Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension
Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension
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DOI：
10.1096/fj.09-146589
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发表时间：
2010-06-01
期刊：
影响因子：
4.8
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Oishi, Yumiko;Manabe, Ichiro;Nagai, Ryozo
Kruppel样因子5（KLF 5）是一种锌指型转录因子，在动脉粥样硬化、再狭窄、心肌肥厚等心血管疾病中起重要作用。我们以前的研究表明KLF 5是由血管紧张素II（AII）诱导的，尽管精确的分子机制尚不清楚。在这里，我们分析了调节单核苷酸多态性（SNPs）内KLF 5基因座，以确定临床相关的信号通路连接AII和KLF 5。一个SNP位于-1282 bp，与高血压风险增加相关：-1282位点A/A和A/G基因型的受试者患高血压的风险显著高于G/G基因型。有趣的是，对应于-1282G基因型的报告构建体显示出比对应于-1282A的构建体弱得多的对AII的应答。电泳迁移率改变、染色质免疫沉淀和报告基因分析共同表明，-1282 SNP位于功能性肌细胞增强因子2（MEF 2）结合位点内，-1282 G基因型破坏该位点并降低启动子的AII反应性。此外，MEF 2激活通过活性氧和p38丝裂原活化蛋白激酶诱导KLF 5的表达响应AII，KLF 5和MEF 2共表达在冠状动脉粥样硬化斑块。这些结果表明，涉及MEF 2A和KLF 5的新型信号传导和转录网络在高血压等心血管疾病的发病机制中起着重要作用。Oishi，Y.，真锅岛Imai，Y.，Hara，K.，Horikoshi，M.，Fujiu，K.，田中，T.，Aizawa，T.，Kadowaki，T.，永井河转录因子KLF 5在MEF 2元件的调节多态性改变了对血管紧张素II的反应，并与人类高血压相关。FASEB J.24，1780-1788（2010）。www.fasebj.org
Kruppel-like factor 5 (KLF5) is a zinc-finger-type transcription factor that mediates the tissue remodeling in cardiovascular diseases, such as atherosclerosis, restenosis, and cardiac hypertrophy. Our previous studies have shown that KLF5 is induced by angiotensin II (AII), although the precise molecular mechanism is not yet known. Here we analyzed regulatory single nucleotide polymorphisms (SNPs) within the KLF5 locus to identify clinically relevant signaling pathways linking AII and KLF5. One SNP was located at -1282 bp and was associated with an increased risk of hypertension: subjects with the A/A and A/G genotypes at -1282 were at significantly higher risk for hypertension than those with the G/G genotype. Interestingly, a reporter construct corresponding to the -1282G genotype showed much weaker responses to AII than a construct corresponding to -1282A. Electrophoretic mobility shift, chromatin immunoprecipitation, and reporter assays collectively showed that the -1282 SNP is located within a functional myocyte enhancer factor 2 (MEF2) binding site, and that the -1282G genotype disrupts the site and reduces the AII responsiveness of the promoter. Moreover, MEF2 activation via reactive oxygen species and p38 mitogen-activated protein kinase induced KLF5 expression in response to AII, and KLF5 and MEF2 were coexpressed in coronary atherosclerotic plaques. These results suggest that a novel signaling and transcription network involving MEF2A and KLF5 plays an important role in the pathogenesis of cardiovascular diseases such as hypertension.-Oishi, Y., Manabe, I., Imai, Y., Hara, K., Horikoshi, M., Fujiu, K., Tanaka, T., Aizawa, T., Kadowaki, T., Nagai, R. Regulatory polymorphism in transcription factor KLF5 at the MEF2 element alters the response to angiotensin II and is associated with human hypertension. FASEB J. 24, 1780-1788 (2010). www.fasebj.org