Overexpression of Glutathione Peroxidase Prevents Left Ventricular Remodeling and Failure After Myocardial Infarction in Mice

Abstract

Background-Oxidative stress plays an important role in the pathophysiology of heart failure. We determined whether the overexpression of glutathione peroxidase (GSHPx) could attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI). Methods and Results-We created MI in 12-to 16-week-old, male GSHPx transgenic mice (TGϩMI) and nontransgenic wild-type littermates (WTϩMI) by ligating the left coronary artery. GSHPx activity was increased in the hearts of TG mice, with no significant changes in other antioxidant enzymes. LV concentrations of thiobarbituric acid-reactive substances measured in TGϩMI at 4 weeks were significantly lower than those in WTϩMI. The survival rate during 4 weeks of MI was significantly higher in TGϩMI than in WTϩMI, although the infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in TGϩMI. LV end-diastolic pressure was increased in WTϩMI and reduced in TGϩMI. Improvement of LV function in TGϩMI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis in the noninfarcted LV. Myocardial matrix metalloproteinase-9 zymographic and protein levels were increased in WTϩMI after 3 days but were attenuated in TGϩMI. Conclusions-Overexpression of GSHPx inhibited LV remodeling and failure after MI. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac failure.

Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart

“…After 8 wk of injection, echocardiographic studies were performed under light anesthesia with tribromoethanol-amylene hydrate (Avertin; 2.5% wt/ vol, 8 l/g ip) and spontaneous respiration. Two-dimensional targeted M-mode tracings were recorded at a paper speed of 50 mm/s (28).…”

“…Our previous studies have demonstrated that H 2 O 2 and hydroxyl radical (⅐OH), generated via superoxide anion (O 2 Ϫ ⅐), play an important role in the development and progression of myocardial remodeling in the pacing-induced heart failure as well as in the postinfarct heart failure model (10,28). Furthermore, in vitro studies demonstrated that ROS could directly induce hypertrophy and apoptosis in cardiac myocytes (30).…”

“…However, greater dismutation of O 2 Ϫ ⅐ by SOD results in an increase of H 2 O 2 . Therefore, among these antioxidants, GSHPx is an important enzyme that performs several vital functions (28). GSHPx not only functions by removing H 2 O 2 formed after the SOD-catalyzed dismutation reaction, but also detoxifies the lipid hydroperoxides.…”

“…These beneficial characteristics make GSHPx an important candidate for therapy against myocardial remodeling and failure due to increased ROS production. Our previous studies have demonstrated that GSHPx overexpression can attenuate oxidative stress as well as postinfarct cardiac remodeling and failure (28). Therefore, the purpose of this study was to determine whether overexpression of GSHPx could attenuate the structural remodeling and func-tional decline in the hearts with diabetes using GSHPx transgenic (TG) mice (20).…”

Bone marrow mononuclear cells enhance anti-inflammatory effects of pravastatin against isoproterenol-induced myocardial infarction in rats

“…Several studies have shown that anti-oxidant treatment reduces infarct size in the rat AMI model (Hung et al 2002;Sahna et al 2002). The acute release of large amounts of ROS is directly related to cell death associated with AMI, whereas the chronic release of ROS may be associated with the development of left ventricular hypertrophy and HF (Sorescu and Griendling 2002;Shiomi et al 2004). Anti-oxidant treatment appears to reduce cardiac fibrosis (Sia et al 2002).…”