Angiotensin II Signaling Through A Novel NF-kB Pathway

描述（由申请人提供）：血管紧张素II （Ang II）最近被认为是一种强大的促炎介质。虽然最初人们认为这种肽激素在调节血压方面起着关键作用，但现在人们知道它可以刺激许多组织的炎症途径，包括心脏和动脉。慢性暴露于Ang II可能导致多种与炎症状态升高相关的病理状况。也许最好的例子是在肌肉动脉中，Ang II通过刺激巨噬细胞和其他炎症细胞的募集，刺激平滑肌的增殖和激活，促进内皮功能障碍，从而促进动脉粥样硬化的发展。Ang II的主要受体（AT1R）是G蛋白偶联受体超家族的成员。在该受体的配体激活后，许多信号通路被启动，但NF-:B转录因子的刺激似乎是Ang II的大多数促炎作用的基础。重要的是，虽然蛋白激酶C （PKC）的激活是这种作用的先决条件，但对于连接Ang ii依赖性PKC激活与最终刺激NF-:B的中间步骤知之甚少。然而，我们的初步数据现在揭示了一种分子联系来解释这一现象。我们的数据表明，支架蛋白（CARMA3）将来自PKC的上游信号与下游效应蛋白（Bcl10和MALT1）整合在一起，共同刺激NF-:B激活的典型途径。我们拟通过以下4个目标来探索这一信号通路的生理生化意义：(1)确定AT1受体与CARMA3通讯的分子机制。(2)确定Ang II刺激后IKK复合物被激活的分子机制。(3)检测CARMA3、Bcl10和MALT1在内皮和血管平滑肌细胞中介导angii依赖性炎症反应中的作用。(4)通过对CARMA3基因敲除小鼠的分析，检验CARMA3在介导angii依赖性心血管病理中的作用。

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.