The IκB Kinase β/Nuclear Factor κB Signaling Pathway Protects the Heart From Hemodynamic Stress Mediated by the Regulation of Manganese Superoxide Dismutase Expression
The IκB Kinase β/Nuclear Factor κB Signaling Pathway Protects the Heart From Hemodynamic Stress Mediated by the Regulation of Manganese Superoxide Dismutase Expression
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DOI：
10.1161/circresaha.108.193318
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发表时间：
2009-07-02
影响因子：
20.1
通讯作者：
Otsu, Kinya
中科院分区：
文献类型：
--
作者：
Hikoso, Shungo;Yamaguchi, Osamu;Otsu, Kinya
心肌细胞死亡在心力衰竭的发病机制中起重要作用。核因子（nuclear factor，NF）-κ B信号通路调节细胞死亡，但NF-κ B通路对细胞死亡的影响在不同的细胞或刺激物中可能不同。本研究的目的是阐明NF-κ B B通路在压力超负荷反应中的体内作用。首先，我们通过横主动脉缩窄（TAC）使C57 B16/J小鼠承受压力超负荷，并检测NF-κ B通路对压力超负荷的反应活性。TAC后I κ B激酶（IKK）和NF-κ B被激活。然后，我们使用心脏特异性IKK β缺陷小鼠（CKO）研究了激活的作用。CKO显示正常的整体心脏结构和功能与对照同窝仔。我们将CKO和对照小鼠压力超负荷。TAC后一周，CKO表现为心脏扩张、功能障碍和肺充血，这些都是心力衰竭的特征。TAC后CKO小鼠心脏中凋亡细胞数量显著增加。与对照组小鼠相比，TAC后CKO中锰超氧化物歧化酶mRNA和蛋白表达水平显著降低。TAC后CKO中的氧化应激和c-Jun N-末端激酶（JNK）活化水平显著高于对照小鼠。用锰超氧化物歧化酶模拟物或JNK抑制剂治疗可抑制异丙肾上腺素诱导的成年CKO心肌细胞死亡。因此，IKK β/NF-κ B信号通路在心肌细胞中起保护作用，因为在急性压力超负荷的情况下氧化应激和JNK活化的减弱。(Circ Res. 2009; 105：70-79。）
Cardiomyocyte death plays an important role in the pathogenesis of heart failure. The nuclear factor (NF)-kappa B signaling pathway regulates cell death, however, the effect of NF-kappa B pathway on cell death can vary in different cells or stimuli. The purpose of the present study was to clarify the in vivo role of the NF-kappa B pathway in response to pressure overload. First, we subjected C57B16/J mice to pressure overload by means of transverse aortic constriction (TAC) and examined the activity of the NF-kappa B pathway in response to pressure overload. I kappa B kinase (IKK) and NF-kappa B were activated after TAC. Then, we investigated the role of the activation using cardiac-specific IKK beta-deficient mice (CKO). CKO displayed normal global cardiac structure and function compared with control littermates. We subjected CKO and control mice to pressure overload. One week after TAC, CKO showed cardiac dilation, dysfunction, and lung congestion, which are characteristics of heart failure. The number of apoptotic cells in the hearts of CKO mice increased significantly after TAC. The levels of manganese superoxide dismutase mRNA and protein expression in CKO after TAC were significantly attenuated compared with control mice. The levels of oxidative stress and c-Jun N-terminal kinase (JNK) activation in CKO after TAC were significantly greater than those in control mice. Isoproterenol-induced cell death of isolated adult CKO cardiomyocytes was inhibited by treatment with either a manganese superoxide dismutase mimetic or a JNK inhibitor. Thus, the IKK beta/NF-kappa B signaling pathway plays a protective role in cardiomyocytes because of the attenuation of oxidative stress and JNK activation in a setting of acute pressure overload. (Circ Res. 2009; 105: 70-79.)