Overexpression of angiotensin AT(1) receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block
Overexpression of angiotensin AT(1) receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block
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DOI：
10.1073/pnas.94.12.6391
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发表时间：
1997-06-10
影响因子：
11.1
通讯作者：
Dzau, VJ
中科院分区：
文献类型：
--
作者：
Hein, L;Stevens, ME;Dzau, VJ
以往的研究表明，血管紧张素II（Ang II）调节心脏的收缩力、节律、代谢和结构，但尚不清楚心脏效应是由于Ang II对心肌的直接作用还是由于Ang II的血流动力学作用介导的继发性效应。我们用α-肌球蛋白重链（α MHC）启动子，以产生在心肌细胞中选择性过表达血管紧张素II 1型（AT（1a））受体的转基因小鼠，通过放射性配体结合研究和逆转录-PCR证实了转基因后代中转基因表达的特异性。后代在出生时表现出巨大的心房增大伴肌细胞增生，出现显著的心动过缓伴心脏传导阻滞，因此，在体内心肌细胞中AT（1）受体信号的直接激活足以诱导心肌细胞生长并改变电传导。
Previous studies have suggested that angiotensin II (Ang II) modulates cardiac contractility, rhythm, metabolism, and structure, However, it is unclear whether the cardiac effects are due to direct actions of Ang II on the myocardium or if they are due to secondary effects mediated through the hemodynamic actions of Ang II, In this study, we used the alpha-myosin heavy chain (alpha MHC) promoter to generate transgenic mice overexpressing angiotensin II type 1 (AT(1a)) receptor selectively in cardiac myocytes, The specificity of transgene expression in the transgenic offspring was confirmed by radioligand binding studies and reverse transcription-PCR, The offspring displayed massive atrial enlargement with myocyte hyperplasia at birth, developed significant bradycardia with heart block, and died within the first weeks after birth, Thus, direct activation of AT(1) receptor signaling in cardiac myocytes in vivo is sufficient to induce cardiac myocyte growth and alter electrical conduction.