Phytoestrogens were widely used as natural alternatives to estrogen for treating cardiovascular diseases. They have been reported to have cardioprotective and anti-inflammatory response, but the mechanisms remain unclear. In this study, we found cryptotanshinone and wogonin exhibited phytoestrogenic property in an estrogen-responsive reporter assay. In EA.hy926 cells, treatment of cryptotanshinone and wogonin led to significant increase in NO production levels, which were inhibited by co-incubation of estrogen receptor (ER)α antagonist methyl-piperidino-pyrazole (MPP). The expression of endothelial NO synthase (eNOS) and ERα were up-regulated with the same treatment, indicating they stimulate NO and eNOS expression via ERα-dependent pathway in endothelial cells. While in lipopolysaccharide activated vascular smooth muscle cell line A7r5, cryptotanshinone and wogonin exerted anti-inflammatory effects by inhibiting NO and inducible NO synthase expression via ERβ-dependent pathway. The reduction of NO synthesis was not affected by MPP, and was abrogated by ERβ antagonist R,R-tetrahydrochrysene. Our findings provide the potential molecular mechanism of cryptotanshinone and wogonin as phytoestrogens for their cardioprotective effects, which exerted regulatory effects on NO synthesis through differential regulation of estrogen receptors. It can be employed as a basis for evaluating the beneficial effects of phytoestrogens in the treatment of patients at risk of cardiovascular disease.
1) These compounds might contribute to the anti-hypertensive effect collectively. However, the anti-hypertensive effect of Eucommia ulmoides OLIV. bark remains largely unclear.Pharmacological studies have revealed that Eucommia ulmoides OLIV. bark extract induce endothelium and NO-cyclic guanosine monophosphate (cGMP) dependent relaxation in the rat thoracic aorta.2) Another report demonstrated that the endothelium-dependent vascular relaxation induced by the bark extract is mediated by NO and endothelium-derived hyperpolarizing factor in small vessels.3) However, the vasorelaxing components have been unclear. Recently, we found oroxylin A and wogonin isolated from Eucommia ulmoides OLIV. bark could significantly lower the perfusion pressure.4) In the previous study, we had reported that oroxylin A could relax rat thoracic aorta and it was endothelium and NO dependent.5)The present study was undertaken to investigate vasodilatory effect of wogonin and its mechanism.Wogonin ( Fig. 1) is a flavone and has a variety of cardiovascular protective effect. It could regulate migration, proliferation and apoptosis of vascular smooth muscle cells. [6][7][8] Besides, wogonin could inhibit angiogenesis, suppress collagen deposition in cardiac fibroblasts and inhibit ischemic brain injury. [9][10][11][12] There is no evidence for vascular relaxation effect of wogonin. We describe here that wogonin, unlike oroxylin A, is an endothelium-and NO-independent vasodilatory flavonoid. One report demonstrated that wogonin offered a wide margin of safety.13) It has therapeutic potential for the treatment of cardiovascular and cerebrovascular diseases.
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