Therapeutic application of vascular diseases by novel angiotensin II receptor signal regulating molecule

血管紧张素II（angiotensin II，Ang II）的心血管作用主要是通过其1型受体（angiotensin II type 1，AT_1）介导的。我们利用酵母双杂交筛选系统克隆了一个新的AT_1受体相关蛋白（ATRAP）。为了探讨ATRAP在血管重塑中的作用，我们开发了小鼠ATRAP-cDNA转基因小鼠，并检查了聚乙烯袖套放置诱导的炎性血管损伤后的重塑。在ATRAP转基因（ATRAP-Tg）小鼠中，ATRAP mRNA在心脏、主动脉和股动脉中增加3至4倍。ATRAP-Tg小鼠的体重、收缩压、心率和心脏/体重比没有显著变化。然而，在ATRAP-Tg小鼠中，损伤动脉中的细胞增殖和新生内膜形成减弱。在<phox>ATRAP-Tg小鼠中，套囊放置后NADPH氧化酶活性和p22 α（一种NADH/NADPH氧化酶亚基）表达的增加也减弱。此外，在ATRAP-Tg小鼠中，袖带放置后细胞外信号调节激酶（ERK）、信号转导和转录激活因子（STAT）1和STAT 3的激活显著降低。此外，我们观察到，ATRAP-Tg小鼠的压力超负荷和血管紧张素II输注引起的心肌肥厚减弱，并且ATRAP-Tg小鼠对血管紧张素II的升压反应也降低。提示ATRAP作为负性调节因子在心血管重构中起重要作用。

The cardiovascular actions of angiotensin II (Ang II) are mainly mediated by the Ang II type 1 (AT_1) receptor. We cloned a novel AT_1 receptor-associated protein (ATRAP) using a yeast two-hybrid screening system. To explore the role of ATRAP in vascular remodeling, we developed transgenic mice for mouse ATRAP-cDNA, and examined remodeling after inflammatory vascular injury induced by polyethylene-cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3- to 4-fold in the heart, aorta and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate and heart-to-body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22^<phox>, an NADH/NADPH oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription (STAT)1, and STAT3 after cuff placement were significantly reduced in ATRAP-Tg mice. In addition, we observed that cardiac hypertrophy induced by pressure-overload and Ang II infusion was attenuated in ATRAP-Tg mice, and that pressor response to Ang II was also decreased in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in cardiovascular remodeling as a negative regulator.