Identification of Amino Acid Residues in Angiotensin II Type 1 Receptor Sensing Mechanical Stretch and Function in Cardiomyocyte Hypertrophy
Identification of Amino Acid Residues in Angiotensin II Type 1 Receptor Sensing Mechanical Stretch and Function in Cardiomyocyte Hypertrophy
复制标题
血管紧张素 II 1 型受体中氨基酸残基的鉴定，感受心肌细胞肥大中的机械拉伸和功能
DOI：
10.1159/000430337
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发表时间：
2015-01-01
影响因子：
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通讯作者：
Zou, Yunzeng
中科院分区：
文献类型：
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作者：
Jiang, Guoliang;Gong, Hui;Zou, Yunzeng
背景/目标：在心肌肥厚的发生发展过程中，机械应力可激活血管紧张素Ⅱ（AngII）1型受体（AT（1）R），而不涉及AngII。我们的目的是确定感应网站AT（1）R激活的机械拉伸。研究方法：我们构建了AT（1）R（K199 Q）、AT（1）R（L212 F）、AT（1）R（Q257 A）和AT（1）R（C289 A））的定点突变体，分别转染COS 7细胞和血管紧张素原敲除心肌细胞（ATG（-/-）-CMs），观察机械牵张后细胞的变化。结果如下：在AT（1）R（K199 Q）-或AT（1）R（Q257 A）-COS 7细胞或-ATG（-/-）-CM中，AT（1）R（WT）-COS 7或-ATG（-/-）-CM中AngII诱导的ERK和Jak 2磷酸化以及G α q11的再分布显著降低，而机械牵张诱导的这些作用在COS 7细胞或表达AT（1）R（L212 F）的ATG（-/-）-CM中受到极大抑制，AT（1）R（Q257 A）或AT（1）R（C289 A）与这些表达AT（1）R（WT）的细胞相比。AngII诱导的肥大反应在AT（1）R（K199 Q）-ATG（-/-）-CM或AT（1）R（Q257 A）-ATG（-/-）-CM中，AT（1）R（WT）-ATG（-/-）-CM中的肥大基因表达和横截面积的增加被部分消除，而在过表达AT（1）R（L212 F）的ATG（-/-）-CM中，AT（1）R（Q257A）或AT（1）R（C289A）。结论：这些结果表明，AT（1）R中Leu 212、GIn 257和Cys 289不仅是机械牵张的敏感位点，而且是机械牵张诱导的受体激活和心肌细胞肥大的功能性氨基酸残基。版权所有（C）2015 S. Karger AG，巴塞尔
Background/Aims: Angiotensin II (AngII) type 1 receptor (AT(1)R) could be activated by mechanical stress without the involvement of AngII during the development of cardiac hypertrophy. We aimed to identify sensing sites of AT(1)R for activation by mechanical stretch. Methods: We constructed several site-directed mutations of AT(1)R (AT(1)R(K199Q), AT(1)R(L212F), AT(1)R(Q257A) and AT(1)R(C289A)), transfected them respectively into COS7 cells or angiotensinogen knockout cardiomyocytes (ATG(-/-)-CMs), and observed cellular events after mechanical stretch. Results: AngII-induced phosphorylation of ERKs and Jak2, and redistribution of G alpha q11 in AT(1)R(WT)-COS7 or -ATG(-/-)-CMs were dramatically decreased in AT(1)R(K199Q)- or AT(1)R(Q257A)- COS7 cells or -ATG(-/-)-CMs, while those effects induced by mechanical stretch were greatly suppressed in COS7 cells or ATG(-/-)-CMs expressing AT(1)R(L212F), AT(1)R(Q257A) or AT(1)R(C289A) compared with these cells expressing AT(1)R(WT). AngII-induced hypertrophic responses (the increase in hypertrophic genes expression and cross-sectional area) in AT(1)R(WT)-ATG(-/-)-CMs were partly abolished in AT(1)R(K199Q)-ATG(-/-)-CMs or AT(1)R(Q257A)-ATG(-/-)-CMs, while these responses induced by mechanical stretch were greatly inhibited in ATG(-/-)-CMs overexpressing AT(1)R (L212F), AT(1)R(Q257A) or AT(1)R(C289A). Conclusion: These results indicated that Leu212, GIn257 and Cys289 in AT(1)R are not only sensing sites for mechanical stretch but also functional amino residues for activation of the receptor and cardiomyocytes hypertrophy induced by mechanical stretch. Copyright (C) 2015 S. Karger AG, Basel