Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice
Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice
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DOI：
10.1161/hq0302.105593
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发表时间：
2002-03-01
影响因子：
8.7
通讯作者：
Showell, HJ
中科院分区：
文献类型：
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作者：
Aiello, RJ;Bourassa, PA;Showell, HJ
白三烯B4 （LTB4）是一种有效的趋化剂，通过LTB4受体（BLTR）激活单核细胞。我们验证了LTB4受体阻断可以通过抑制单核细胞募集来减缓动脉粥样硬化进展的假设。纯合子低密度受体敲除（LDLr-/-）小鼠和载脂蛋白E缺陷（apoE(-/-)）小鼠用特异性LTB4受体拮抗剂CP-105,696治疗35天。在apoE（-/-）小鼠中，LTB4拮抗剂治疗不影响血浆脂质浓度，但显著降低了血管病变和全血中的CD11b水平。与年龄匹配的对照组相比，在测试的所有时间点，处理apoE（-/-）小鼠的脂质积累和单核细胞浸润均显著减少。在维持高脂肪饮食的LDLr-/-小鼠中也显示出病变面积减少。LTB4拮抗剂对具有另一种趋化剂单核细胞趋化蛋白-1(MCP-1（-/-) X apoE(-/-)）零等位基因的小鼠的病变大小没有显著影响，表明MCP-1和LTB4可能通过共同的机制相互作用或发挥作用。这些结果表明，在动脉粥样硬化的临床前模型中，LTB4受体阻断可减少病变进展，并进一步表明LTB4或其他被BLTR受体识别的氧化脂质在该疾病的发病机制中具有先前未被认识到的作用。
Leukotriene B4 (LTB4) is a potent chemotactic agent that activates monocytes through the LTB4 receptor (BLTR). We tested the hypothesis that LTB4 receptor blockade would slow atherosclerotic progression by inhibiting monocyte recruitment. Homozygous low-density receptor knockout (LDLr-/-) mice and apolipoprotein E deficient (apoE(-/-)) mice were treated with a specific LTB4 receptor antagonist, CP-105,696, for 35 days. In apoE(-/-) mice, treatment with the LTB4 antagonist did not affect plasma lipid concentrations but significantly reduced CD11b levels both in vascular lesions and whole blood. Compared with age-matched controls, lipid accumulation and monocyte infiltration were significantly reduced in treated apoE(-/-) niice at all time points tested. Lesion area reduction was also demonstrated in LDLr-/- mice maintained on a high-fat diet. LTB4 antagonism had no significant effect on lesion size in mice possessing the null alleles for another chemotactic agent, monocyte chemoattractant protein-1 (MCP-1(-/-) X apoE(-/-)), suggesting MCP-1 and LTB4 may either interact or exert their effects by a common mechanism. These results demonstrate that in a preclinical model of atherosclerosis LTB4 receptor blockade reduces lesion progression and further suggest a previously unrecognized role for LTB4 or other oxidized lipids recognized by the BLTR receptor in the pathogenesis of this disease.