KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R-/- Mice
KRP-203, Sphingosine 1-Phosphate Receptor Type 1 Agonist, Ameliorates Atherosclerosis in LDL-R-/- Mice
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DOI：
10.1161/atvbaha.113.301347
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发表时间：
2013-07-01
影响因子：
8.7
通讯作者：
Nofer, Jerzy-Roch
中科院分区：
文献类型：
--
作者：
Poti, Francesco;Gualtieri, Fabio;Nofer, Jerzy-Roch
目的：神经鞘氨醇1-磷酸(S1P)是高密度脂蛋白抗动脉粥样硬化的部分原因。我们之前证明了FTY720，一种针对所有S1P受体的合成S1P类似物，但S1P受体2型，抑制小鼠动脉粥样硬化。方法和结果：高胆固醇饮食低密度脂蛋白受体缺陷小鼠给予选择性S1P受体1型激动剂Krp-203(3.0 mg/kg/d，6周和16周)。KRP-203显著减少了动脉粥样硬化病变的形成，而不影响血脂浓度。但KRP-203可导致淋巴细胞减少，外周淋巴器官中T细胞总数(CD4(+)、CD8(+))和活化的(CD69(+)/CD8(+)、CD69(+)/CD4(+))细胞减少，并干扰淋巴细胞功能，表现为T细胞增殖和活化脾细胞中IL-2和干扰素-γ的产生减少。Krp-203可降低血浆和主动脉中细胞和趋化因子(肿瘤坏死因子-α，调节和正常T细胞的表达和分泌)水平。此外，KRP-203处理的小鼠的巨噬细胞显示激活标记MCH-II的表达减少，多聚(I：C)诱导的肿瘤坏死因子-α、单核细胞趋化蛋白-1和白细胞介素6的产生减少。体外研究表明，KRP-203可分别减少聚(I：C)刺激的骨髓巨噬细胞中肿瘤坏死因子-α、白介素6和干扰素-γ诱导的蛋白-10的产生；I-kappaB和信号转导及转录激活因子-1的磷酸化；核因子kappaB和信号转导及转录激活因子-1的激活。结论S1P信号通路的激活可能通过调节淋巴细胞和巨噬细胞的功能来抑制动脉粥样硬化，提示S1P受体1至少部分介导了S1P的抗动脉粥样硬化作用。
Objective-Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P.Approach and Results-Low-density lipoprotein receptor-deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 (3.0 mg/kg per day; 6 and 16 weeks). KRP-203 substantially reduced atherosclerotic lesion formation without affecting plasma lipid concentrations. However, KRP-203 induced lymphopenia, reduced total (CD4(+), CD8(+)) and activated (CD69(+)/CD8(+), CD69(+)/CD4(+)) T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-gamma production in activated splenocytes. Cyto- and chemokine (tumor necrosis factor-alpha, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203-treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-alpha, interleukin-6, and interferon-gamma-induced protein-10 production; I kappa B and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor kappa B and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-gamma-stimulated bone marrow macrophages, respectively.Conclusions-Present results demonstrate that activation of S1P signaling pathways inhibit atherosclerosis by modulating lymphocyte and macrophage function and suggest that S1P receptor type 1 at least partially mediates antiatherogenic effects of S1P.