Genistein, a soy phytoestrogen, upregulates the expression of human endothelial nitric oxide synthase and lowers blood pressure in spontaneously hypertensive rats
Genistein, a soy phytoestrogen, upregulates the expression of human endothelial nitric oxide synthase and lowers blood pressure in spontaneously hypertensive rats
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DOI：
10.1093/jn/138.2.297
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发表时间：
2008-02-01
影响因子：
4.2
通讯作者：
Liu, Dongmin
中科院分区：
文献类型：
--
作者：
Si, Hongwei;Liu, Dongmin
染料木素是一种大豆植物雌激素，可能改善血管功能，但其作用机制尚不清楚。内皮源性一氧化氮（NO）是血管张力和动脉粥样硬化的关键调节剂。已有研究证实，雌激素可通过基因组刺激内皮NO合成酶（eNOS）表达，直接作用于血管内皮细胞（EC），促进NO合成。然而，染料木素是否有类似的效果尚不清楚。因此，我们研究染料木素是否直接调节原发性人主动脉EC （HAEC）和人脐静脉EC （HUVEC）的NO合成。在食用豆制品的个体中，在生理可达到的浓度下，染料木素增强了eNOS的表达，随后提高了HAEC和HUVEC中NO的合成，其中1-10 μ mol/L染料木素诱导的效果最大。而染料木素对eNOS和NO的影响不通过激活雌激素信号或抑制酪氨酸激酶介导，染料木素（1-10 μ mol/L）对eNOS基因的2个已知生物作用，使eNOS基因的表达增加（是对照的1.8- 2.6倍），并显著提高人eNOS基因在HAEC和HUVEC中的eNOS启动子活性，提示染料木素激活eNOS转录。在自发性高血压大鼠的饮食中添加染料木素可以恢复主动脉eNOS水平，改善主动脉壁厚度，减轻高血压，证实了体外研究结果的生物学相关性。我们的数据表明染料木素对血管壁有直接的基因组效应，而这种效应与其已知的作用无关，导致eNOS表达和NO合成增加，从而改善高血压。
Genistein, a soy phytoestrogen, may improve vascular function, but the mechanism of this effect is unclear. Endothelial-derived nitric oxide (NO) is a key regulator of vascular tone and atherogenesis. Previous studies have established that estrogen can act directly on vascular endothelial cells (EC) to enhance NO synthesis through genomic stimulation of endothelial NO synthase (eNOS) expression. However, it is unknown whether genistein has a similar effect. We therefore investigated whether genistein directly regulates NO synthesis in primary human aortic EC (HAEC) and human umbilical vein EC (HUVEC). Genistein, at physiologically achievable concentrations in individuals consuming soy products, enhanced the expression of eNOS and subsequently elevated NO synthesis in both HAEC and HUVEC, with 1-10 mu mol/L genistein inducing the maximal effects. However, the effects of genistein on eNOS and NO were not mediated by activation of estrogen signaling or inhibition of tyrosine kinases, 2 known biological actions of genistein, Genistein (1-10 mu mol/L) increased eNOS gene expression (1.8- to 2.6-fold of control) and significantly increased eNOS promoter activity of the human eNOS gene in HAEC and HUVEC, suggesting that genistein activates eNOS transcription. Dietary supplementation of genistein to spontaneously hypertensive rats restored aortic eNOS levels, improved aortic wall thickness, and alleviated hypertension, confirming the biological relevance of the in vitro findings. Our data suggest that genistein has direct genomic effects on the vascular wall that are unrelated to its known actions, leading to increased eNOS expression and NO synthesis, thereby improving hypertension.