Lanuti Mirko, Talamonti Emanuela, Maccarrone Mauro, Chiurchiù Valerio
European Center for Brain Research (CERC), IRCCS, Santa Lucia Foundation, Rome, Italy.
European Center for Brain Research (CERC), IRCCS, Santa Lucia Foundation, Rome, Italy; Center of Integrated Research, Campus Bio-Medico University of Rome, Rome, Italy.
PLoS One. 2015 May 13;10(5):e0126839. doi: 10.1371/journal.pone.0126839. eCollection 2015.
The G protein-coupled receptor GPR55 has been proposed as a new cannabinoid receptor associated with bone remodelling, nervous system excitability, vascular homeostasis as well as in several pathophysiological conditions including obesity and cancer. However, its physiological role and underlying mechanism remain unclear. In the present work, we demonstrate for the first time its presence in human macrophages and its increased expression in ox-LDL-induced foam cells. In addition, pharmacological activation of GPR55 by its selective agonist O-1602 increased CD36- and SRB-I-mediated lipid accumulation and blocked cholesterol efflux by downregulating ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, as well as enhanced cytokine- and pro-metalloprotease-9 (pro-MMP-9)-induced proinflammatory responses in foam cells. Treatment with cannabidiol, a selective antagonist of GPR55, counteracted these pro-atherogenic and proinflammatory O-1602-mediated effects. Our data suggest that GPR55 could play deleterious role in ox-LDL-induced foam cells and could be a novel pharmacological target to manage atherosclerosis and other related cardiovascular diseases.
G蛋白偶联受体GPR55被认为是一种与骨重塑、神经系统兴奋性、血管稳态以及包括肥胖和癌症在内的多种病理生理状况相关的新型大麻素受体。然而，其生理作用和潜在机制仍不清楚。在本研究中，我们首次证明了它在人巨噬细胞中的存在以及在氧化低密度脂蛋白（ox-LDL）诱导的泡沫细胞中表达增加。此外，其选择性激动剂O-1602对GPR55的药理学激活增加了CD36和SRB-I介导的脂质积累，并通过下调ATP结合盒（ABC）转运蛋白ABCA1和ABCG1阻断胆固醇外流，以及增强了泡沫细胞中细胞因子和前基质金属蛋白酶-9（pro-MMP-9）诱导的促炎反应。用大麻二酚（一种GPR55的选择性拮抗剂）处理可抵消这些由O-1602介导的促动脉粥样硬化和促炎作用。我们的数据表明，GPR55可能在ox-LDL诱导的泡沫细胞中发挥有害作用，并且可能是治疗动脉粥样硬化和其他相关心血管疾病的新型药理学靶点。
