Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice.
Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice.
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DOI：
10.1016/j.ijcard.2013.03.035
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发表时间：
2013-10-03
影响因子：
3.5
通讯作者：
Liu D
中科院分区：
文献类型：
--
作者：
Jia Z;Babu PV;Si H;Nallasamy P;Zhu H;Zhen W;Misra HP;Li Y;Liu D
染料木黄酮是一种大豆黄酮，因其改善血管功能的潜力而受到广泛关注，但其作用机制尚不清楚。在此，我们报道了生理浓度（0.1 µM-5 µM）的染料木黄酮显著抑制TNF-α诱导的单核细胞与人脐静脉内皮细胞（HUVECs）的粘附，这是动脉粥样硬化发病机制中的关键事件。Genistein还能显著抑制TNF-α诱导的单核细胞与活化的内皮细胞（EC）粘附分子和趋化因子sICAM-1、sVCAM-1、sE-selectin、MCP-1和IL-8的产生。生理浓度的染料木黄酮不诱导抗氧化酶活性和自由基生成。此外，阻断内皮细胞的雌激素受体（ER）并不改变染料木黄酮对内皮炎症的预防作用。然而，蛋白激酶A（PKA）的抑制显着减弱金雀异黄素对TNF-α诱导的单核细胞与EC粘附以及MCP-1和IL-8的产生的抑制作用。在动物实验中，饮食中的染料木黄酮（0.1%的饮食中的染料木黄酮）显著抑制TNF-α诱导的C57 BL/6小鼠循环趋化因子和粘附分子的增加。金雀异黄素处理还减少了TNF-α处理小鼠主动脉中VCAM-1和单核细胞源性F4/80阳性巨噬细胞。结论：金雀异黄素对TNF-α诱导的血管内皮炎症具有保护作用。染料木黄酮的这种抗炎作用不依赖于ER介导的信号传导机制或抗氧化活性，而是通过PKA信号传导途径介导的。
Genistein, a soy isoflavone, has received wide attention for its potential to improve vascular function, but the mechanism of this effect is unclear. Here, we report that genistein at physiological concentrations (0.1 µM–5 µM) significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells (HUVECs), a key event in the pathogenesis of atherosclerosis. Genistein also significantly suppressed TNF-α-induced production of adhesion molecules and chemokines such as sICAM-1, sVCAM-1,sE-selectin, MCP-1 and IL-8, which play key role in the firm adhesion of monocytes to activated endothelial cells (ECs). Genistein at physiologically relevant concentrations didn’t significantly induce antioxidant enzyme activities or scavenge free radicals. Further, blocking the estrogen receptors (ERs) in ECs didn’t alter the preventive effect of genistein on endothelial inflammation. However, inhibition of protein kinase A (PKA) significantly attenuated the inhibitory effects of genistein on TNF-α-induced monocyte adhesion to ECs as well as the production of MCP-1 and IL-8. In animal study, dietary genistein (0.1% genistein in the diet) significantly suppressed TNF-α-induced increase in circulating chemokines and adhesion molecules in C57BL/6 mice. Genistein treatment also reduced VCAM-1 and monocytes-derived F4/80-positive macrophages in the aorta of TNF-α treated mice. In conclusion, genistein protects against TNF-α induced vascular endothelial inflammation both in vitro and in vivo models. This anti-inflammatory effect of genistein is independent of the ER-mediated signaling machinery or antioxidant activity, but mediated via the PKA signaling pathway.
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