Cryptotanshinone and wogonin up-regulate eNOS in vascular endothelial cells via ERα and down-regulate iNOS in LPS stimulated vascular smooth muscle cells via ERβ.
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.
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Barnabas
B
Oche
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Tianjin Key Laboratory of Traditional Chinese Medicine Pharmacology, Tianjin, China.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Lu
L
Chen
Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Ya-Ke
YK
Ma
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Yue
Y
Yang
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Chun-Xiao
CX
Li
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Xiao
X
Geng
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China.
Li-Zhen
LZ
Qiu
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China.|Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China.|Tianjin Key Laboratory of Traditional Chinese Medicine Pharmacology, Tianjin, China.
Xiu-Mei
XM
Gao
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin, China. wanghongsys@126.com.|Tianjin Key Laboratory of Traditional Chinese Medicine Pharmacology, Tianjin, China. wanghongsys@126.com.|Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, # 312 Anshanxi Road, Nankai District, Tianjin, 300193, China. wanghongsys@126.com.
Hong
H
Wang
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D044950:Flavanones / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology*; D048789:Phytoestrogens / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; C506487:ESR1 protein, human; C000600034:ESR2 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D044950:Flavanones; D008070:Lipopolysaccharides; D010616:Phenanthrenes; D048789:Phytoestrogens; D009569:Nitric Oxide; C037886:cryptotanshinone; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C085514:wogonin
Cardiovascular disease; Cryptotanshinone; Estrogen receptors; Nitric oxide synthase; Phytoestrogens; Wogonin