NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling?
NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling?
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DOI：
10.1385/ct:3:3:229
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发表时间：
2003-01-01
影响因子：
3.2
通讯作者：
McGuinness, Michael
中科院分区：
文献类型：
--
作者：
Jones, W Keith;Brown, Maria;McGuinness, Michael
NF-κ B是一种多效性转录因子，参与多种生物学现象的调节，包括细胞凋亡、细胞存活、细胞生长、细胞分裂、先天免疫、细胞分化以及对应激、缺氧、拉伸和缺血的细胞反应。在心脏中，NF-κ B已显示在动脉粥样硬化、心肌炎、与心绞痛相关、移植排斥期间、缺血/再灌注后、充血性心力衰竭、扩张型心肌病、缺血和药物预处理后、热休克、烧伤创伤和分离的心肌细胞肥大中被激活。NF-κ B的调节是复杂的;除了被经典的精氨酸介导的途径激活外，NF-κ B还被许多与心脏肥大的发展和对氧化应激的反应相关的信号转导级联激活。这些信号级联中的许多通过激活IkappaB激酶（IKK）复合物（经典途径的主要组分）来激活NF-κ B。这些信号相互作用主要通过涉及丝裂原活化蛋白激酶/细胞外信号调节激酶（MEKK）的信号串扰发生，所述MEKK是丝裂原活化蛋白激酶（MAPK）信号通路的组分。此外，还有其他信号传导因子通过IkappaB或通过NF-κ B亚基的直接磷酸化更直接地激活NF-κ B。最后，在启动子水平上，NF-κ B、其共激活因子和其他转录因子之间存在组合相互作用，其中一些转录因子由MAPK和细胞因子信号通路激活。因此，除了作为心脏中细胞因子效应的主要介体之外，NF-κ B还被定位为信号传导整合剂。因此，NF-κ B在多种生理和病理生理状态下作为心脏基因表达程序下游多个信号转导级联的关键调节因子发挥作用。我们发现，NF-κ B的基因阻断减少了缺血/再灌注（I/R）后小鼠心脏的梗死面积，暗示NF-κ B是I/R后细胞死亡的主要决定因素。这些结果支持NF-κ B可能是特定心血管疾病的重要治疗靶点的概念。
NF-kappaB is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival, cell growth, cell division, innate immunity, cellular differentiation, and the cellular responses to stress, hypoxia, stretch and ischemia. In the heart, NF-kappaB has been shown to be activated in atherosclerosis, myocarditis, in association with angina, during transplant rejection, after ischemia/reperfusion, in congestive heart failure, dilated cardiomyopathy, after ischemic and pharmacological preconditioning, heat shock, burn trauma, and in hypertrophy of isolated cardiomyocytes. Regulation of NF-kappaB is complicated; in addition to being activated by canonical cytokine-mediated pathways, NF-kappaB is activated by many of the signal transduction cascades associated with the development of cardiac hypertrophy and response to oxidative stress. Many of these signaling cascades activate NF-kappaB by activating the IkappaB kinase (IKK) complex a major component of the canonical pathway. These signaling interactions occur largely via signaling crosstalk involving the mitogen-activated protein kinase/extracellular signalregulated kinase kinases (MEKKs) that are components of mitogen activated protein kinase (MAPK) signaling pathways. Additionally, there are other signaling factors that act more directly to activate NF-kappaB via IkappaB or by direct phosphorylation of NF-kappaB subunits. Finally, there are combinatorial interactions at the level of the promoter between NF-kappaB, its coactivators, and other transcription factors, several of which are activated by MAPK and cytokine signaling pathways. Thus, in addition to being a major mediator of cytokine effects in the heart, NF-kappaB is positioned as a signaling integrator. As such, NF-kappaB functions as a key regulator of cardiac gene expression programs downstream of multiple signal transduction cascades in a variety of physiological and pathophysiological states. We show that genetic blockade of NF-kappaB reduces infarct size in the murine heart after ischemia/reperfusion (I/R), implicating NF-kappaB as a major determinant of cell death after I/R. These results support the concept that NF-kappaB may be an important therapeutic target for specific cardiovascular diseases.