Interaction between NFκB and NFAT coordinates cardiac hypertrophy and pathological remodeling.
Interaction between NFκB and NFAT coordinates cardiac hypertrophy and pathological remodeling.
复制标题
DOI：
10.1161/circresaha.111.260729
复制
发表时间：
2012-04-13
影响因子：
20.1
通讯作者：
Molkentin JD
中科院分区：
文献类型：
--
作者：
Liu Q;Chen Y;Auger-Messier M;Molkentin JD
活化T细胞核因子（NFAT）和核因子κB（NFκB）都是含有Rel同源域（RHD）的转录因子，其独立活性在调节心脏肥大和衰竭中发挥着重要作用。确定心肌细胞中 NFAT 和 NFκB 信号通路之间潜在的功能相互作用及其在心脏肥大和重塑中的作用。在这里，我们发现了一种新的转录调节机制，其中 NFκB 和 NFAT 直接相互作用并协同促进心肌细胞的转录激活。我们发现 NFκB 的 p65 亚基与心肌细胞中的 NFAT 发生免疫共沉淀，并且这种相互作用映射到 p65 内的 RHD。 p65-RHD 的过度表达会破坏内源性 p65 和 NFATc1 之间的关联，导致转录活性降低。 IκB 激酶 β (IKKβ) 或 p65-RHD 的过度表达会导致 NFATc1 核转位，而组成型核 NFATc1-SA 突变体的表达同样会促进 p65 核转位。 p65 和 NFATc1 的联合过表达可促进心肌细胞中 NFAT 转录活性的协同激活，而用 IκBαM 或显性失活 IKKβ 抑制 NFκB 会降低 NFAT 活性。重要的是，与野生型 MEF 相比，p65 缺失小鼠胚胎成纤维细胞 (MEF) 中激动剂诱导的 NFAT 激活减少。在体内，使用 Cre-loxP 系统对 p65 进行心脏特异性删除会导致荧光素酶报告小鼠的 NFAT 活性降低约 50%。此外，小鼠心脏中p65的消融降低了压力超负荷刺激后的肥厚反应，降低了病理重塑的程度，并保留了收缩功能。我们的结果表明，NFAT 和 NFκB 之间存在直接相互作用，可有效整合两种不同的信号通路，促进心脏肥大和心室重塑。
Both nuclear factor of activated T cells (NFAT) and nuclear factor κB (NFκB) are Rel homology domain (RHD)-containing transcription factors whose independent activities are critically involved in regulating cardiac hypertrophy and failure. To determine the potential functional interaction between NFAT and NFκB signaling pathways in cardiomyocytes and its role in cardiac hypertrophy and remodeling. Here we identified a novel transcriptional regulatory mechanism whereby NFκB and NFAT directly interact and synergistically promote transcriptional activation in cardiomyocytes. We show that the p65 subunit of NFκB co-immunoprecipitates with NFAT in cardiomyocytes, and this interaction maps to the RHD within p65. Overexpression of the p65-RHD disrupts the association between endogenous p65 and NFATc1, leading to reduced transcriptional activity. Overexpression of IκB kinase β (IKKβ) or p65-RHD causes nuclear translocation of NFATc1, and expression of a constitutively nuclear NFATc1-SA mutant similarly facilitated p65 nuclear translocation. Combined overexpression of p65 and NFATc1 promotes synergistic activation of NFAT transcriptional activity in cardiomyocytes while inhibition of NFκB with IκBαM or dominant negative IKKβ reduces NFAT activity. Importantly, agonist-induced NFAT activation is reduced in p65 null mouse embryonic fibroblasts (MEFs) compared to wild-type MEFs. In vivo, cardiac-specific deletion of p65 using a Cre-loxP system causes a ~ 50% reduction in NFAT activity in luciferase reporter mice. Moreover, ablation of p65 in the mouse heart decreases the hypertrophic response following pressure overload stimulation, reduces the degree of pathological remodeling, and preserves contractile function. Our results suggest a direct interaction between NFAT and NFκB that effectively integrates two disparate signaling pathways in promoting cardiac hypertrophy and ventricular remodeling.