Thaliporphine ameliorates cardiac depression in endotoxemic rats through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-κB signaling
Thaliporphine ameliorates cardiac depression in endotoxemic rats through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-κB signaling
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DOI：
10.1007/s00210-010-0562-1
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发表时间：
2010-12-01
影响因子：
3.6
通讯作者：
Su, Ming-Jai
中科院分区：
文献类型：
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作者：
Chen, Wen-Pin;Tzeng, Hsiao-Jung;Su, Ming-Jai
塔利泊芬被发现可以改善内毒素引起的啮齿动物循环衰竭和死亡率。本研究的目的是评估太利泊芬能否改善内毒素血症大鼠的心功能，并探讨其可能的机制。在戊巴比妥钠麻醉大鼠静脉注射脂多糖(4 mg/kg)后24 h，用压力-容量环分析法评价心功能。用荧光指示剂测定酶法分离的心室肌细胞内钙瞬变、一氧化氮(NO)和活性氧(ROS)的变化。用Western blotting分析脂多糖对大鼠脑室、H9C2和Raw264.7细胞蛋白表达的影响。大鼠内毒素血症24小时后，心肌抑制与细胞内钙瞬变减少和SERCA2上硝基酪氨酸表达增加相一致。他利泊芬可降低心肌细胞内NO和ROS水平，减少SERCA2的亚硝化，从而恢复细胞内钙处理和心肌收缩的功能。在H9C2细胞中，Thaliporphine可减弱内毒素诱导的核因子-kappaB(NF-kappa B)核转位。在Raw264.7细胞中，thaliporphine通过抑制诱导型一氧化氮合酶(INOS)和肿瘤坏死因子-α(TNF-α)的表达以及NO和ROS的产生来减弱脂多糖诱导的TAK-1的磷酸化和I kappa Bα的降解。结论：泰利泊芬通过抑制心肌细胞和巨噬细胞中TAK-1磷酸化下游的TLR4信号和核因子-kappaB信号，通过减少iNOS和TNF-α的表达来阻止过氧亚硝酸盐对心肌SERCA2的亚硝化，从而减轻内毒素所致的心脏抑制。
Thaliporphine was found to ameliorate endotoxin-induced circulatory failure and mortality in rodents. The aims of the present study were to assess whether thaliporphine could improve cardiac function in endotoxemic rats and to investigate the underlying mechanisms. Cardiac function was evaluated by pressure-volume loop analysis in pentobarbital-anesthetized rats 24 h after intravenous injection of lipopolysaccharide (LPS) (4 mg/kg) with or without thaliporphine (1 mg/kg, iv). The intracellular Ca2+ transients, nitric oxide (NO), and reactive oxygen species (ROS) in enzymatically isolated ventricular cells were measured by fluorescent indicators. Western blotting was used to analyze the change of protein expression in response to LPS with or without thaliporphine in rat ventricle, H9C2 and Raw264.7 cells. Cardiac depression was found to coincide with the decreased intracellular Ca2+ transients and the increased expression of nitrotyrosine on SERCA2 in rat ventricles after 24-h endotoxemia. Thaliporphine decreased intracellular NO and ROS level in ventricular cells and the nitrosylation of SERCA2, which resulted in recovering the functional properties of intracellular Ca2+ handling and cardiac contraction. In H9C2 cells, LPS-induced nuclear translocation of nuclear factor kappa B (NF-kappa B) could be attenuated by thaliporphine. In Raw264.7 cells, thaliporphine attenuated LPS-induced TAK-1 phosphorylation and I kappa B alpha degradation in association with the inhibition of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-alpha) expression and the production of NO and ROS. In conclusion, thaliporphine ameliorates LPS-induced cardiac depression through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-kappa B signaling in both cardiomyocytes and macrophage to prevent cardiac SERCA2 from nitrosylation by peroxynitrite via decreasing iNOS and TNF-alpha expression.