ADAM activation by Angiotensin II

描述(申请人提供)：血管紧张素II(AngII)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，血管紧张素转换酶通过诱导血管重塑来促进这些疾病，血管重塑涉及血管平滑肌细胞(VSMCs)的肥大、增殖和迁移。在我们过去的资金支持期间，我们已经证明了ErbB家族受体EGF受体(EGFR)的反式激活对于血管紧张素转换酶II的VSMC肥大和迁移是必不可少的。此外，成熟的HB-EGF的产生/脱落通过激活金属蛋白酶ADAM17，似乎是血管紧张素转换酶诱导的血管内皮细胞EGFR反式激活不可或缺的信号事件。此外，我们过去和初步的结果有力地表明，通过AT1受体在ADAM17激活的上游存在GQ衍生的第二信使。然而，Angii促进VSMC中ADAM17活化的确切信号转导机制(S)及其在体内介导血管重构中的作用尚不清楚，因此我们的研究团队必须进行探索。基于我们过去的发现和我们最近的初步结果，我们建立了关于上述机制的有吸引力的假设(S)。因此，这一更新应用的具体目的是探索ADAM17在VSMCs中激活的新的信号转导概念，并证明体内激活的功能和“翻译”意义。目的1.验证酪氨酸磷酸化和随后与新发现的ADAM17结合蛋白(S)相互作用是血管平滑肌细胞AT1受体激活ADAM17所必需的假说。目的2.验证富含胆固醇的膜微区为血管紧张素转换酶激活ADAM17及由此产生的HB-EGF脱落提供不可或缺的环境的假说。目的3.验证上述机制激活血管平滑肌ADAM17是预防体内血管重塑干预的关键靶点的假说。我们过去取得的重大成就，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紧张素转换酶刺激的血管重塑的关键分子机制，也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细胞中血管紧张素II功能的新信号机制，这将潜在地帮助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.