Interferon-γ induces X-linked inhibitor of apoptosis-associated factor-1 and noxa expression and potentiates human vascular smooth muscle cell apoptosis by STAT3 activation
Interferon-γ induces X-linked inhibitor of apoptosis-associated factor-1 and noxa expression and potentiates human vascular smooth muscle cell apoptosis by STAT3 activation
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DOI：
10.1074/jbc.m706021200
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发表时间：
2008-03-14
影响因子：
4.8
通讯作者：
Tellides, George
中科院分区：
文献类型：
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作者：
Bai, Yalai;Ahmad, Usman;Tellides, George
干扰素(IFN)- γ对血管壁的作用在动脉硬化的发病机制中起重要作用，但不同的IFN- γ信号通路对血管平滑肌细胞（VSMCs）表型调节的贡献尚不清楚。我们通过信号换能器和转录激活因子（STAT）蛋白的相互作用研究了ifn - γ对VSMCs和动脉的影响。除了STAT1激活外，ifn - γ在人VSMCs中持续磷酸化STAT3，但在人内皮细胞或小鼠VSMCs中则弱或根本不磷酸化STAT3。STAT3激活导致该转录因子的核易位。通过选择性抑制STAT3而非STAT1信号，我们通过微阵列分析确定了许多候选的ifn - γ诱导的STAT3依赖基因产物。选择的基因，包括促凋亡分子X-linked inhibitor of apoptosis associated factor-1 （XAF1）和Noxa，通过实时定量逆转录pcr和免疫印迹分析进行验证。ifn - γ诱导的VSMCs中STAT3和STAT1信号通路表现出相互抑制作用。ifn - γ激活STAT3使VSMCs对死亡受体和线粒体介导的途径引发的凋亡敏感。抑制XAF1和Noxa的表达可抑制VSMCs对ifn - γ凋亡刺激的启动。最后，我们通过植入人冠状动脉移植物的免疫缺陷小鼠嵌合动物模型证实了我们观察结果的体内相关性，其中XAF1和Noxa的表达以及ifn - γ诱导的促凋亡作用依赖于STAT3。这些数据表明ifn - γ通过STAT3介导的stat1非依赖性信号通路促进了人类VSMCs的死亡。
Interferon (IFN)-gamma actions on the vessel wall play an important role in the pathogenesis of arteriosclerosis, yet the contribution of different IFN-gamma signaling pathways to the phenotypic modulation of vascular smooth muscle cells (VSMCs) are poorly understood. We investigated the effects of IFN-gamma on VSMCs and arteries through interactions involving signal transducer and activator of transcription (STAT) proteins. In addition to STAT1 activation, IFN-gamma consistently phosphorylated STAT3 in human VSMCs but weakly or not at all in human endothelial cells or mouse VSMCs. STAT3 activation resulted in nuclear translocation of this transcription factor. By selectively inhibiting STAT3 and not STAT1 signaling, we identified a number of candidate IFN-gamma-inducible, STAT3-dependent gene products by microarray analysis. Results for selected genes, including the pro-apoptotic molecules X-linked inhibitor of apoptosis associated factor-1 (XAF1) and Noxa, were verified by real time quantitative reverse transcription-PCR and immunoblot analyses. IFN-gamma-induced STAT3 and STAT1 signaling in VSMCs demonstrated reciprocal inhibition. STAT3 activation by IFN-gamma sensitized VSMCs to apoptosis triggered by both death receptor- and mitochondrial-mediated pathways. Knock down of XAF1 and Noxa expression inhibited the priming of VSMCs to apoptotic stimuli by IFN-gamma. Finally, we confirmed the in vivo relevance of our observations using a chimeric animal model of immunodeficient mice bearing human coronary artery grafts in which the expression of XAF1 and Noxa as well as the pro-apoptotic effects induced by IFN-gamma were dependent on STAT3. The data suggest STAT1-independent signaling by IFN-gamma via STAT3 that promotes the death of human VSMCs.