Attenuation of angiotensin II-induced hypertension and cardiac hypertrophy in transgenic mice overexpressing a type 1 receptor mutant.
Attenuation of angiotensin II-induced hypertension and cardiac hypertrophy in transgenic mice overexpressing a type 1 receptor mutant.
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DOI：
10.1038/ajh.2009.181
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发表时间：
2009-12
影响因子：
3.2
通讯作者：
Yu, Jun
中科院分区：
文献类型：
--
作者：
Ahmad, Saad;Cesana, Francesca;Lamperti, Edward;Gavras, Haralambos;Yu, Jun
血管紧张素 II (AngII) 1 型受体 (AT1) 通过激活各种信号通路来调节心血管功能。本研究的目的是评估突变 AT1 受体对 AngII 响应血压和心脏肥大以及 RhoA 和 Akt 的 AngII 激活改变的影响。使用普遍存在的表达载体 pCAGGS 构建了突变 AT1 受体并在 FVB 小鼠中过表达。将转基因小鼠的表型和信号转导与野生型（WT）小鼠进行比较。转基因小鼠表现出与 WT 小鼠相似的基线表型，但在第 3、4、7 和 14 天测量，它们对连续 AngII 输注的反应显着降低，到第 14 天相差 20 mmHg。WT 小鼠的心脏与总体重的比例也显着更大，与转基因小鼠相比，WT 小鼠的心脏重量为总体重的 0.441 ± 0.008%。 0.416±0.008%。从这些转基因小鼠中分离出的主动脉内皮细胞显示出改变的信号传导谱，例如响应 AngII 的 Akt 和 RhoA 激活减弱。相反，Gαq 偶联和 ERK/JNK 激活没有改变。在 WT 受体存在的情况下，AT1 突变受体的表达可以有效调节 AngII 影响的信号传导。此外，AngII 消除 Akt 和 RhoA 激活可显着降低但不会消除其高血压作用。
The angiotensin II (AngII) type 1 receptor (AT1) regulates cardiovascular function by activating various signal pathways. The purpose of this study was to evaluate the effects of a mutant AT1 receptor on AngII responding blood pressure and cardiac hypertrophy in conjunction with altered AngII activation of RhoA and Akt. A mutant AT1 receptor was constructed and overexpressed in FVB mice using a ubiquitous-expression vector pCAGGS. The phenotype and signal transduction of the transgenic mice were compared with the wild type (WT) mice. The transgenic mice showed a similar baseline phenotype as WT mice, but their blood pressure in response to continuous AngII infusion was significantly lower, as measured on day 3, 4, 7 and 14, with a difference of 20 mmHg by day 14. There was also a significantly larger heart to total body weight ratio in the WT mice, whose heart weight was 0.441 ± 0.008 % of total body weight compared to the transgenic mice at 0.416 ± 0.008 %. Aortic endothelial cells isolated from these transgenic mice displayed an altered signaling profile, such as diminished activation of Akt and RhoA in response to AngII. In contrast, Gαq coupling and ERK/JNK activation did not change. The expression of an AT1 mutant receptor in the presence of WT receptor can effectively modulate AngII effected signaling. Furthermore, the elimination of Akt and RhoA activation by AngII significantly reduces but does not eliminate its hypertensive effect.
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