Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation
Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation
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DOI：
10.1161/atvbaha.118.311185
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发表时间：
2018-11-01
影响因子：
8.7
通讯作者：
Steffens, Sabine
中科院分区：
文献类型：
--
作者：
Rinne, Petteri;Guillamat-Prats, Raquel;Steffens, Sabine
目的棕榈酰乙醇酰胺是一种内源性脂肪酸介质，由N-酰基磷脂酰乙醇胺磷脂酶D从膜磷脂合成，其生物学作用主要由PPAR-（过氧化物酶体增殖物激活受体）和孤儿受体GPR55介导。棕榈酰乙醇酰胺具有有效的抗炎作用，但其生理作用和作为慢性动脉炎症（如动脉粥样硬化）治疗药物的前景仍未得到探索。方法和结果首先，发现小鼠原代巨噬细胞向促炎表型的极化会减少 N-酰基磷脂酰乙醇胺磷脂酶 D 的表达， 棕榈酰乙醇酰胺的生物利用度。在动脉粥样硬化形成过程中，载脂蛋白 E 缺陷 (ApoE(-/-)) 小鼠的主动脉中 N-酰基磷脂酰乙醇胺磷脂酶 D 的表达逐渐下调。 N-酰基磷脂酰乙醇胺磷脂酶 D mRNA 水平在不稳定的人类斑块中也下调，并且与平滑肌细胞标记呈正相关，与巨噬细胞标记呈负相关。其次，ApoE(-/-) 小鼠被喂食高脂肪饮食 4 或 16 周，并用媒介物或棕榈酰乙醇酰胺（每天 3 mg/kg，4 周）治疗，以研究棕榈酰乙醇酰胺对早期形成和预先形成的动脉粥样硬化的影响。棕榈酰乙醇酰胺治疗可减少早期动脉粥样硬化中的斑块大小，而在预先形成的动脉粥样硬化中，棕榈酰乙醇酰胺可促进斑块稳定性的迹象，如减少巨噬细胞积累和坏死核心大小、增加胶原蛋白沉积和下调 M1 型巨噬细胞标记物所证明的。从机制上讲，我们发现棕榈酰乙醇酰胺通过激活 GPR55，增加吞噬受体 MerTK（原癌基因酪氨酸蛋白激酶 MER）的表达，并增强巨噬细胞胞吞作用，表明其具有促溶解特性。 结论 本研究表明，棕榈酰乙醇酰胺通过促进 病变巨噬细胞的抗炎和促消退表型，代表了解决动脉炎症的新治疗方法。
Objective Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR- (peroxisome proliferator-activated receptors ) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored.Approach and Results First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce N-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability. N-acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE(-/-)) mice during atherogenesis. N-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE(-/-) mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties.Conclusions The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.