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Atherosclerotic disease is the leading cause of death world-wide. Our goal was to explore the effect of phytocannabinoids on the molecular mechanisms triggering the development of the atheromatous lesion. Three cannabis sativa extracts of different chemotypes were chemically characterized by UPLC-DAD. The capacity of the extracts to prevent the oxidation of LDL, the formation of foam cells and the activation of an inflammatory response by J774 cells, were monitored by UV-Vis spectrometry, confocal-microscopy and western blot. Three varieties of cannabis sativa, with high (E1), intermediate (E2) and low (E3) THC/CBD ratios were selected. The three cannabis extracts inhibited the oxidation of LDL by copper ions and the formation of foam cells by J774.1 cells challenged with oxLDL (ED50 5–12 μg mL-1). The effect of the cannabinoid extracts on the endocytic process was independent of the canonical cannabinoid receptors, CB1 and CB2, but related to the action of non-canonical receptors (TRPV1, TRPV4 and GPR55), involved in calcium signaling. Decreased levels of CD36 and OLR1 scavenger receptors were, at least partially, responsible for the diminished uptake of oxLDL induced by phytocannabinoids. The downregulation of CD36 and OLR1 could be explained by the observed inhibitory effect of the cannabis extracts on the activation of the NFκB pathway by oxLDL. Phytocannabinoids interfere with the main events leading to the development of the atheromatous plaque, opening new venues on atherosclerosis therapy.

动脉粥样硬化性疾病是全球范围内首要的致死病因。本研究旨在探究植物大麻素（phytocannabinoids）对触发动脉粥样硬化斑块病变发生的分子机制的调控效应。我们通过超高效液相色谱-二极管阵列检测器（UPLC-DAD）对三种不同化学型的大麻（Cannabis sativa）提取物完成了化学表征。分别采用紫外-可见分光光度法、激光共聚焦显微镜成像及蛋白质免疫印迹（Western Blot），检测提取物预防低密度脂蛋白（LDL）氧化、抑制泡沫细胞形成，以及调控J774细胞炎症应答激活的能力。本研究选取了三种大麻品种，其四氢大麻酚（THC）/大麻二酚（CBD）比值分别为高（E1）、中（E2）与低（E3）。三种大麻提取物均可抑制铜离子诱导的LDL氧化，以及经氧化型低密度脂蛋白（oxLDL）刺激的J774.1细胞的泡沫细胞形成，半数有效剂量（ED50）为5~12 μg·mL⁻¹。大麻素提取物对胞吞过程的调控作用不依赖于经典大麻素受体CB1和CB2，而是与参与钙信号通路的非经典受体（TRPV1、TRPV4及GPR55）的功能相关。CD36与OLR1清道夫受体的表达水平下调，至少部分解释了植物大麻素介导的oxLDL摄取量降低现象。大麻提取物对氧化型低密度脂蛋白激活的核因子κB（NFκB）通路的抑制效应，可阐明CD36与OLR1的下调机制。植物大麻素可干预动脉粥样硬化斑块发生的核心病理事件，为动脉粥样硬化的治疗开辟了全新的研究路径。