Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney, 1-clip hypertension
Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney, 1-clip hypertension
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DOI：
10.1161/01.hyp.0000164571.77710.19
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发表时间：
2005-05-01
期刊：
影响因子：
8.3
通讯作者：
Okamoto, H
中科院分区：
文献类型：
--
作者：
Hiyoshi, H;Yayama, K;Okamoto, H
为探讨血管紧张素Ⅱ（AngII）2型受体（AT（2））在肾血管性高血压中的作用，我们观察了2肾1夹（2K 1C）高血压小鼠胸主动脉AT（2）受体和内皮型一氧化氮合酶（eNOS）的表达。血管夹闭后14天AT（2）受体mRNA水平升高，而AT（1）和缓激肽B-2受体mRNA水平无明显变化。血管紧张素Ⅱ（>0.1 μ mol/L）引起的收缩反应在夹闭后14天被减弱，AT（2）受体拮抗剂（PD 123319）和B-2受体拮抗剂（艾替班特）使其恢复到假手术小鼠的收缩反应。在第14天，2K 1C小鼠的总eNOS、Ser（1177）处的磷酸化eNOS（p-eNOS）、总Akt和Ser（473）处的磷酸化Akt（p-Akt）的主动脉水平增加，而在第42天仅eNOS水平增加。与假手术小鼠相比，2K 1C小鼠在第14天的主动脉cGMP水平大约高20倍。在夹闭后14天切除动脉瘤前给予尼卡地平4天不仅降低了血压，而且还将主动脉eNOS、p-eNOS、Akt、p-Akt和cGMP水平降低至假手术水平，而给予2K 1C小鼠PD 123319或艾替班特将p-eNOS和cGMP降低至假手术水平，而不影响血压和eNOS、Akt和p-Akt水平。这些结果表明，在2K 1C高血压过程中，通过激活AT（2）受体，eNOS磷酸化增加，血管NO产生增加。
To evaluate the role of vascular angiotensin II (Ang II) type 2 (AT(2)) receptor in renovascular hypertension, we investigated expressions of AT(2) receptor and endothelial nitric oxide synthase (eNOS) in thoracic aortas of mice with 2-kidney, 1-clip (2K1C) hypertension. The mRNA levels of AT(2) receptor in aortas, but not those of AT(1) and bradykinin B-2 receptors, increased 14 days but not 42 days after clipping. The contractile response to Ang II (>0.1 mu mol/L) was attenuated in aortic rings excised 14 days after clipping and was restored to that of rings from sham mice by antagonists of AT(2) receptor (PD123319) and B-2 receptor ( icatibant). The aortic levels of total eNOS, phosphorylated eNOS at Ser(1177) (p-eNOS), total Akt, and phosphorylated Akt at Ser(473) (p-Akt) were increased in 2K1C mice on day 14, whereas only eNOS levels were increased on day 42. The aortic cGMP levels were approximate to 20-fold greater in 2K1C mice on day 14 compared with sham mice. Administration of nicardipine for 4 days before the excision of aortas 14 days after clipping not only reduced blood pressure but also decreased the aortic levels of eNOS, p-eNOS, Akt, p-Akt, and cGMP to sham levels, whereas the administration of PD123319 or icatibant to 2K1C mice decreased p-eNOS and cGMP to sham levels without affecting blood pressure and the levels of eNOS, Akt and p-Akt. These results suggest that vascular NO production is enhanced by increased eNOS phosphorylation via the activation of AT(2) receptors in the course of 2K1C hypertension.