Published Online
on July 25, 2005

A more recent version of this article appeared on August 2, 2005

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Submitted on November 30, 2004
Revised on April 17, 2005
Accepted on April 22, 2005

Overexpression of Mitochondrial Transcription Factor A Ameliorates Mitochondrial Deficiencies and Cardiac Failure After Myocardial Infarction

Masaki Ikeuchi MD, Hidenori Matsusaka MD, Dongchon Kang MD, PhD, Shouji Matsushima MD, Tomomi Ide MD, PhD, Toru Kubota MD, PhD, Toshiyuki Fujiwara MD, PhD, Naotaka Hamasaki MD, PhD, Akira Takeshita MD, PhD, Kenji Sunagawa MD, PhD, and Hiroyuki Tsutsui MD, PhD^*

From the Department of Cardiovascular Medicine (M.I., H.M., S.M., T.I., T.K., A.T., K.S.) and Clinical Chemistry and Laboratory Medicine (D.K., N.H.), Graduate School of Medical Sciences, Kyushu University, Fukuoka; Department of Biochemistry, Fukuoka University School of Medicine, Fukuoka (T.F.); and Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo (H.T.), Japan.

^* To whom correspondence should be addressed. E-mail: htsutsui{at}med.hokudai.ac.jp.

Background--Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state.

Methods and Results--We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermates (WT-MI), although infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT-MI, and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV.

Conclusions--Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure.

Key words: free radicals • genes • heart failure • myocardial infarction • remodeling

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