristow, C. A. Johnson, M. L. Rees, M. L. Maxey, S. A. McCune, and R. L. Moore Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure J. Lipid Res., July 1, 2007; 48(7): 1559 - 1570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Srivastava, B. Chandrasekar, Y. Gu, J. Luo, T. Hamid, B. G. Hill, and S. D. Prabhu Downregulation of CuZn-superoxide dismutase contributes to {beta}-adrenergic receptor-mediated oxidative stress in the heart Cardiovasc Res, June 1, 2007; 74(3): 445 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Doerries, K. Grote, D. Hilfiker-Kleiner, M. Luchtefeld, A. Schaefer, S. M. Holland, S. Sorrentino, C. Manes, B. Schieffer, H. Drexler, et al. Critical Role of the NAD(P)H Oxidase Subunit p47phox for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction Circ. Res., March 30, 2007; 100(6): 894 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Neubauer The Failing Heart -- An Engine Out of Fuel N. Engl. J. Med., March 15, 2007; 356(11): 1140 - 1151. [Full Text] [PDF]
|
|
|
|
|
|
J. H. Rennison, T. A. McElfresh, I. C. Okere, E. J. Vazquez, H. V. Patel, A. B. Foster, K. K. Patel, Q. Chen, B. D. Hoit, K.-Y. Tserng, et al. High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1498 - H1506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. C. Spikings, J. Alderson, and J. C. St. John Regulated Mitochondrial DNA Replication During Oocyte Maturation Is Essential for Successful Porcine Embryonic Development Biol Reprod, February 1, 2007; 76(2): 327 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Takimoto and D. A. Kass Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling Hypertension, February 1, 2007; 49(2): 241 - 248. [Full Text] [PDF]
|
|
|
|
 |
|
 H. Nojiri, T. Shimizu, M. Funakoshi, O. Yamaguchi, H. Zhou, S. Kawakami, Y. Ohta, M. Sami, T. Tachibana, H. Ishikawa, et al. Oxidative Stress Causes Heart Failure with Impaired Mitochondrial Respiration J. Biol. Chem., November 3, 2006; 281(44): 33789 - 33801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Murdoch, M. Zhang, A. C. Cave, and A. M. Shah NADPH oxidase-dependent redox signalling in cardiac hypertrophy, remodelling and failure Cardiovasc Res, July 15, 2006; 71(2): 208 - 215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wang, T. Miura, N. Harada, R. Kametani, M. Shibuya, Y. Fukagawa, S. Kawamura, Y. Ikeda, M. Hara, and M. Matsuzaki Pleiotropic Effects of the beta-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 45 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Petermann, C. Mayer, J. Stypmann, M. L. Biniossek, D. J. Tobin, M. A. Engelen, T. Dandekar, T. Grune, L. Schild, C. Peters, et al. Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice FASEB J, June 1, 2006; 20(8): 1266 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Matsushima, T. Ide, M. Yamato, H. Matsusaka, F. Hattori, M. Ikeuchi, T. Kubota, K. Sunagawa, Y. Hasegawa, T. Kurihara, et al. Overexpression of Mitochondrial Peroxiredoxin-3 Prevents Left Ventricular Remodeling and Failure After Myocardial Infarction in Mice Circulation, April 11, 2006; 113(14): 1779 - 1786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Grieve, J. A. Byrne, A. Siva, J. Layland, S. Johar, A. C. Cave, and A. M. Shah Involvement of the Nicotinamide Adenosine Dinucleotide Phosphate Oxidase Isoform Nox2 in Cardiac Contractile Dysfunction Occurring in Response to Pressure Overload J. Am. Coll. Cardiol., February 21, 2006; 47(4): 817 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cave, D. Grieve, S. Johar, M. Zhang, and A. M Shah NADPH oxidase-derived reactive oxygen species in cardiac pathophysiology Phil Trans R Soc B, December 29, 2005; 360(1464): 2327 - 2334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Mollnau, M. Oelze, M. August, M. Wendt, A. Daiber, E. Schulz, S. Baldus, A. L. Kleschyov, A. Materne, P. Wenzel, et al. Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2554 - 2559. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nimata, T.