Jain Sudhir, Tang Xiangna, Narayanan Chittampalli S, Agarwal Yogesh, Peterson Stephen M, Brown Clinton D, Ott Jurg, Kumar Ashok
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA.
J Biol Chem. 2002 Sep 27;277(39):36889-96. doi: 10.1074/jbc.M204732200. Epub 2002 Jul 26.
Hypertension is a serious health problem in Western society, in particular for the African-American population. Although previous studies have suggested that the angiotensinogen (AGT) gene locus is involved in human essential hypertension, the molecular mechanisms involved in hypertension in African-Americans remain unknown. We show that an A/G polymorphism at -217 in the promoter of the AGT gene plays a significant role in hypertension in African-Americans. The frequency of the -217A allele was increased significantly in African-American hypertensive subjects compared with normotensive controls. We also show that the nucleotide sequence of this region of the AGT gene promoter bound strongly to CAAT/enhancer-binding protein (C/EBP) family transcription factors when nucleoside A was present at -217. In addition, we show that reporter constructs containing the human AGT gene promoter with nucleoside A at -217 had increased basal transcriptional activity upon transient transfection in HepG2 cells compared with reporter constructs with nucleoside G at -217. Finally, we show that interleukin-6 treatment in the presence or absence of overexpressed C/EBPbeta increased the promoter activities of reporter constructs containing nucleoside A at -217 compared with reporter constructs containing nucleoside G at -217. Because the AGT gene is expressed primarily in liver and adipose tissue, and C/EBP family transcription factors play an important role in gene expression in these tissues, we propose that increased transcriptional activity of the -217A allele of the human AGT gene is associated with hypertension in African-Americans.
高血压在西方社会是一个严重的健康问题，对非裔美国人来说尤其如此。尽管先前的研究表明血管紧张素原（AGT）基因位点与人类原发性高血压有关，但非裔美国人高血压所涉及的分子机制仍不清楚。我们发现，AGT基因启动子-217位点的A/G多态性在非裔美国人的高血压中起重要作用。与血压正常的对照组相比，非裔美国高血压患者中-217A等位基因的频率显著增加。我们还发现，当-217位点存在核苷A时，AGT基因启动子该区域的核苷酸序列与CCAAT/增强子结合蛋白（C/EBP）家族转录因子紧密结合。此外，我们发现，与-217位点含有核苷G的报告基因构建体相比，-217位点含有核苷A的人类AGT基因启动子的报告基因构建体在瞬时转染HepG2细胞后基础转录活性增加。最后，我们发现，无论是否存在过表达的C/EBPβ，白细胞介素-6处理后，与-217位点含有核苷G的报告基因构建体相比，-217位点含有核苷A的报告基因构建体的启动子活性增加。由于AGT基因主要在肝脏和脂肪组织中表达，且C/EBP家族转录因子在这些组织的基因表达中起重要作用，我们认为人类AGT基因-217A等位基因转录活性增加与非裔美国人的高血压有关。
