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(Circulation. 2006;113:1779-1786.)
© 2006 American Heart Association, Inc.

Heart Failure

Overexpression of Mitochondrial Peroxiredoxin-3 Prevents Left Ventricular Remodeling and Failure After Myocardial Infarction in Mice

Shouji Matsushima, MD; Tomomi Ide, MD, PhD; Mayumi Yamato, PhD; Hidenori Matsusaka, MD; Fumiyuki Hattori, PhD; Masaki Ikeuchi, MD; Toru Kubota, MD, PhD; Kenji Sunagawa, MD, PhD; Yasuhiro Hasegawa, PhD; Tatsuya Kurihara, PhD; Shinzo Oikawa, PhD; Shintaro Kinugawa, MD, PhD; Hiroyuki Tsutsui, MD, PhD

From the Department of Cardiovascular Medicine, Graduate School of Medical Sciences (S.M., T.I., H.M., M.I., T.K., K.S.), and the Department of Redox Medicinal Science, Graduate School of Pharmaceutical Sciences (M.Y.), Kyushu University, Fukuoka; Biomedical Research Laboratories (F.H., Y.H., T.K., S.O.), Daiichi Suntory Pharma Co, Ltd, Osaka; and the Department of Cardiovascular Medicine (S.K., H.T.), Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to Hiroyuki Tsutsui, MD, PhD, Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. E-mail htsutsui{at}med.hokudai.ac.jp

Received August 10, 2005; revision received January 26, 2006; accepted February 2, 2006.

Background— Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process.

Methods and Results— We created MI in 12- to 16-week-old, male Prx-3–transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid–reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean±SEM, 1.5±0.2 vs 2.2±0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56±1% vs 55±1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice.

Conclusions— Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure.

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