ErbB Activation via a Metalloprotease by Angiotensin II

描述（由申请人提供）：血管紧张素II（AngII）及其G蛋白偶联的AT 1受体在介导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起关键作用。普遍认为AngII通过诱导涉及血管平滑肌细胞（VSMC）的肥大、增生和迁移的血管重塑来促进这些疾病。已经显示ErbB家族受体EGF受体（ErbB 1/EGFR）的反式激活对于血管平滑肌细胞肥大和AngII的迁移是必需的。然而，AngII反式激活EGFR/ErbB 1的精确信号转导机制以及AngII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反式激活。因此，我们的中心假设是AT 1衍生的第二信使促进ADAM金属蛋白酶的激活，导致ErbB受体的反式激活和随后的重塑VSMC。我们过去和现在的初步研究强烈支持我们的中心假设。因此，本申请的具体目的被设计为鉴定VSMC中AngII激活金属蛋白酶/ErbB的信号传导机制和功能意义。研究的具体目标是：目标1。验证G蛋白和第二信使通过AT 1受体参与金属蛋白酶激活的假设。目标二。验证ADAM金属蛋白酶通过涉及ADAM胞质尾区和胞质酪氨酸激酶的机制激活的假设。目标3.为了检验几种ErbB配体由AngII产生并介导AngII诱导的ErbB受体反式激活的假设。目标4。为了验证ErbB受体的反式激活是AngII诱导的VSMCs肥大和迁移所必需的假设。这些特定目标的实现不仅使我们更好地理解AngII刺激血管重塑的关键分子机制，而且还将有助于开发针对心血管疾病的新治疗策略。

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.