Angiotensin II Signaling Through A Novel NF-kB Pathway

说明(申请人提供)：血管紧张素II(Ang II)最近被认为是一种强有力的促炎介质。虽然最初被认为在调节血压中起着关键作用，但现在已知这种多肽激素可以刺激许多组织中的炎症途径，包括心脏和动脉。慢性暴露于血管紧张素转换酶II可能会导致与高度炎症状态相关的各种病理情况。也许最好的例子是肌性动脉，Ang II通过刺激巨噬细胞和其他炎性细胞的募集，刺激平滑肌的增殖和激活，以及促进内皮功能障碍，促进动脉粥样硬化的发展。血管紧张素Ⅱ的主要受体(AT1R)是G蛋白偶联受体超家族的成员。该受体的配体激活后启动了许多信号通路，但核因子-：B转录因子的刺激似乎是血管紧张素Ⅱ的大部分促炎作用的基础。重要的是，尽管蛋白激酶C(PKC)的激活是这一效应的先决条件，但对连接依赖于血管紧张素Ⅱ的PKC激活与最终刺激核因子-B的中间步骤知之甚少。然而，我们的初步数据现在揭示了解释这一现象的分子联系。我们的数据表明，一个支架蛋白(CARMA3)用于将来自PKC的上游信号与下游的效应蛋白BCL10和MALT1整合，这两个蛋白共同刺激了一条典型的NF-：B激活途径。我们建议通过四个目的来探讨这一信号通路的生理和生化意义：(1)确定AT1受体与CARMA3通讯的分子机制。(2)明确血管紧张素Ⅱ刺激后IKK复合体被激活的分子机制。(3)检测CARMA3、Bcl10和MALT1在介导血管内皮细胞和血管平滑肌细胞Ang II依赖的炎症反应中的作用。(4)通过对CARMA3基因敲除小鼠的分析，验证CARMA3在介导血管紧张素Ⅱ依赖性心血管病变中的作用。 项目相关性：血管紧张素II依赖性高血压是心血管疾病的一个主要因素。了解Ang II激活的促炎细胞内信号事件对于我们最终控制Ang II的不良影响至关重要。对这些信号事件的详细了解将允许合理设计针对这些事件的药理学药物。

DESCRIPTION (provided by applicant): Angiotensin II (Ang II) has recently become recognized as a powerful pro-inflammatory mediator. Although originally appreciated for its critical role in regulating blood pressure, this peptide hormone is now known to stimulate inflammatory pathways in numerous tissues, including the heart and arteries. Chronic exposure to Ang II may then lead to a variety of pathologic conditions related to a heightened inflammatory state. Perhaps the best example is in muscular arteries, where Ang II contributes to the development of atherosclerosis by stimulating the recruitment of macrophages and other inflammatory cells, stimulating smooth muscle proliferation and activation, and promoting endothelial dysfunction. The principal receptor for Ang II (AT1R) is a member of the G protein-coupled receptor superfamily. Numerous signaling pathways are initiated following ligand activation of this receptor, but stimulation of the NF-:B transcription factor appears to underlie most of the pro-inflammatory effects of Ang II. Importantly, while activation of protein kinase C (PKC) is a prerequisite for this effect, very little is known about the intermediate steps that bridge Ang II-dependent PKC activation with the eventual stimulation of NF-:B. However, our preliminary data now reveal a molecular link to explain this phenomenon. Our data indicate that a scaffolding protein (CARMA3) serves to integrate an upstream signal from PKC with the downstream effector proteins, Bcl10 and MALT1, which together stimulate a canonical pathway for NF-:B activation. We propose to explore the physiologic and biochemical implications of this signaling pathway through 4 aims: (1) Identify the molecular mechanism by which the AT1 receptor communicates with CARMA3. (2) Identify the molecular mechanism by which the IKK complex is activated following Ang II stimulation. (3) Test the role of CARMA3, Bcl10, and MALT1 in mediating Ang II-dependent inflammatory responses in endothelial and vascular smooth muscle cells. (4) Test the role of CARMA3 in mediating Ang II-dependent cardiovascular pathology, through analysis of CARMA3 knockout mice. Project Relevance: Ang II-dependent hypertension is a major contributing factor to cardiovascular disease. Understanding the pro-inflammatory, intracellular signaling events activated by Ang II is critical for our ability to eventually control the adverse effects of Ang II. Detailed knowledge of these signaling events will allow for the rational design of pharmacologic agents to target these events.