Direct Vasorelaxation by a Novel Phytoestrogen Tanshinone IIA Is Mediated by Nongenomic Action of Estrogen Receptor Through Endothelial Nitric Oxide Synthase Activation and Calcium Mobilization
Direct Vasorelaxation by a Novel Phytoestrogen Tanshinone IIA Is Mediated by Nongenomic Action of Estrogen Receptor Through Endothelial Nitric Oxide Synthase Activation and Calcium Mobilization
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DOI：
10.1097/fjc.0b013e31820a0da1
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发表时间：
2011-03-01
影响因子：
3
通讯作者：
Gao, Xiumei
中科院分区：
文献类型：
--
作者：
Fan, Guanwei;Zhu, Yan;Gao, Xiumei
丹参（Salvia miltiorrhiza，Danshen）具有改善冠状动脉微循环、增加冠状动脉血流量的作用，在中国和亚洲其他国家被广泛用于治疗各种心血管疾病。丹参酮IIA（Tan IIA）是丹参的主要活性亲脂性成分，其有益作用已被证明可诱导冠状动脉中的血管舒张。由于我们最近的研究确定了Tan IIA作为植物雌激素的新成员，我们推测其作用可能是通过血管内皮细胞中的雌激素受体（ER）介导的。本研究的目的是评估Tan IIA对心血管的保护作用是否由ER信号通路介导，以及ER的基因组或非基因组作用是否参与动脉和血管内皮细胞。采用内皮完整和去内皮大鼠血管环测定法研究了Tan IIA对血管的作用。与雌激素类似，Tan IIA引起一氧化氮和内皮依赖性舒张，可被ER拮抗剂ICI 182，780阻断。以原代心脏微血管内皮细胞为模型，研究Tan IIA诱导血管舒张的细胞和分子机制。我们证明，谭IIA是能够激活雌激素受体信号通路，导致增加内皮型一氧化氮合酶基因表达，一氧化氮的生产，ERK 1/2磷酸化，和Ca 2+动员。这些作用共同参与了Tan IIA对心血管疾病的γ ER拮抗剂Cnt的扩血管活性作用。我们的研究结果支持继续努力发现和开发新的植物雌激素作为替代激素替代疗法，更安全，更有效地治疗心血管疾病。
Salvia miltiorrhiza (Danshen) has been widely used in China and other Asian countries for treating various cardiovascular diseases resulting from its ability to improve coronary microcirculation and increase coronary blood flow. Tanshinone IIA (Tan IIA), the major active lipophilic ingredient responsible for the beneficial actions of Salvia miltiorrhiza, has been shown to induce vasodilation in coronary arteries. Because our recent study identified Tan IIA as a new member of the phytoestrogens, we hypothesized that its action might be mediated by estrogen receptor (ER) in vascular endothelial cells. The aim of the present study was to assess whether cardiovascular protection exerted by Tan IIA is mediated by the ER signal pathway and whether the genomic or nongenomic action of ER is involved within arteries and vascular endothelial cells. The effect of Tan IIA on blood vessels was investigated by vascular ring assay using endothelium-intact and endothelium-denuded rat aortas. Similar to estrogen, Tan IIA caused an nitric oxide-and endothelium-dependent relaxation, which was blocked by ER antagonist ICI 182,780. Primary cardiac microvascular endothelial cells were used as a model to study the cellular and molecular mechanisms of Tan IIA-induced vasorelaxation. We demonstrate that Tan IIA is capable of activating the estrogen receptor signal pathway, leading to increased endothelial nitric oxide synthase gene expression, nitric oxide production, ERK1/2 phosphorylation, and Ca2+ mobilization. Collectively, these effects contribute to Tan IIA's vasodilative activity effects of y ER antagonist Cnt of cardiovascular diseases. Our findings support a continued effort in discovering and developing novel phytoestrogens as an alternative hormone replacement therapy for safer and more effective treatment of cardiovascular diseases.