Differential sensitivity to LPS-induced myocardial dysfunction in the isolated brown Norway and Dahl S rat hearts: roles of mitochondrial function, NF-κB activation, and TNF-α production.
Differential sensitivity to LPS-induced myocardial dysfunction in the isolated brown Norway and Dahl S rat hearts: roles of mitochondrial function, NF-κB activation, and TNF-α production.
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DOI：
10.1097/shk.0b013e31823f146f
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Shi Y
中科院分区：
文献类型：
--
作者：
An J;Du J;Wei N;Guan T;Camara AK;Shi Y
最近我们报道了BN大鼠比SS大鼠更能抵抗脂多糖（LPS）诱导的心肌功能障碍。这种差异的敏感性体现在促炎细胞因子的产生减少和NFκB通路激活减弱。为了进一步阐明这两种菌株对内毒素不同敏感性的机制，本研究旨在研究心脏分离并暴露于LPS后心脏和线粒体生物能量学，促炎细胞因子和信号通路的变化。Langendorff制剂中LPS （4 μg/ml）灌注离体BN和SS心脏30min。LPS抑制心功能，SS心脏左室压力降低，收缩和舒张峰值速率降低，而BN心脏无此现象。这些发现与我们之前的体内数据一致。在复合物I底物作用下，SS心脏线粒体的O2消耗和H2O2产量高于BN心脏。LPS显著提高了SS和BN心肌线粒体中H2O2水平；BN心肌线粒体耗氧量和H2O2产生量的增加明显低于SS心肌线粒体。此外，LPS显著降低SS心脏复合体I活性，而BN心脏复合体I活性无显著降低。此外，与BN相比，LPS在SS心脏中诱导更高水平的TNF-α和i - κ b和p65磷酸化。我们的研究结果清楚地表明，线粒体功能障碍减少、TNF-α产生减少和NFκB活化减少与分离的BN心脏更能抵抗lps诱导的心肌功能障碍的机制有关。
Recently we reported that BN rats were more resistant to lipopolysaccharide (LPS)-induced myocardial dysfunction than SS rats. This differential sensitivity was exemplified by reduced production of proinflammatory cytokines and diminished NFκB pathway activation. To further clarify the mechanisms of different susceptibility of these two strains to endotoxin, this study was designed to examine the alterations of cardiac and mitochondrial bioenergetics, proinflammatory cytokines, and signaling pathways after hearts were isolated and exposed to LPS ex vivo. Isolated BN and SS hearts were perfused with LPS (4 μg/ml) for 30 min in the Langendorff preparation. LPS depressed cardiac function as evident by reduced left ventricular developed pressure as well as decreased peak rate of contraction and relaxation in SS hearts, but not in BN heart. These findings are consistent with our previous in vivo data. Under complex I substrates a higher O2 consumption and H2O2 production were observed in mitochondria from SS hearts than that from BN hearts. LPS significantly increased H2O2 levels in both SS and BN heart mitochondria; however the increase in O2 consumption and H2O2 production in BN heart mitochondria was much lower than that in SS heart mitochondria. Additionally LPS significantly decreased complex I activity in SS hearts but not in BN hearts. Furthermore, LPS induced higher levels of TNF-α and increased phosphorylation of IκB and p65 more in SS hearts than BN hearts. Our results clearly demonstrate that less mitochondrial dysfunction combined with a reduced production of TNF-α and diminished activation of NFκB are involved in the mechanisms by which isolated BN hearts were more resistant to LPS-induced myocardial dysfunction.