Differential regulation of myocardial NFκB following acute or chronic TNF-α exposure
Differential regulation of myocardial NFκB following acute or chronic TNF-α exposure
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DOI：
10.1006/jmcc.2001.1388
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发表时间：
2001-06-01
影响因子：
5
通讯作者：
Giroir, BP
中科院分区：
文献类型：
--
作者：
Haudek, SB;Bryant, DD;Giroir, BP
肿瘤坏死因子α（TNF-α）是急性炎症状态下心肌功能障碍的关键介质。TNF-α也存在于慢性心脏病患者的血清中。在单核细胞中，TNF-α通过激活涉及NF-κ B核转位的不同信号通路来刺激细胞。由于NF κ B也可以调节可能导致心肌功能障碍的基因的表达，因此研究了急性或慢性TNF-α攻击后的心肌细胞NF κ B活化。为了实现这一点，作者要么急性施用TNF-α。健康小鼠，或使用仅在心肌细胞中长期过表达TNF-α的转基因小鼠。急性给予TNF-α后，从激发后15 min至2 h检测到心脏NF κ B易位。I kappaB α降解的时间过程与NF kappaB易位的动力学一致。I κ B β降解较慢且不太剧烈。在长期过度表达TNF-α的转基因小鼠中，在所有测试年龄（21、40和75天）均检测到心肌NF κ B活化。与急性激发的动物相反，两种不同的NF κ B蛋白在慢性激发的动物中被激活，p50-p65异二聚体以及p50同源二聚体。两者的激活可以通过施用重组嵌合TNF-α受体拮抗剂（rhTNTR：Fc）来暂时阻断。与野生型动物相比，转基因动物的I-κ B α水平升高，但I-κ B β水平没有升高。这些数据表明，急性TNF-α给药（模拟细菌性脓毒症）后，心肌p50-p65在几分钟内易位。慢性TNF-α暴露被认为发生在长期充血性心力衰竭中，除了转录活性p50-p65异源二聚体外，还导致转录失活的p50同源二聚体易位。据推测，p50同源二聚体的激活构成了一种适应性反应，以最大限度地减少慢性心脏TNT-α暴露的炎症后果。(C)北京：科学出版社.
Tumor necrosis factor alpha (TNF-alpha) is a critical mediator of myocardial dysfunction during acute inflammatory states. TNF-alpha is also present in the serum of patients with chronic cardiac diseases. In monocytes, TNF-alpha stimulates cells by activating distinct signaling pathways that involve nuclear translocation of NF-kappaB. Since NF kappaB may also regulate the expression of genes that could contribute to myocardial dysfunction, the cardiomyocyte NF kappaB activation following acute or chronic TNF-alpha challenges was investigated. To accomplish this, the authors either acutely administered TNF-alpha. to healthy mice, or used transgenic mice which chronically overexpress TNF-alpha exclusively in cardiac myocytes. Following acute administration of TNF-alpha, cardiac NF kappaB translocation was detected from 15 min to 2 h post-challenge. The time course of I kappaB alpha degradation was consistent with the kinetics of NF kappaB translocation. I kappaB beta degradation was slower and less dramatic. In transgenic mice chronically overexpressing TNF-alpha, myocardial NF kappaB activation was detected at all ages tested (21, 40, and 75 days). In contrast to acutely challenged animals, two distinct NF kappaB proteins were activated in chronically challenged animals, p50-p65 heterodimers as well as p50 homodimers. Activation of both could be transiently blocked by administration of a recombinant chimeric TNF-alpha receptor antagonist (rhTNTR:Fc). I kappaB alpha, but not I kappaB beta, levels were elevated in transgenics when compared to wild-type animals. These data indicate that following acute TNF-alpha administration, which simulates bacterial sepsis, myocardial p50-p65 translocates within minutes. Chronic TNF-alpha exposure, which is thought to occur in long-standing congestive heart failure, results in translocation of transcriptionally inactive p50 homodimers in addition to transcription ally active p50-p65 heterodimers. It is speculated that activation of p50 homodimers constitutes an adaptive response to minimize the inflammatory consequences of chronic cardiac TNT-alpha exposure. (C) 2001 Academic Press.