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

新型血管紧张素II受体信号调节分子在血管疾病治疗中的应用

基本信息

批准号：
15390247
负责人：
HORIUCHI Masatsugu
金额：
$ 9.22万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

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.

血管紧张素II(Ang II)的心血管作用主要由血管紧张素II 1型(AT_1)受体介导。我们利用酵母双杂交筛选系统克隆了一个新的AT1受体相关蛋白(ATRAP)。为了探讨ATRAP在血管重塑中的作用，我们建立了小鼠ATRAP-cDNA转基因小鼠，并检测了聚乙烯袖带置入诱导的炎性血管损伤后的重塑。在ATRAP转基因小鼠(ATRAP-TG)中，ATRAP mRNA在心脏、主动脉和股动脉中增加了3-4倍。ATRAP-TG小鼠在体重、收缩压、心率和心体比方面没有明显变化。然而，ATRAP-TG组小鼠损伤动脉的细胞增殖和新生内膜形成减少。ATRAP-TG小鼠放置袖带后NADPH氧化酶活性的升高和NADH/NADPH氧化酶亚基p22^&lt；Phox&gt；的表达也减弱。此外，ATRAP-TG小鼠放置袖带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STAT3的激活显著减少。此外，我们还观察到压力超负荷和血管紧张素Ⅱ输注引起的心肌肥厚在ATRAP-TG小鼠中被减弱，在ATRAP-TG小鼠中对血管紧张素II的升压反应也降低。这些结果提示，ATRAP作为一种负性调节因子在心血管重构中起着重要作用。