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(Circulation. 2001;104:2883.)
© 2001 American Heart Association, Inc.

Brief Rapid Communications

8-Oxo-dGTPase, Which Prevents Oxidative Stress-Induced DNA Damage, Increases in the Mitochondria From Failing Hearts

Hiroyuki Tsutsui, MD; Tomomi Ide, MD; Tetsuya Shiomi, MD; Dongchon Kang, MD; Shunji Hayashidani, MD; Nobuhiro Suematsu, MD; Jing Wen, MD; Hideo Utsumi, PhD; Naotaka Hamasaki, MD; Akira Takeshita, MD

From the Department of Cardiovascular Medicine (H.T., T.I., T.S., S.H., N.S., J.W., A.T.) and the Department of Clinical Chemistry and Laboratory Medicine (D.K., N.H.), Graduate School of Medical Sciences, Kyushu University, and the Department of Biophysics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka (H.U.), Japan.

Correspondence to Hiroyuki Tsutsui, MD, PhD, Department of 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

Background— Reactive oxygen species (ROS) can cause an oxidative modification of nucleotides, such as 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP), which can lead to defects in DNA replication. The misincorporation of 8-oxo-dGTP into DNA is prevented by 8-oxo-dGTPase, which hydrolyzes 8-oxo-dGTP into 8-oxo-dGMP. The changes in this defensive system have not yet been examined in failing hearts, in which the generation of ROS increases.

Methods and Results— Myocardial infarction (MI) was created in mice by ligating the left coronary artery. Four weeks later, the left ventricle was dilated and contractility was diminished on echocardiography. The generation of ROS, as measured by electron spin resonance spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, increased in the noninfarcted left ventricle from MI mice. The formation of thiobarbituric acid-reactive substances also increased in the mitochondria from MI mice. 8-Oxo-dGTPase was detected in the mitochondrial fractions isolated from MI mice using a Western blot analysis with an antibody to its human homologue (hMTH1). Immunohistochemistry showed positive staining for hMTH1 was localized in the cardiac myocytes.

Conclusions— The level of 8-oxo-dGTPase increased in the mitochondria isolated from post-MI hearts as oxidative stress increased, thus suggesting that a preventive mechanism is activated against ROS-induced DNA damage. As a result, 8-oxo-dGTPase is considered a useful marker of mitochondrial oxidative stress in heart failure.

Key Words: free radicals • heart failure • DNA • mitochondria

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