ErbB Activation via a Metalloprotease by Angiotensin II

描述（申请人提供）：血管紧张素II （Angll）及其G蛋白偶联AT1受体在介导高血压、动脉粥样硬化、血管损伤后再狭窄等心血管疾病中起关键作用。人们普遍认为，Angll通过诱导血管重构，包括血管平滑肌细胞（VSMCs）的肥大、增生和迁移来促进这些疾病。研究表明，ErbB家族受体EGF受体（ErbB1/EGFR）的反激活对VSMC的肥大和Angll的迁移至关重要。然而，Angll激活EGFR/ErbB1的确切信号转导机制以及Angll功能是否也需要其他erbb仍不清楚。最近的研究表明，金属蛋白酶依赖的ErbB家族配体的生产参与了交易活化。因此，我们的中心假设是at1衍生的第二信使促进ADAM金属蛋白酶的激活，导致VSMCs中ErbB受体的反激活和随后的重塑。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，本应用的具体目的是确定Angll在vsmc中金属蛋白酶/ErbB活化的信号机制和功能意义。本研究的具体目的是：目的1。为了验证G蛋白和第二信使通过AT1受体参与金属蛋白酶激活的假设。目标2。为了验证ADAM金属蛋白酶是由一个涉及ADAM细胞质尾部和胞质酪氨酸激酶的机制激活的假设。目标3。为了验证几种ErbB配体由Angll产生并介导Angll诱导的ErbB受体的转激活的假设。目标4。为了验证Angll诱导的VSMCs肥大和迁移需要ErbB受体的反激活的假设。这些特定目标的实现不仅将使我们更好地理解Angll刺激血管重构的关键分子机制，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.