Role of peripheral endocannabinoid system in atherosclerosis

外周内源性大麻素系统在动脉粥样硬化中的作用

• 批准号: 262061163
• 负责人: Professor Dr. Alexander Faußner
• 金额: --
• 依托单位: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/262061163?language=en
• 关键词: Role; peripheral; endocannabinoid; system; atherosclerosis

Despite major advances in cardiovascular research, atherosclerosis remains a major health burden and is responsible for the majority of all deaths worldwide. An endogenous lipid signaling system, the so-called endocannabinoid system has recently evolved as an important regulator in both physiological and pathophysiological processes. This system comprises at least two distinct membrane receptors, CB1 and CB2, their endogenous ligands (named endocannabinoids) as well as enzymes for ligand biosynthesis and inactivation. We and others have shown increased activity of the endocannabinoid system in atherosclerosis and its related cardiovascular risk factors, obesity, dyslipidemia, diabetes and endothelial dysfunction. However, the causal role of the elevated endocannabinoid tone and proposed opposing role of CB1 and CB2 receptors in atherosclerosis is not well understood. Simple genetic approaches based on global receptor deficiency are hampered by the fact that both receptors are widely expressed within the central nervous system as well as most peripheral organs, including the cardiovascular system. Thus, it is difficult to dissect the specific contribution of vascular and immune cell CB1 and CB2 signaling.Secific aims: (1) To clarify the specific role of vascular and hematopoietic cannabinoid receptors in the pathogenesis of atherosclerosis based on bone marrow chimeras and cell-specific mutation. (2) To investigate the specific contribution of elevated endocannabinoid 2-AG tone and endocannabinoid-related fatty acid amides in the pathogenesis of atherosclerosis (3) To shed light on the intracellular signaling pathways underlying the opposing pathophysiological effects of the two cannabinoid receptors.Based on this multi-disciplinary approach which combines cardiovascular biology, immunology and receptor biochemistry, we hope to gain a detailed view of the complex immunomodulatory and cardiometabolic effects of endocannabinoids that are key determinants of atherosclerosis. This should help advancing our current understanding of the pathology and potentially lead to more efficient and specific therapies and better cardiovascular risk assessment.

尽管心血管研究取得了重大进展，但动脉粥样硬化仍然是一个主要的健康负担，是全球大多数死亡的原因。内源性脂质信号系统，即内源性大麻素系统，近年来已发展成为生理和病理生理过程中的重要调节因子。该系统包括至少两种不同的膜受体，CB 1和CB 2，它们的内源性配体（称为内源性大麻素）以及用于配体生物合成和失活的酶。我们和其他人已经表明，动脉粥样硬化及其相关的心血管危险因素，肥胖，血脂异常，糖尿病和内皮功能障碍的内源性大麻素系统的活性增加。然而，动脉粥样硬化中内源性大麻素水平升高的因果作用和CB 1和CB 2受体的相反作用尚不清楚。基于整体受体缺陷的简单遗传方法受到这两种受体在中枢神经系统以及大多数外周器官（包括心血管系统）内广泛表达的事实的阻碍。因此，很难对血管和免疫细胞CB 1和CB 2信号通路的具体作用进行剖析。具体目的：（1）基于骨髓嵌合体和细胞特异性突变，阐明血管和造血大麻素受体在动脉粥样硬化发病机制中的具体作用。(2)探讨内源性大麻素2-AG张力升高和内源性大麻素相关脂肪酸酰胺在动脉粥样硬化发病机制中的具体作用（3）揭示两种大麻素受体相反病理生理作用的细胞内信号通路。基于这种结合心血管生物学、免疫学和受体生物化学的多学科方法，我们希望能详细了解内源性大麻素的复杂免疫调节和心脏代谢作用，它们是动脉粥样硬化的关键决定因素。这将有助于推进我们目前对病理学的理解，并可能导致更有效和更具体的治疗方法以及更好的心血管风险评估。

项目成果

Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation

• DOI: 10.1161/atvbaha.118.311185
• 发表时间: 2018-11-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Rinne, Petteri;Guillamat-Prats, Raquel;Steffens, Sabine
• 通讯作者: Steffens, Sabine

Deficiency of Monoacylglycerol Lipase Enhances IgM Plasma Levels and Limits Atherogenesis in a CB2-Dependent Manner

单酰甘油脂肪酶的缺乏会增强 IgM 血浆水平并以 CB2 依赖性方式限制动脉粥样硬化形成

• DOI: 10.1055/s-0038-1676769
• 发表时间: 2019
• 期刊: Thrombosis and Haemostasis
• 影响因子: 6.7
• 作者: Guillamat-Prats R;Rami M;Ring L;Rinne P;Lauer E;Lenglet S;Thomas A;Pagano S;Vuilleumier N;Caravatt BF;Weber C;Faussner A;Steffens S
• 通讯作者: Steffens S