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


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.
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Shouji
S
Matsushima
Tomomi
T
Ide
Mayumi
M
Yamato
Hidenori
H
Matsusaka
Fumiyuki
F
Hattori
Masaki
M
Ikeuchi
Toru
T
Kubota
Kenji
K
Sunagawa
Yasuhiro
Y
Hasegawa
Tatsuya
T
Kurihara
Shinzo
S
Oikawa
Shintaro
S
Kinugawa
Hiroyuki
H
Tsutsui
D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism*; D009203:Myocardial Infarction / Q000503:physiopathology*; D016366:Open Reading Frames; D018384:Oxidative Stress; D010544:Peroxidases / Q000235:genetics* / Q000378:metabolism; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D051381:Rats; D017382:Reactive Oxygen Species; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
C516116:Prdx3 protein, mouse; D017382:Reactive Oxygen Species; D010544:Peroxidases; D061105:Peroxiredoxin III; D054464:Peroxiredoxins