ErbB Activation via a Metalloprotease by Angiotensin II

描述(申请人提供)：血管紧张素II(Ang11)及其G蛋白偶联AT1受体在调节心血管疾病，如高血压、动脉粥样硬化和血管损伤后再狭窄中发挥关键作用。人们普遍认为，Ang11通过诱导血管重塑而促进这些疾病，血管重塑涉及血管平滑肌细胞(VSMCs)的肥大、增殖和迁移。已有研究表明，ErbB家族受体EGF受体(ErbB1/EGFR)的反式激活在血管紧张素Ⅱ诱导的VSMC肥大和迁移过程中起重要作用。然而，Ang11反式激活EGFR/ErbB1的确切信号转导机制以及其他ERBB是否也是Angll功能所必需的仍不清楚。最近的研究表明，依赖于金属蛋白酶的ErbB家族配体的产生参与了反式激活。因此，我们的中心假设是AT1衍生的第二信使促进了ADAM金属蛋白酶的激活，导致ErbB受体的反式激活和随后的VSMC重塑。我们过去和现在的初步研究有力地支持了我们的中心假设。因此，本研究旨在明确血管紧张素转换酶11激活血管内皮细胞金属蛋白酶/ErbB的信号转导机制(S)及其功能意义。本研究的具体目的是：1.验证G蛋白和第二信使通过AT1受体参与金属蛋白酶激活的假说。目的2.验证ADAM金属蛋白水解酶被激活的假说，该机制涉及ADAM胞质尾巴和胞浆酪氨酸激酶。目的3.验证Ang11产生多个ErbB配体的假说，并介导Ang11诱导的ErbB受体反式激活。目的4.验证血管紧张素转换酶11诱导VSMCs肥大和迁移需要ErbB受体反式激活的假说。这些特定目标的实现不仅将使我们更好地了解血管紧张素转换酶11刺激血管重塑的关键分子机制，而且将有助于开发新的心血管疾病治疗策略。

DESCRIPTION (provided by applicant): Angiotensin II (Angll) and its G protein-coupled AT1 receptor play critical roles in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. It is widely believed that Angll promotes these diseases by inducing vascular remodeling that involves hypertrophy, hyperplasia, and migration of vascular smooth muscle cells (VSMCs). It has been shown that transactivation of an ErbB family receptor, EGF receptor (ErbB1/EGFR), is essential for VSMC hypertrophy and migration by Angll. However, the precise signal transduction mechanism by which Angll transactivates EGFR/ErbB1 and whether other ErbBs are also required for Angll function remains unclear. Recent studies suggest an involvement of a metalloprotease-dependent ErbB family ligand production in the transactivation. Thus, our central hypothesis is that an AT1-derived second messenger promotes activation of ADAM metalloprotease leading to ErbB receptors transactivation and subsequent remodeling in VSMCs. Our past and current preliminary studies strongly support our central hypothesis. Therefore, the specific aims of this application are designed to identify the signaling mechanism(s) and functional significance of the metalloprotease/ErbB activation by Angll in VSMCs. The specific aims of the study are: Aim 1. To test the hypothesis that G protein and second messengers are involved in metalloprotease activation through the AT1 receptor. Aim 2. To test the hypothesis that ADAM metalloprotease is activated by a mechanism involving ADAM cytoplasmic tail and a cytosolic tyrosine kinase. Aim 3. To test the hypothesis that several ErbB ligands are produced by Angll and mediate Angll-induced transactivation of ErbB receptors. Aim 4. To test the hypothesis that the transactivation of ErbB receptors is required for hypertrophy and migration of VSMCs induced by Angll. Accomplishment of these specific aims will not only give us a better understanding of the critical molecular mechanism underlying vascular remodeling stimulated by Angll but will also contribute to development of novel treatment strategies toward cardiovascular diseases.