Sakamoto Aiji, Ishibashi-Ueda Hatsue, Sugamoto Yuka, Higashikata Takeo, Miyamoto Susumu, Kawashiri Masa-Aki, Yagi Kunimasa, Konno Tetsuo, Hayashi Kenshi, Fujino Noboru, Ino Hidekazu, Takeda Yoshiyu, Yamagishi Masakazu
Division of Biotechnology, National Cardiovascular Center, Osaka, Japan.
Clin Sci (Lond). 2008 May;114(10):643-50. doi: 10.1042/CS20070339.
Although several cytokines and chemokines have been demonstrated to play pivotal roles in the pathophysiological conditions of atherosclerosis, few findings exist regarding the expression and function of cytokine-modulating molecules such as ephrin-Bs and their cognate receptors, EphBs, in human atherosclerosis. Therefore, in the present study, we screened novel genes modulating atherogenesis by cDNA array and quantitatively determined them by real-time RT (reverse transcription)-PCR in human carotid atherosclerotic plaques. Ephrin-B1 and EphB2, key regulators of embryogenesis, were significantly up-regulated in plaques compared with those in adjacent control tissues [ephrin-B1, 0.638+/-0.106 compared with 0.831+/-0.152, or 130% (P<0.05); EphB2, 1.296+/-0.281 compared with 2.233+/-0.506, or 172% (P<0.05)]. Immunohistological analysis demonstrated that both ephrin-B1 and EphB2 were expressed in macrophages and T-lymphocytes in plaques as well as in monocytes, T-lymphocytes and arterial endothelial cells isolated from healthy adults. Interestingly, the extracellular domains of ephrin-B1 and EphB2, the expression of which were both enhanced in stimulated THP-1 cells, significantly inhibited spontaneous (22.5 and 27.6% respectively; P<0.01) and MCP-1 (monocyte chemoattractant protein-1)-dependent (29.7 and 22.6% respectively; P<0.01) migration of monocytes. In conclusion, these results demonstrate that ephrin-B1 and EphB2 are overexpressed in atherosclerotic tissue and might locally regulate cell migration, possibly through modulating cytokine-related chemotaxic activity; however, the functional role of these molecules in atherogenesis should be investigated further.
尽管已证明多种细胞因子和趋化因子在动脉粥样硬化的病理生理状况中起关键作用，但关于诸如ephrin-Bs及其同源受体EphBs等细胞因子调节分子在人类动脉粥样硬化中的表达和功能的研究发现却很少。因此，在本研究中，我们通过cDNA阵列筛选了调节动脉粥样硬化发生的新基因，并通过实时RT（逆转录）-PCR对人类颈动脉粥样硬化斑块中的这些基因进行了定量测定。与相邻对照组织相比，胚胎发育的关键调节因子Ephrin-B1和EphB2在斑块中显著上调[Ephrin-B1，0.638±0.106，而对照为0.831±0.152，即130%（P<0.05）；EphB2，1.296±0.281，而对照为2.233±0.506，即172%（P<0.05）]。免疫组织学分析表明，Ephrin-B1和EphB2在斑块中的巨噬细胞和T淋巴细胞以及从健康成年人分离的单核细胞、T淋巴细胞和动脉内皮细胞中均有表达。有趣的是，Ephrin-B1和EphB2的细胞外结构域在刺激的THP-1细胞中表达均增强，它们显著抑制了单核细胞的自发迁移（分别为22.5%和27.6%；P<0.01）以及依赖MCP-1（单核细胞趋化蛋白-1）的迁移（分别为29.7%和22.6%；P<0.01）。总之，这些结果表明Ephrin-B1和EphB2在动脉粥样硬化组织中过度表达，并可能通过调节细胞因子相关的趋化活性在局部调节细胞迁移；然而，这些分子在动脉粥样硬化发生中的功能作用仍需进一步研究。
