IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction
IRAK1 deletion disrupts cardiac Toll/IL-1 signaling and protects against contractile dysfunction
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DOI：
10.1152/ajpheart.0655.2001
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发表时间：
2003-08-01
影响因子：
4.8
通讯作者：
Giroir, BP
中科院分区：
文献类型：
--
作者：
Thomas, JA;Haudek, SB;Giroir, BP
心肌收缩功能障碍伴随全身和心脏损伤。感染性休克和烧伤可导致可逆性收缩缺陷，而心脏缺血和直接炎症可导致收缩性的短暂或永久性损伤。许多引发收缩功能障碍的损伤也会激活先天免疫系统。对感染的先天免疫应答的激活由保守的Toll/白细胞介素-1（IL-1）信号转导途径协调。有趣的是，该通路的组分也在正常和衰竭的心脏中表达，尽管它们的功能尚不清楚。Toll/IL-1信号传导发生在心脏中，并且在不同损伤后收缩功能障碍需要完整的通路功能的假设被测试。这些实验的结果表明，脂多糖（LPS）激活Toll/IL-1信号传导和IL-1受体相关激酶-1（IRAK 1），这是心脏中的关键途径中间体，表明该途径的功能不仅限于免疫系统组织。此外，缺乏IRAK 1的心脏表现出LPS触发的下游信号转导受损。来自IRAK 1缺陷小鼠的心脏也抵抗急性LPS诱导的收缩功能障碍。最后，IRAK 1的失活提高了转基因小鼠的存活率，这些小鼠发展为严重的心肌炎和致命的心力衰竭。因此，Toll/IL-1通路在心肌组织中是活跃的，并且通过IRAK 1失活来干扰通路功能可能代表了防止心脏收缩功能障碍的新策略。
Myocardial contractile dysfunction accompanies both systemic and cardiac insults. Septic shock and burn trauma can lead to reversible contractile deficits, whereas ischemia and direct inflammation of the heart can precipitate transient or permanent impairments in contractility. Many of the insults that trigger contractile dysfunction also activate the innate immune system. Activation of the innate immune response to infection is coordinated by the conserved Toll/interleukin-1 (IL-1) signal transduction pathway. Interestingly, components of this pathway are also expressed in normal and failing hearts, although their function is unknown. The hypotheses that Toll/IL-1 signaling occurs in the heart and that intact pathway function is required for contractile dysfunction after different insults were tested. Results from these experiments demonstrate that lipopolysaccharides (LPS) activate Toll/IL-1 signaling and IL-1 receptor-associated kinase-1 (IRAK1), a critical pathway intermediate in the heart, indicating that the function of this pathway is not limited to immune system tissues. Moreover, hearts lacking IRAK1 exhibit impaired LPS-triggered downstream signal transduction. Hearts from IRAK1-deficient mice also resist acute LPS-induced contractile dysfunction. Finally, IRAK1 inactivation enhances survival of transgenic mice that develop severe myocarditis and lethal heart failure. Thus the Toll/IL-1 pathway is active in myocardial tissue and interference with pathway function, through IRAK1 inactivation, may represent a novel strategy to protect against cardiac contractile dysfunction.