Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart
Overexpression of glutathione peroxidase attenuates myocardial remodeling and preserves diastolic function in diabetic heart
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DOI：
10.1152/ajpheart.00427.2006
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发表时间：
2006-11-01
影响因子：
4.8
通讯作者：
Tsutsui, Hiroyuki
中科院分区：
文献类型：
--
作者：
Matsushima, Shouji;Kinugawa, Shintaro;Tsutsui, Hiroyuki
氧化应激在糖尿病心脏结构和功能异常中起重要作用。谷胱甘肽过氧化物酶（GSHPx）是一种重要的抗氧化酶，可以清除细胞质和线粒体中的H2 O2。我们推测GSHPx基因过表达可减轻糖尿病左室重构。我们通过在雄性GSHPx转基因小鼠（TG + DM）和非转基因野生型同窝小鼠（WT + DM）中注射链脲佐菌素（160 mg/kg ip）诱导DM。与WT小鼠相比，TG小鼠心脏中的GSHPx活性更高，其他抗氧化酶无显著变化。TG + DM组8周时左室硫代巴比妥酸反应物显著低于WT + DM组（58 ± 3 vs. 71 ± 5 nmol/g，P < 0.05）。两组之间的心率和主动脉血压相当。WT + DM和TG + DM小鼠的心血管功能保持正常。与此相反，舒张功能在WT DM中受损，而在TG + DM中改善，通过二尖瓣舒张期血流峰值速度的减速时间和50%最大LV压力松弛至基线值所需的时间来评估（tau; 13.5 +/- 1.2 vs. 8.9 +/- 0.7 ms，P < 0.01）。TG + DM值与WT +对照的值相当（tau; 7.8 +/- 0.2 ms）。左室舒张功能的改善伴随着心肌细胞肥大、间质纤维化和细胞凋亡的减轻。GSHPx基因过表达可改善DM患者左室重构和舒张功能障碍。旨在干扰氧化应激的治疗可能有利于预防糖尿病患者的心脏异常。
Oxidative stress plays an important role in the structural and functional abnormalities of diabetic heart. Glutathione peroxidase (GSHPx) is a critical antioxidant enzyme that removes H2O2 in both the cytosol and mitochondia. We hypothesized that the overexpression of GSHPx gene could attenuate left ventricular (LV) remodeling in diabetes mellitus (DM). We induced DM by injection of streptozotocin (160 mg/kg ip) in male GSHPx transgenic mice (TG + DM) and nontransgenic wildtype littermates (WT + DM). GSHPx activity was higher in the hearts of TG mice compared with WT mice, with no significant changes in other antioxidant enzymes. LV thiobarbituric acid-reactive substances measured in TG + DM at 8 wk were significantly lower than those in WT + DM (58 +/- 3 vs. 71 +/- 5 nmol/g, P < 0.05). Heart rate and aortic blood pressure were comparable between groups. Systolic function was preserved normal in WT + DM and TG + DM mice. In contrast, diastolic function was impaired in WT DM and was improved in TG + DM as assessed by the deceleration time of peak velocity of transmitral diastolic flow and the time needed for relaxation of 50% maximal LV pressure to baseline value (tau; 13.5 +/- 1.2 vs. 8.9 +/- 0.7 ms, P < 0.01). The TG + DM values were comparable with those of WT + Control (tau; 7.8 +/- 0.2 ms). Improvement of LV diastolic function was accompanied by the attenuation of myocyte hypertrophy, interstitial fibrosis, and apoptosis. Overexpression of GSHPx gene ameliorated LV remodeling and diastolic dysfunction in DM. Therapies designed to interfere with oxidative stress might be beneficial to prevent cardiac abnormalities in DM.