-a. Okabe, M. Hattori, Z. Yuan, K. Shioji, and C. Kishimoto MCI-186 (edaravone), a novel free radical scavenger, protects against acute autoimmune myocarditis in rats Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2514 - H2518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. G. Kevin, E. Novalija, and D. F. Stowe Reactive Oxygen Species as Mediators of Cardiac Injury and Protection: The Relevance to Anesthesia Practice Anesth. Analg., November 1, 2005; 101(5): 1275 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Perseghin, P. Fiorina, F. De Cobelli, P. Scifo, A. Esposito, T. Canu, M. Danna, C. Gremizzi, A. Secchi, L. Luzi, et al. Cross-Sectional Assessment of the Effect of Kidney and Kidney-Pancreas Transplantation on Resting Left Ventricular Energy Metabolism in Type 1 Diabetic-Uremic Patients: A Phosphorous-31 Magnetic Resonance Spectroscopy Study J. Am. Coll. Cardiol., September 20, 2005; 46(6): 1085 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ikeuchi, H. Matsusaka, D. Kang, S. Matsushima, T. Ide, T. Kubota, T. Fujiwara, N. Hamasaki, A. Takeshita, K. Sunagawa, et al. Overexpression of Mitochondrial Transcription Factor A Ameliorates Mitochondrial Deficiencies and Cardiac Failure After Myocardial Infarction Circulation, August 2, 2005; 112(5): 683 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Di Lisa and P. Bernardi Mitochondrial function and myocardial aging. A critical analysis of the role of permeability transition Cardiovasc Res, May 1, 2005; 66(2): 222 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Freimann, M. Scheinowitz, D. Yekutieli, M. S. Feinberg, M. Eldar, and G. Kessler-Icekson Prior exercise training improves the outcome of acute myocardial infarction in the rat: Heart structure, function, and gene expression J. Am. Coll. Cardiol., March 15, 2005; 45(6): 931 - 938. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ruchko, O. Gorodnya, S. P. LeDoux, M. F. Alexeyev, A.-B. Al-Mehdi, and M. N. Gillespie Mitochondrial DNA damage triggers mitochondrial dysfunction and apoptosis in oxidant-challenged lung endothelial cells Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L530 - L535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. van Bilsen, P. J.H Smeets, A. J Gilde, and G. J van der Vusse Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res, February 1, 2004; 61(2): 218 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Lightfoot, S. Khov, and H. Ischiropoulos Transient injury to rat lung mitochondrial DNA after exposure to hyperoxia and inhaled nitric oxide Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L23 - L29. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Garnier, D Fortin, C Delomenie, I Momken, V Veksler, and R Ventura-Clapier Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles J. Physiol., September 1, 2003; 551(2): 491 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Qin, J. Shite, and C.-s. Liang Antioxidants attenuate myocyte apoptosis and improve cardiac function in CHF: association with changes in MAPK pathways Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H822 - H832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Suematsu, H. Tsutsui, J. Wen, D. Kang, M. Ikeuchi, T. Ide, S. Hayashidani, T. Shiomi, T. Kubota, N. Hamasaki, et al. Oxidative Stress Mediates Tumor Necrosis Factor-{alpha}-Induced Mitochondrial DNA Damage and Dysfunction in Cardiac Myocytes Circulation, March 18, 2003; 107(10): 1418 - 1423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Machida, T. Kubota, N. Kawamura, H. Funakoshi, T. Ide, H. Utsumi, Y. Y. Li, A. M. Feldman, H. Tsutsui, H. Shimokawa, et al. Overexpression of tumor necrosis factor-alpha increases production of hydroxyl radical in murine myocardium Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H449 - H455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Scheubel, M. Tostlebe, A. Simm, S. Rohrbach, R. Prondzinsky, F. N. Gellerich, R.-E. Silber, and J. Holtz Dysfunction of mitochondrial respiratory chain complex I in human failing myocardium is not due to disturbed mitochondrial gene expression J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2174 - 2181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Young, P. McNulty, and H. Taegtmeyer Adaptation and Maladaptation of the Heart in Diabetes: Part II: Potential Mechanisms Circulation, April 16, 2002; 105(15): 1861 - 1870. [Full Text] [PDF]
|
|
|
|
|
|
H. Tsutsui, T. Ide, T. Shiomi, D. Kang, S. Hayashidani, N. Suematsu, J. Wen, H. Utsumi, N. Hamasaki, and A. Takeshita 8-Oxo-dGTPase, Which Prevents Oxidative Stress-Induced DNA Damage, Increases in the Mitochondria From Failing Hearts Circulation, December 11, 2001; 104(24): 2883 - 2885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Y. Li, D. Chen, S. C. Watkins, and A. M. Feldman Mitochondrial Abnormalities in Tumor Necrosis Factor-{alpha}-Induced Heart Failure Are Associated With Impaired DNA Repair Activity Circulation, November 13, 2001; 104(20): 2492 - 2497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kanazawa, Y. Nishio, A. Kashiwagi, H. Inagaki, R. Kikkawa, and K. Horiike Reduced activity of mtTFA decreases the transcription in mitochondria isolated from diabetic rat heart Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E778 - E785. [Abstract] [Full Text] [PDF]
|
|