Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPARγ
Anti-inflammatory effects of isoflavones are dependent on flow and human endothelial cell PPARγ
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DOI：
10.1093/jn/137.2.351
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发表时间：
2007-02-01
影响因子：
4.2
通讯作者：
Patel, Rakesh P.
中科院分区：
文献类型：
--
作者：
Chacko, Balu K.;Chandler, Robert T.;Patel, Rakesh P.
β-内酰胺酮预防炎性血管疾病的机制尚不清楚。我们以前的观察表明，一种机制涉及抑制单核细胞-内皮细胞相互作用的过程中，是绝对依赖于流量。所涉及的分子机制和结构上不同的异黄酮对这一过程的影响是未知的，并在此进行了研究。使用静态和流动依赖性单核细胞粘附试验，我们的数据表明，暴露的内皮细胞的生物学相关浓度的马诺龙抑制随后的TNF-α诱导的单核细胞粘附仅在流动。这种抑制作用涉及通过β-内酰胺酮刺激含有PPAR γ反应元件的启动子序列来激活内皮细胞PPAR γ，并通过靶向PPAR γ的siRNA来减弱抗粘附作用。结构上不同的异黄酮的比较表明A环的关键作用。使用大豆苷元的氯化衍生物，PPAR γ激动剂活性的关键结构要求似乎是存在7-OH基团并且在A环中的6-或8-位缺乏氯。总的来说，这些数据支持1）血管内皮细胞中PPAR γ配体的一种新的流动依赖性抗炎机制，以及2）支持营养素通过调节特定细胞信号传导途径调节疾病的当前概念。
The mechanisms by which isoflavones protect against inflammatory vascular disease remain unclear. Our previous observations suggest that one mechanism involves inhibition of monocyte-endothelial cell interactions in a process that is absolutely dependent on flow. The molecular mechanisms involved and the effects of structurally distinct isoflavones on this process are not known and are investigated herein. Using static and flow-dependent monocyte adhesion assays, our data show that exposure of endothelial cells to biologically relevant concentrations of isoflavones inhibits subsequent TNF-alpha induced monocyte adhesion only during flow. This inhibition involved activating endothelial PPAR gamma by stimulating promoter sequences containing the PPAR gamma response element by isoflavones and attenuating antiadhesive effects by siRNA targeting of PPAR gamma. A comparison of structurally distinct isoflavones suggested a critical role for the A-ring. Using chlorinated derivatives of daidzein, a key structural requirement for PPAR gamma agonist activity appears to be the presence of the 7-OH group and the lack of chlorine at the 6- or 8-positions in the A-ring. Collectively, these data support 1) a novel flow-dependent anti-inflammatory mechanism for PPAR gamma ligands in vascular endothelial cells and 2) exemplify the current concepts of nutrients modulating disease via regulating specific cell signaling pathways.