Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice.
Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice.
复制标题
DOI：
10.18632/oncotarget.14933
复制
发表时间：
2017-02-28
期刊：
影响因子：
--
通讯作者：
Meng X
中科院分区：
文献类型：
--
作者：
Hui H;Zhai Y;Ao L;Cleveland JC Jr;Liu H;Fullerton DA;Meng X
衰老会加剧内毒素血症性心脏功能障碍，但其机制仍不清楚。研究发现抗衰老蛋白 Klotho 可以调节组织炎症反应。我们测试了这样的假设：衰老心脏中 Klotho 水平降低在增强的内毒素血症性心功能障碍中发挥作用。将内毒素（0.5 mg/kg，静脉注射）注射给成年（4-6 个月）和衰老（18-20 个月）C57BL/6 小鼠。注射内毒素后，对一组衰老小鼠施用重组 Klotho（10 μg/kg，静脉注射）。内毒素给药后 24 小时和 48 小时使用微导管分析心脏功能。通过免疫印迹法测定心肌中 Klotho 和热休克蛋白 70 (HSP70) 的水平，并使用 ELISA 分析血浆和心肌细胞因子。老年小鼠更严重的心脏功能障碍伴随着血浆和心肌中更高的细胞因子水平。在心肌组织中检测到 Klotho。衰老心脏中的 Klotho 水平较低，在内毒素血症期间进一步降低。心肌 HSP70 水平与 Klotho 水平相关。重组 Klotho 可增加衰老内毒素血症小鼠的心肌 HSP70、抑制 NF-κB 激活、降低细胞因子水平并改善心脏功能。将 HSP70 递送至培养的巨噬细胞中可抑制内毒素诱导的 NF-κB 激活。与衰老相关的炎症反应和心功能障碍的增强与相对的 Klotho 缺乏有关。重组 Klotho 后处理可抑制衰老内毒素血症小鼠的炎症反应并改善心脏功能。 Klotho 调节 HSP70 水平，HSP70 似乎参与 Klotho 的抗炎机制。 Klotho 可能具有改善与衰老相关的内毒素血症性心功能障碍的治疗潜力。
Aging augments endotoxemic cardiac dysfunction, but the mechanism remains unclear. Anti-aging protein Klotho has been found to modulate tissue inflammatory responses. We tested the hypothesis that a reduced Klotho level in aging heart plays a role in the augmented endotoxemic cardiac dysfunction. Endotoxin (0.5 mg/kg, iv) was injected to adults (4-6 months) and aging (18-20 months) C57BL/6 mice. Recombinant Klotho (10 μg/kg, iv) was administered to a group of aging mice after endotoxin injection. Cardiac function was analyzed using a microcatheter at 24 and 48 h after endotoxin administration. Myocardial levels of Klotho and heat shock protein 70 (HSP70) were determined by immunoblotting, and plasma and myocardial cytokines were analyzed using ELISA. More severe cardiac dysfunction in aging mice were accompanied by greater cytokine levels in the plasma and myocardium. Klotho was detected in the myocardial tissue. Klotho levels were lower in aging hearts and were further reduced during endotoxemia. Myocardial HSP70 levels were correlated with Klotho levels. Recombinant Klotho increased myocardial HSP70, inhibited NF-κB activation, reduced cytokine levels, and improved cardiac function in aging endotoxemic mice. Delivery of HSP70 into cultured macrophages suppressed endotoxin-induced NF-κB activation. Aging-related augmentation of inflammatory responses and cardiac dysfunction is associated with relative Klotho deficiency. Post-treatment with recombinant Klotho suppresses the inflammatory responses and improves cardiac function in aging endotoxemic mice. Klotho modulates HSP70 levels and HSP70 appears to be involved in the anti-inflammatory mechanism of Klotho. Klotho may have therapeutic potential in amelioration of aging-related endotoxemic cardiac dysfunction.