The role of CB2 receptors in oxLDL-induced apopotosis and atherogenesis

描述(申请人提供)：我们实验室一直在进行研究，以确定自然产生的氧化甾醇诱导各种血管细胞，特别是巨噬细胞凋亡的信号转导途径。我们发表的结果表明，这些氧甾醇的花生四烯基酯是细胞凋亡反应的第二信使。为了了解这些化合物诱导细胞凋亡的机制，我们已经开始检验花生四烯氧基甾醇通过大麻素2(CB2)受体产生这些效应的假设。在这项提案中提出的初步发现，在CB2信号缺陷的各种细胞模型中，氧固醇治疗的凋亡反应丧失，与这一假说一致。我们实验室的其他研究表明，氧化甾醇诱导巨噬细胞凋亡的重要生理后果之一是作为一种保护机制来对抗动脉粥样硬化。这增加了巨噬细胞中的CB2信号可能作为抗动脉粥样硬化作用的信号通路之一的可能性。为了验证花生四烯氧基甾醇信号转导巨噬细胞凋亡的机制和生理意义，我们提出了以下具体目标：1)确定花生四烯氧基甾醇是否能诱导巨噬细胞凋亡。2)确定花生四烯氧基甾醇是否能与大麻素受体结合并调节其活性。3)研究CB2受体在小鼠动脉粥样硬化形成过程中的作用。这项研究的结果可能会扩大我们对大麻素信号机制和巨噬细胞凋亡调控机制之间的联系的理解。它们还可能为开发治疗动脉粥样硬化的新药提供新的药理上可利用的靶点。

DESCRIPTION (provided by applicant): Our laboratory has been engaged in studies to determine the signal transduction pathway by which naturally occurring oxysterols induce apoptosis in various vascular cells, particularly macrophages. Our published results indicate that arachidonyl esters of these oxysterols are second messengers of the apoptotic response. In an effort to understand the mechanism by which these compounds entrain apoptosis we have begun to examine the hypothesis that arachidonyl oxysterols produce these effects via the cannabinoid 2 (CB2) receptor. Preliminary findings, presented in this proposal, of a loss of the apoptotic response to oxysterol treatment in various cell models defective in CB2 signaling are consistent with this hypothesis. Other studies from our laboratory indicate that one of the physiologically significant consequences of macrophage apoptosis in response to oxysterols is as a protective mechanism against atherosclerosis. This raises the possibility that CB2 signaling of apoptosis in macrophages may serve as one of the signaling pathways of this anti-atherosclerotic effect. To test these ideas regarding the mechanism and physiological significance of arachidonyl oxysterol signaling of apoptosis in macrophages we propose the following specific aims: 1) Determine if arachidonyl oxysterols can induce apoptosis in macrophages. 2) Determine if arachidonyl oxysterols can bind to cannabinoid receptors and modulate their activity. 3) Examine the role of the CB2 receptor in the development of atherosclerosis in mouse models. The results from this investigation may expand our understanding of the link between cannabinoid signaling mechanisms and the mechanisms regulating apoptosis in macrophages. They may also provide new pharmacologically exploitable targets for the development of novel pharmaceuticals for treatment of atherosclerosis.