Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice

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

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Abstract

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.

Original languageEnglish
Pages (from-to)1779-1786
Number of pages8
JournalCirculation
Volume113
Issue number14
DOIs
Publication statusPublished - Apr 1 2006

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Peroxiredoxin III
Ventricular Remodeling
Myocardial Infarction
Antioxidants
Oxidative Stress

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. / Matsushima, Shouji; Ide, Tomomi; Yamato, Mayumi; Matsusaka, Hidenori; Hattori, Fumiyuki; Ikeuchi, Masaki; Kubota, Toru; Sunagawa, Kenji; Hasegawa, Yasuhiro; Kurihara, Tatsuya; Oikawa, Shinzo; Kinugawa, Shintaro; Tsutsui, Hiroyuki.

In: Circulation, Vol. 113, No. 14, 01.04.2006, p. 1779-1786.

Research output: Contribution to journalArticle

Matsushima, S, Ide, T, Yamato, M, Matsusaka, H, Hattori, F, Ikeuchi, M, Kubota, T, Sunagawa, K, Hasegawa, Y, Kurihara, T, Oikawa, S, Kinugawa, S & Tsutsui, H 2006, 'Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice', Circulation, vol. 113, no. 14, pp. 1779-1786. https://doi.org/10.1161/CIRCULATIONAHA.105.582239
Matsushima, Shouji ; Ide, Tomomi ; Yamato, Mayumi ; Matsusaka, Hidenori ; Hattori, Fumiyuki ; Ikeuchi, Masaki ; Kubota, Toru ; Sunagawa, Kenji ; Hasegawa, Yasuhiro ; Kurihara, Tatsuya ; Oikawa, Shinzo ; Kinugawa, Shintaro ; Tsutsui, Hiroyuki. / Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice. In: Circulation. 2006 ; Vol. 113, No. 14. pp. 1779-1786.
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abstract = "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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T1 - Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice

AU - Matsushima, Shouji

AU - Ide, Tomomi

AU - Yamato, Mayumi

AU - Matsusaka, Hidenori

AU - Hattori, Fumiyuki

AU - Ikeuchi, Masaki

AU - Kubota, Toru

AU - Sunagawa, Kenji

AU - Hasegawa, Yasuhiro

AU - Kurihara, Tatsuya

AU - Oikawa, Shinzo

AU - Kinugawa, Shintaro

AU - Tsutsui, Hiroyuki

PY - 2006/4/1

Y1 - 2006/4/1

N2 - 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.

AB - 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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