ADAM activation 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（VSMCs）的肥大、增殖和迁移的血管重塑来促进这些疾病。在我们过去的资助期间，我们已经表明，ErbB家族受体，EGF受体（EGFR）的反式激活，是血管紧张素II的VSMC肥大和迁移所必需的。此外，成熟的HB-EGF生产/脱落通过激活的金属蛋白酶，ADAM 17，似乎是一个不可或缺的信号事件血管紧张素II诱导的EGFR在血管平滑肌细胞的反式激活。此外，我们过去和初步的结果强烈表明存在Gq衍生的第二信使，其通过AT 1受体在ADAM 17激活的上游。然而，AngII促进VSMCs中ADAM 17活化的确切信号转导机制及其在体内介导血管重塑中的影响尚不清楚，因此对于我们的研究团队来说至关重要。基于我们过去的发现以及我们最近的初步结果，我们对上述机制建立了有吸引力的假设。因此，本更新申请的具体目的旨在探索VSMC中ADAM 17激活的新信号转导概念，并证明体内激活的功能和“翻译”意义。目标1。检验酪氨酸磷酸化和随后与新鉴定的ADAM 17结合蛋白的相互作用对VSMC中AT 1受体激活ADAM 17至关重要的假设。目标2.为了检验富含胆固醇的膜微区为血管生成素II激活ADAM 17和由此产生的HB-EGF脱落提供不可或缺的环境的假设。目标3.验证通过上述机制激活血管平滑肌中的ADAM 17是预防体内血管重塑的关键干预靶点的假设。我们过去取得的巨大成就，加上积累的初步成果和我们研究团队的重大能力，有力地证明了整个提案的可行性。这些特定目标的成功实现不仅将为我们提供血管生成素II刺激血管重塑的关键分子机制，而且还将有助于开发新的心血管疾病治疗策略。公共卫生相关性：该项目旨在确定血管紧张素II在血管细胞中功能的新信号机制，这将有助于我们开发更好的心血管疾病治疗方法。

DESCRIPTION (provided by applicant): Angiotensin II (AngII) 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 AngII promotes these diseases by inducing vascular remodeling that involves hypertrophy, proliferation, and migration of vascular smooth muscle cells (VSMCs). During our past funding period, we have shown that transactivation of an ErbB family receptor, EGF receptor (EGFR), is essential for VSMC hypertrophy and migration by AngII. Also, mature HB-EGF production/shedding through activation of a metalloprotease, ADAM17, appears to be an indispensable signaling event for the AngII-induced EGFR transactivation in VSMCs. Moreover, our past and preliminary results strongly suggest existence of Gq-derived 2nd messengers that are upstream of the ADAM17 activation via the AT1 receptor. However, the exact signal transduction mechanism(s) by which AngII promotes ADAM17 activation in VSMCs as well as its impact in mediating vascular remodeling in vivo remains unclear, and thus is essential for our research team to explore. Based on our past findings together with our recent preliminary results, we have built attractive hypotheses on the above- mentioned mechanism(s). Therefore, the specific aims of this renewal application are designed to explore the novel signal transduction concepts of the ADAM17 activation in VSMCs as well as to prove the functional and "translational" significance of the activation in vivo. Aim 1. To test the hypothesis that tyrosine phosphorylation and subsequent interaction with newly-identified ADAM17 binding protein(s) are essential for ADAM17 activation by the AT1 receptor in VSMCs. Aim 2. To test the hypothesis that the cholesterol-rich membrane micro-domains provide an indispensable environment for ADAM17 activation by AngII and the resultant shedding of HB-EGF. Aim 3. To test the hypothesis that activation of ADAM17 in vascular smooth muscle by the above mechanism is the critical target of intervention for prevention of vascular remodeling in vivo. Our past substantial accomplishments together with accumulating preliminary results and the significant capabilities of our research team strongly warrant the feasibilities of the entire proposal. Successful accomplishment of these specific aims will not only provide us with the critical molecular mechanisms underlying vascular remodeling stimulated by AngII, but will also contribute to the development of novel treatment strategies toward cardiovascular diseases. PUBLIC HEALTH RELEVANCE: This project was designed to identify novel signaling mechanisms regarding the function of angiotensin II in vascular cells, which will potentially help us to develop better treatments toward cardiovascular diseases.