Angiotensin II type(1a) receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload
Angiotensin II type(1a) receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload
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DOI：
10.1073/pnas.94.14.7543
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发表时间：
1997-07-08
影响因子：
11.1
通讯作者：
Markham, BE
中科院分区：
文献类型：
--
作者：
Herzig, TC;Jobe, SM;Markham, BE
哺乳动物心肌肥大部分由血管紧张素II通过血管紧张素II型（1a）受体（AT（1a）R）依赖性机制介导。为了了解AT（1a）Rs的水平在这种病理状态下是如何改变的，我们研究了注射AT（1a）R启动子-荧光素酶报告基因在主动脉缩窄引起急性压力超负荷的成年大鼠心脏中的表达。该模型通过证明缩窄增加α-骨架肌动蛋白启动子的表达1.7倍而α-肌球蛋白重链启动子不受影响来验证。与对照组相比，压力超负荷使AT（1a）R启动子的表达增加了1.6倍。在对照动物中，将突变引入AP-1或加塔转录因子的共有结合位点可消除压力超负荷反应，但对AT（1a）R启动子活性无影响。在缩窄心脏的提取物中，检测到Fos-JunB-JunD复合物和加塔-4分别与AP-1和加塔位点相关，而对照心脏则没有。这些结果证实AT（1a）R启动子在心肌中是活性的，其表达是由压力超负荷诱导的，并表明这种反应部分是由压力超负荷介导的。通过AP-1和加塔-4转录因子之间的功能性相互作用。
Hypertrophy of mammalian cardiac muscle is mediated, in part, by angiotensin II through an angiotensin II type(1a) receptor (AT(1a)R)-dependent mechanism. To understand how the level of AT(1a)Rs is altered in this pathological state, we studied the expression of an injected AT(1a)R promoter-luciferase reporter gene in adult rat hearts subjected to an acute pressure overload by aortic coarctation. This model was validated by demonstrating that coarctation increased expression of the alpha-skeletal actin promoter 1.7-fold whereas the alpha-myosin heavy chain promoter was unaffected. Pressure overload increased expression from the AT(1a)R promoter by 1.6-fold compared with controls. Mutations introduced into consensus binding sites for AP-1 or GATA transcription factors abolished the pressure overload response but had no effect on AT(1a)R promoter activity in control animals. In extracts from coarcted hearts, but not from control hearts, a Fos-JunB-JunD complex and GATA-4 were detected in association with the AP-1 and GATA sites, respectively, These results establish that the AT(1a)R promoter is active in cardiac muscle and its expression is induced by pressure overload, and suggest that this response is mediated, in part, by a functional interaction between AP-1 and GATA-4 transcription factors.