ADAM activation by Angiotensin II

血管紧张素II(AngII)及其G蛋白偶联AT1受体在心血管调节中的重要作用 高血压、动脉粥样硬化和血管损伤后再狭窄等疾病。人们普遍认为 血管紧张素转换酶通过诱导血管重塑促进这些疾病，血管重塑涉及肥大、增殖和 血管平滑肌细胞(VSMCs)迁移。在我们过去的资助期内，我们已经表明 ErbB家族受体EGF受体(EGFR)的反式激活对VSMC肥大和 安吉的移民。此外，成熟的HB-EGF通过激活金属蛋白酶产生/脱落， ADAM17似乎是血管紧张素转换酶Ⅱ诱导的血管内皮细胞生长因子受体反式激活不可或缺的信号事件。 VSMCS。此外，我们过去和初步的结果有力地表明了Gq衍生的第二信使的存在。 它们是通过AT1受体激活ADAM17的上游。然而，确切的信号转导 血管紧张素转换酶促进血管内皮细胞ADAM17活化的机制(S)及其在调节中的作用 体内的血管重塑尚不清楚，因此对我们的研究团队来说是必不可少的。基于 我们过去的研究结果，连同我们最近的初步研究结果，都建立在上述有吸引力的假设之上- 提到机制(S)。因此，此次续期申请的具体目的旨在探索 VSMC中ADAM17激活的新信号转导概念以及证明其功能和 体内激活的“翻译”意义。 目的1.验证酪氨酸磷酸化及其与新发现的 ADAM17结合蛋白(S)是血管平滑肌细胞AT1受体激活ADAM17所必需的。 目的2.验证富含胆固醇的膜微域提供不可或缺的 血管紧张素转换酶激活ADAM17的环境以及由此产生的HB-EGF脱落。 目的3.通过上述机制验证ADAM17在血管平滑肌激活的假说 是预防体内血管重塑的重要干预靶点。 我们过去取得的实质性成就以及积累的初步成果和重大意义 我们研究团队的能力有力地保证了整个提案的可行性。成功 这些特定目标的实现不仅将为我们提供关键的分子机制 底层血管重塑受血管紧张素Ⅱ刺激，但也将有助于小说的发展 心血管疾病的治疗策略。

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.