The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway
The atheroprotective role of lipoxin A4 prevents oxLDL-induced apoptotic signaling in macrophages via JNK pathway
复制标题
脂氧素 A4 的动脉粥样硬化保护作用可通过 JNK 途径阻止 oxLDL 诱导的巨噬细胞凋亡信号传导。
DOI：
10.1016/j.atherosclerosis.2018.09.025
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发表时间：
2018-11-01
期刊：
影响因子：
5.3
通讯作者：
Wang, Jingfeng
中科院分区：
文献类型：
--
作者：
Mai, Jingting;Liu, Wenhao;Wang, Jingfeng
背景和目标：我们检测了炎症消退介质脂氧素A（4）（LXA（4））是否抑制巨噬细胞中泡沫细胞形成和氧化低密度脂蛋白（oxLDL）诱导的凋亡信号，以及循环/局部LXA（4）生物合成在动脉粥样硬化形成中的作用。通过流式细胞术评价Dil-oxLDL和Dil-acLDL与巨噬细胞的结合和摄取。结果：冠心病患者外周血LXA（4）水平明显高于正常对照组（P < 0. 05），冠心病患者外周血LXA（4）水平明显高于正常对照组（P < 0. 05）。兔动脉粥样硬化血管壁局部LXA（4）水平低得多。干扰素γ（IFN-γ）和肿瘤坏死因子α（TNF-α）在动脉粥样硬化血管中升高。在炎症刺激（IFN-γ、TNF-α和C-反应蛋白）后，泡沫细胞中LXA（4）的合成显著减少。LXA（4）剂量依赖性地抑制巨噬细胞胆固醇摄取基因CD 36和SR-A的表达，这种抑制作用可被LXA（4）受体拮抗剂BOC-2阻断。LXA（4）还抑制oxLDL诱导的CD 36上调、Dil-oxLDL摄取和泡沫细胞形成。此外，LXA（4）通过抑制caspase-3的活化和恢复线粒体膜电位，抑制oxLDL激活的c-Jun N-末端激酶途径，减少oxLDL诱导的巨噬细胞凋亡。结论：我们发现LXA（4）抑制泡沫细胞形成，oxLDL诱导的炎症和巨噬细胞凋亡信号。在兔动脉粥样硬化动脉中发现抗炎促消退分子LXA（4）水平不足，这可能有助于阻止动脉粥样硬化形成期间的炎症消退。
Background and aims: We examined whether the inflammation resolution mediator lipoxin A(4) (LXA(4)) inhibits foam cell formation and oxidized low-density lipoprotein (oxLDL)-induced apoptotic signaling in macrophages and the role of circulating/local LXA(4) biosynthesis in atherogenesis.Methods: LXA(4) levels were measured by enzyme-linked immunosorbent assay. Dil-oxLDL and Dil-acLDL binding to and uptake by macrophages were evaluated by flow cytometry. Apoptosis was evaluated by TUNEL and Annexin V/PI assays.Results: Circulating LXA(4) levels in patients with coronary artery disease were much higher than those in respective controls. Local LXA(4) levels were much lower in rabbit atherosclerotic vessel walls. Interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) were elevated in atherosclerotic vessels. After the inflammatory stimulus (IFN-gamma, TNF-alpha, and C-reactive protein), LXA(4) synthesis decreased significantly in foam cells. LXA(4) dose-dependently suppressed the expression of the cholesterol uptake genes CD36 and SR-A in macrophages, which was blocked by the LXA(4) receptor antagonist BOC-2. LXA(4) also inhibited oxLDL-induced CD36 upregulation, Dil-oxLDL uptake, and foam cell formation. Furthermore, LXA(4) inhibited the oxLDL-activated c-Jun N-terminal kinase pathway and reduced oxLDL-induced macrophage apoptosis by inhibiting caspase-3 activation and restoring the mitochondrial membrane potential.Conclusions: We found that LXA(4) inhibited foam cell formation, oxLDL-induced inflammation, and apoptotic signaling in macrophages. Insufficient levels of the anti-inflammatory pro-resolution molecule LXA(4) were found in rabbit atherosclerotic arteries, which might contribute to preventing inflammation resolution during atherogenesis.