Subbarao Krishnaprasad, Jala Venkatakrishna R, Mathis Steven, Suttles Jill, Zacharias Wolfgang, Ahamed Jasimuddin, Ali Hydar, Tseng Michael T, Haribabu Bodduluri
James Graham Brown Cancer Center, University of Louisville Health Sciences, Louisville, KY 40202, USA.
Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):369-75. doi: 10.1161/01.ATV.0000110503.16605.15. Epub 2003 Dec 1.
Leukotriene B4 (LTB4), a potent leukocyte chemoattractant, is known to promote several inflammatory diseases, including atherosclerosis. We sought to determine mechanisms through which LTB4 modulates atherosclerosis in cell lines expressing LTB4 receptors, BLT-1, and in mice deficient in BLT-1 as well as macrophage cell lines derived from BLT-1+/+ and BLT-1-/- mice.
Analysis of global changes in gene expression induced by LTB4 in rat basophilic leukemia cells (RBL-2H3) expressing the human BLT-1 showed highest-fold increase in expression of fatty acid translocase/CD36 and the chemokine MCP1/JE/CCL2, which are critical in atherogenesis. To determine the importance of BLT-1 in atherogenesis, we crossed BLT-1-null mice with apolipoprotein (apo)-E-deficient mice, which develop severe atherosclerosis. Deletion of BLT-1 significantly reduced the lesion formation in apo-E-/- mice only during initiating stages (4 and 8 weeks) but had no effect on the lesion size in mice fed atherogenic diet for 19 weeks. Macrophage cell lines from BLT-1-deficient mice expressed the low-affinity LTB4 receptor, BLT-2, and exhibited chemotaxis to LTB4.
The effects of LTB4 in atherosclerosis are likely mediated through the high-affinity BLT-1 and the low-affinity BLT-2 receptors. LTB4 promotes atherosclerosis by chemo-attracting monocytes, by providing an amplification loop of monocyte chemotaxis via CCL2 production, and by converting monocytes to foam cells by enhanced expression of CD36 and fatty acid accumulation.
白三烯B4（LTB4）是一种强效白细胞趋化因子，已知可促进包括动脉粥样硬化在内的多种炎症性疾病。我们试图确定LTB4在表达LTB4受体BLT-1的细胞系、BLT-1基因缺陷小鼠以及源自BLT-1+/+和BLT-1-/-小鼠的巨噬细胞系中调节动脉粥样硬化的机制。
对表达人BLT-1的大鼠嗜碱性白血病细胞（RBL-2H3）中LTB4诱导的基因表达全局变化进行分析，结果显示脂肪酸转运蛋白/CD36和趋化因子MCP1/JE/CCL2的表达增加倍数最高，而这两种因子在动脉粥样硬化形成过程中至关重要。为确定BLT-1在动脉粥样硬化形成中的重要性，我们将BLT-1基因敲除小鼠与载脂蛋白（apo）-E基因缺陷小鼠杂交，后者会发展为严重的动脉粥样硬化。仅在起始阶段（4周和8周），BLT-1的缺失显著减少了apo-E-/-小鼠的病变形成，但对喂食致动脉粥样硬化饮食19周的小鼠的病变大小没有影响。来自BLT-1基因缺陷小鼠的巨噬细胞系表达低亲和力LTB4受体BLT-2，并表现出对LTB4的趋化性。
LTB4在动脉粥样硬化中的作用可能是通过高亲和力的BLT-1和低亲和力的BLT-2受体介导的。LTB4通过趋化吸引单核细胞、通过CCL2产生提供单核细胞趋化的放大环以及通过增强CD36表达和脂肪酸积累将单核细胞转化为泡沫细胞来促进动脉粥样硬化。
