Unbiased assessment of 2-Arachidonoylglycerol in cardiovascular inflammation and myocardial remodeling

2-arachidonoylglycerol (2-AG) is an endogenous modulator of inflammatory processes and ligand for the endocannabinoid system. Recent scientific investigations accumulated evidences for its key role in inflammatory cardiovascular diseases, like atherosclerosis and left ventricular remodeling. However, molecular mechanisms set in motion by 2-AG are still poorly understood and its role in cardiovascular inflammation is the matter of controversial debate. Yet, there is a dramatic need to understand local effects of 2-AG at the site of heart inflammation, and tissue injury and reconstruction to develop novel therapeutic strategies which modulate both processes for the better and a fast recovery. Myeloid cells, like tissue-resident macrophages and monocytes are central mediators of inflammatory processes and mediate cardiac adverse remodelling after an insult by myocardial infarction, myocarditis or chronic hypertension. In this study, we investigated the impact of 2-AG on the transcriptional programming of peripheral monocytes as model system for resident macrophages in heart tissue or monocytes which are recruited to the site of cardiac tissue remodelling. Data of RNA sequencing analysis and quantification cytokine expression we seeked to clarify the question, if 2-AG induces rather an inflammatory or a wound healing phenotype of monocytes recruited to the site of cardiac tissue injury. Overall design: CD14+ primary human monocytes were isolated from peripheral blood of healthy donors and treated with 2-AG up to 24h. Genes differentially expressed between 2-AG treated monocytes and respective controls were determined by mRNA sequencing and used for bioinformatics analysis of changes in myeloid cell functions and cell signaling pathways.

2-花生四烯酸甘油（2-arachidonoylglycerol，2-AG）是一种内源性炎症调节因子，同时也是内源性大麻素系统（endocannabinoid system）的配体。近年来多项科学研究已积累充足证据，表明其在动脉粥样硬化、左心室重构等炎症性心血管疾病中发挥关键作用。然而，2-AG所启动的分子机制仍不甚明确，其在心血管炎症中的角色也存在诸多争议。学界亟需阐明2-AG在心脏炎症部位、组织损伤与重构中的局部效应，从而开发出能够同时优化上述过程、实现快速康复的新型治疗策略。

髓系细胞（如组织驻留巨噬细胞与单核细胞）是炎症反应的核心介导因子，同时也会在心肌梗死、心肌炎或慢性高血压等损伤事件后介导心脏不良重构。本研究以人外周单核细胞为模型，模拟心脏组织驻留巨噬细胞或被招募至心脏组织重构部位的单核细胞，探究了2-AG对其转录编程的影响。本研究通过RNA测序（RNA sequencing）分析与细胞因子表达定量实验，旨在阐明2-AG会诱导招募至心脏组织损伤部位的单核细胞呈现促炎表型还是创伤愈合表型这一科学问题。

整体实验设计：从健康志愿者外周血中分离CD14+原代人单核细胞，用2-AG处理至多24小时。通过mRNA测序（mRNA sequencing）确定2-AG处理组与对应对照组单核细胞间的差异表达基因，并将其用于髓系细胞功能与细胞信号通路变化的生物信息学分析（bioinformatics analysis）。