NF-κB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes
NF-κB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes
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DOI：
10.1093/cvr/cvp305
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发表时间：
2010-02-01
影响因子：
10.8
通讯作者：
Francis, Joseph
中科院分区：
文献类型：
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作者：
Mariappan, Nithya;Elks, Carrie M.;Francis, Joseph
目的炎症分子及其转录因子核因子κ-B（NF-κ B B）在糖尿病心功能不全中起重要作用。在这里，我们调查的影响吡咯烷二硫代氨基甲酸酯（PDTC），NF-κ B抑制剂，在糖尿病mice.Methods和结果肥胖db/db小鼠和杂合子瘦小鼠（n = 8）被允许自由饮用水（对照）或水含有PDTC（100毫克/公斤）20周。在基线和研究结束时使用超声心动图测量左心室（LV）功能。处死小鼠并取出LV用于基因表达、生化、免疫荧光和线粒体测定。LV和线粒体活性氧（ROS），超氧化物和过氧亚硝酸盐测定使用电子自旋共振光谱。db/db小鼠NF-κ B活性增强与氧化应激增加相关，表现为ROS、超氧化物和过氧亚硝酸盐产生增加，NF-κ B、gp 91 phox和Nox 1表达增加; PDTC改善了这些效应。db/db组的线粒体自由基产生和结构损伤高于对照组、db/db PDTC组和PDTC处理的杂合子动物组。结论本研究表明，PDTC阻断NF-κ B可通过下调增加的氧自由基，从而增加ATP合成并因此恢复II型糖尿病的心脏功能。
Aims Inflammatory molecules and their transcription factor, nuclear factor kappa-B (NF-kappa B), are thought to play important roles in diabetes-induced cardiac dysfunction. Here, we investigated the effects of pyrrolidine dithiocarbamate (PDTC), a NF-kappa B inhibitor, in diabetic mice.Methods and results Obese db/db mice and heterozygous lean mice (n = 8) were allowed free access to drinking water (control) or water containing PDTC (100 mg/kg) for 20 weeks. Left ventricular (LV) function was measured using echocardiography at baseline and at study end. Mice were sacrificed and LV removed for gene expression, biochemical, immunofluorescence, and mitochondrial assays. LV and mitochondrial reactive oxygen species (ROS), superoxide and peroxynitrite were measured using electron spin resonance spectroscopy. Enhanced NF-kappa B activity in db/db mice was associated with increased oxidative stress as demonstrated by increased ROS, superoxide, and peroxynitrite production, and increased NF-kappa B, gp91phox, and Nox1 expression; PDTC ameliorated these effects. Mitochondrial free radical production and structural damage were higher in the db/db group than in the control, db/db PDTC, and PDTC-treated heterozygous animal groups.Conclusion This study demonstrates that NF-kappa B blockade with PDTC mitigates oxidative stress and improves mitochondrial structural integrity directly, through down-regulation of increased oxygen-free radicals, thereby increasing ATP synthesis and thus restoring cardiac function in type II diabetes.