Dietary flavonoids differentially reduce oxidized LDL-induced apoptosis in human endothelial cells: Role of MAPK- and JAK/STAT-signaling
Dietary flavonoids differentially reduce oxidized LDL-induced apoptosis in human endothelial cells: Role of MAPK- and JAK/STAT-signaling
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DOI：
10.1093/jn/138.6.983
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发表时间：
2008-06-01
影响因子：
4.2
通讯作者：
Kang, Young-Hee
中科院分区：
文献类型：
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作者：
Choi, Jung-Suk;Choi, Yean-Jung;Kang, Young-Hee
内皮细胞凋亡是动脉粥样硬化发展的驱动力。氧化的低密度脂蛋白促进炎症和血栓形成过程，并高度致动脉粥样硬化，因为它刺激巨噬细胞胆固醇积累和泡沫细胞形成。本研究探讨了多种丝裂原活化蛋白激酶(MAPK)应答的死亡/生存信号通路，通过这些信号通路，(-)表没食子儿茶素没食子酸酯(EGCG)和橙皮素在氧化型低密度脂蛋白(Ox-LDL)诱导的内皮细胞中发挥抗凋亡作用。EGCG和橙皮素显著降低氧化低密度脂蛋白诱导的2‘，7’-二氯荧光素染色，表明这些黄酮类化合物抑制氧化低密度脂蛋白引发的细胞内活性氧积累和随后的细胞凋亡。Western-blotting结果显示，氧化型低密度脂蛋白可上调c-jun氨基末端激酶(JNK)的磷酸化，而EGCG和橙皮素可迅速逆转这一作用。它们减轻了P53和c-jun下游JNK的激活。此外，氧化型低密度脂蛋白可增加p53启动子构建的内皮细胞中p53的荧光素酶活性，这种增加可被EGCG和橙皮素显著下调。令人惊讶的是，橙皮素而不是EGCG减弱了氧化低密度脂蛋白引起的p38MAPK及其下游c-myc以及信号转导和转录激活因子(STAT)L的磷酸化。本研究还试图探讨在氧化型低密度脂蛋白诱导的内皮细胞凋亡中Janus Kinase(JAK)2/STAT3的激活与MAPK信号转导之间的联系。值得注意的是，我们发现JAK2抑制剂基本上阻断了JNK的激活。我们的发现表明，EGCG和橙皮素可能通过不同的细胞凋亡机制发挥抗动脉粥样硬化的作用，阻断氧化低密度脂蛋白诱导的内皮细胞凋亡。这些数据提供了证据，表明p38MAPK和JAK-STAT通路之间的相互作用参与了饮食中类黄酮对氧化低密度脂蛋白的保护作用，这是通过阻碍涉及JAK2激活的MAPK依赖的通路来实现的。
Endothelial apoptosis is a driving force in atherosclerosis development. Oxidized LDL promotes inflammatory and thrombotic processes and is highly atherogenic, as it stimulates macrophage cholesterol accumulation and foam cell formation. This study investigated multiple mitogen-activated protein kinase (MAPK)-responsive death/survival signaling pathways, through which flavonoids of (-)epigallocatechin gallate (EGCG) and hesperetin exerted antiapoptosis in endothelial cells exposed to oxidized LDL. EGCG and hesperetin substantially diminished the oxidized LDL-induced 2',7'-dichlorofluorecein staining, suggesting that these flavonoids inhibited intracellular accumulation of oxidized LDL-triggered reactive oxygen species and consequent apoptosis. The Western-blot data revealed that oxidized LDL upregulated c-Jun N-terminal kinase (JNK) phosphorylation, which was rapidly reversed by EGCG and hesperetin. They mitigated the consequent activation of the JNK downstream on p53 and c-Jun. Moreover, oxidized LDL increased luciferase activity of p53 in endothelial cells transfected with a p53 promoter construct, the increase of which was strikingly downregulated by EGCG and hesperetin. Surprisingly, hesperetin but not EGCG attenuated phosphorylation of p38MAPK and its downstream c-myc and signal transducers and activators of transcription (STAT)l evoked by oxidized LDL. This study also attempted to explore a linkage of Janus kinase (JAK)2/STAT3 activation to MAPK signaling in oxidized LDL-induced endothelial apoptosis. Notably, we found that the JAK2 inhibitor substantially blocked the JNK activation. Our findings suggest that EGCG and hesperetin may act as antiatherogenic agents blocking oxidized LDL-induced endothelial apoptosis via differential cellular apoptotic machinery. These data provide evidence that the interplay between p38MAPK and JAK-STAT pathways is involved in dietary flavonoid protection against oxidized LDL through hampering MAPK-dependent pathways involving the activation of JAK2.