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首页> 外文期刊>Journal of cellular biochemistry. >Low over-expression of TNFalpha in the mouse heart increases contractile performance via TNFR1.
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Low over-expression of TNFalpha in the mouse heart increases contractile performance via TNFR1.

机译:小鼠心脏中TNFalpha的过低表达可通过TNFR1增加收缩能力。

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TNFalpha is a cytokine wit pleiotropic functions in many organs. In the heart increased TNFalpha levels are not only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNFalpha in the heart is concentration-dependent, we studied two mouse heart models with low (two- to threefold) over-expression of endogenous TNFalpha: mice deficient in a translational repressor of TNFalpha mRNA, TIA-1(-/-), and mice over-expressing human TNFalpha. Hearts lacking TIA-1 were characterized for their endogenous TNFalpha over-expression during normal Langendorff perfusion. To define which TNFalpha receptor mediates cardiac protection, we also used mice lacking the TNFR1 receptor. Contractile function was assessed in isolated hearts perfused in the isovolumic Langendorff mode during and following global no-flow ischemic stress and in response to varying extracellular [Ca(2+)] to determine their contractile response and Ca(2+) sensitivity. All hearts with low over-expression of TNFalpha, independent of human or murine origin, have improved contractile performance and increased Ca(2+) sensitivity (by 0.2-0.26 pCa). Hearts lacking TNFR1 have contractile performance equal to wild type hearts. Recovery from ischemia was greater in TIA-1(-/-) and was diminished in TNFR1(-/-). Better contractile function in TNFalpha over-expressing hearts is not due to improved cardiac energetics assessed as [ATP] and glucose uptake or to differences in expression of SERCA2a or calmodulin. We suggest that low levels of TNFalpha increase the Ca(2+) sensitivity of the heart via a TNFR1-mediated mechanism.
机译:TNFα是许多器官中具有多效性的细胞因子。在心脏中,TNFα水平升高不仅与心力衰竭有关,而且反而与缺血性损伤的保护作用有关。为了测试TNFalpha在心脏中的保护作用是否是浓度依赖性的,我们研究了两种内源性TNFalpha过低(两倍至三倍)过表达的小鼠心脏模型:缺乏TNFalpha mRNA,TIA-1的翻译抑制子的小鼠(-/-),以及过度表达人类TNFalpha的小鼠。缺乏TIA-1的心脏的特征是在正常Langendorff灌注过程中内源性TNFalpha过度表达。为了确定哪种TNFalpha受体介导心脏保护,我们还使用了缺少TNFR1受体的小鼠。收缩功能在孤立的心脏,在等体积的Langendorff模式期间和之后的全球无血流缺血性应力和响应变化的细胞外[Ca(2+)]来确定其收缩反应和Ca(2+)敏感性进行了评估。所有具有低水平的TNFalpha过度表达的心脏,独立于人或鼠源,都具有改善的收缩性能和增加的Ca(2+)敏感性(0.2-0.26 pCa)。缺少TNFR1的心脏的收缩能力与野生型心脏相同。在TIA-1(-/-)中缺血恢复更大,而在TNFR1(-/-)中则减少。在过表达TNFalpha的心脏中更好的收缩功能不是由于改善了以[ATP]和葡萄糖摄取评估的心脏能量,也不是由于SERCA2a或钙调蛋白表达的差异。我们建议低水平的TNFalpha通过TNFR1介导的机制增加心脏的Ca(2+)敏感性。

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