Involvement of estrogen receptor-β in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation

Li, Qunyi; Chen, Li; Zhu, Yanhui; Zhang, Meng; Wang, Yiping; Wang, Mingwei

doi:10.1038/aps.2011.1

Cited by 45 publications

(26 citation statements)

References 38 publications

(30 reference statements)

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“…Alterations in hormonal levels inducing hypertrophy and the growth of the SMC layer in varicose veins have been suggested in different studies (28)(29)(30)(31). However, augmented estrogen levels have also been reported to reduce SMC migration and proliferation (17,32,33). These dual or opposite effects of estrogen have also been demonstrated in other cell types (34); however, the mechanisms invovled…”

Section: Discussionmentioning

confidence: 99%

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IQGAP1 modulates the proliferation and migration of vascular smooth muscle cells in response to estrogen

Huang

Jin

Zhou

et al. 2015

International Journal of Molecular Medicine

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Abstract. Vascular smooth muscle cell (VSMC) proliferation and migration has been proven to be a critical event in the development of varicosity. Variations in estrogen levels, a pathological event related to age and pregnancy, play a role in the pathogenesis of varicosity. Previous studies have reported a different response of VSMCs following estrogen stimulation. However, the exact mechanisms involved have not yet been elucidated. In the present study, we examined the responses of lesion and normal VSMCs treated with 10 -8 M 17β-estradiol (E 2 ) for 24 h. A differential effect of exposure to E 2 was observed in these cells. IQ-domain GTPase-activating protein 1 (IQGAP1), a scaffold protein, was overexpressed in the lesion VSMCs and was shown to modulate VSMC proliferation and migration in response to E 2 . Furthermore, the increased expression of IQGAP1 was found to be intimately associated with a high activity of estrogen receptor α (ERα), which has been implicated in the regulation of VSMC physiological function. Additionally, we found that two critical kinases, Akt and extracellular signal-regulated kinase (ERK), mediated the activation of ERα and VSMC proliferation. According to our results, we thus concluded that high levels of IQGAP1 in VSMCs regulate the physiological reaction of the cells in response to estrogen exposure, and that kinases are involved in the process by mediating ERα activation. In view of the essential role of IQGAP1 in the physiological function of VSMCs, targeting this molecule may prove to be a promising strategy for the treatment of varicosity.

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Section: Discussionmentioning

confidence: 99%

“…The abnormal growth of vascular smooth muscle cells (VSMCs) plays an essential role in intimal formation in the early stages of atherosclerosis and restenosis, as well as in varicosity (17). Differences in phenotype and function between VSMCs derived from normal veins and those derived from varicose veins have been identified.…”

Section: Introductionmentioning

confidence: 99%

IQGAP1 modulates the proliferation and migration of vascular smooth muscle cells in response to estrogen

Huang

Jin

Zhou

et al. 2015

International Journal of Molecular Medicine

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“…Estrogen also has antioxidant properties by inhibiting the expression of Nox and the generation of O 2 一 superoxide anion [24]. Furthermore, estrogen exerts its atheroprotective effects by binding to its receptors to generate nitrogen monoxide in endothelial cells, which tends to have a protective function on blood vessels [25][26][27]. Unfortunately, the expression levels of estrogen receptors decline during the late stage of menopause.…”

Section: Introductionmentioning

confidence: 99%

Alpha-Lipoic Acid Protects Human Aortic Endothelial Cells Against H2O2-Induced Injury and Inhibits Atherosclerosis in Ovariectomized Low Density Lipoprotein Receptor Knock-Out Mice

Shen

Tian

Shen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diseases caused by atherosclerosis are the leading causes of death in postmenopausal women, owing to the loss of estradiol. Hormone replacement therapy (HRT) provides short-term beneficial effects in the treatment of cardiovascular disease for postmenopausal women but may increase the risk of stroke and gynecological cancer. Therefore, a substitute for HRT is urgently in needed. Methods: In this study, we examined the effectiveness of alpha-lipoic acid (ALA), a natural potent antioxidant, in preventing the development and progression of atherosclerosis in the low density lipoprotein receptor deficient (Ldlr-/-) mouse model, using western blot analysis, immunohistochemistry, Oil-red-O, elastin staining and TUNEL assay. We also examined the protective effect of ALA in human aortic endothelial cells (HAECs) against H₂O₂-induced oxidative injury, using western blotting, immunofluorescence staining, and monocyte adhesion assay. Results: We showed that ALA treatment significantly reduced the atherosclerosis induced by ovariectomy and high fat diet in the Ldlr-/- mouse model and restored expression of estrogen receptors (ERα and ERβ), which reduced the progression of atherosclerosis. Moreover, ALA treatment attenuated monocyte adhesion, suppressed cellular apoptosis, and eliminated excessive generation of intracellular reactive oxygen species (ROS) by reducing the protein levels of ROS-generating enzymes Nox4 and p22phox, as well as inhibiting NF-κB activation in HAECs stimulated by H₂O₂. Conclusions: ALA could provide a potential treatment for atherosclerosis in postmenopausal patients.

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“…Among these compounds, flavonoids [19] are the most commonly investigated agents due to their prominent aromatase inhibitory activity and high breast selectivity [18] . Moreover, flavonoids may modulate the multi-step process of carcinogenesis through cellular and molecular mechanisms [19] . Biochanin A (BCA), isolated from red clover (Trifolium pretense), is a common isoflavone product that can inhibit aromatase activity and cell growth in MCF-7 cells [20] .…”

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

Lao

et al. 2014

Acta Pharmacol Sin

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Aim: aromatase is an important target for drugs to treat hormone-dependent diseases, including breast cancer. The aim of this study was to develop a homogeneous time-resolved fluorescence (HTRF) aromatase assay suitable for high-throughput screening (HTS). Methods: A 384-well aromatase HTRF assay was established, and used to screen about 7000 compounds from a compound library. Anti-proliferation activity of the hit was evaluated using alamarBlue(R) assay in a hormone-dependent breast cancer cell line T47D. Molecular docking was conducted to elucidate the binding mode of the hit using the Discovery Studio program. Results: The Z′ value and signal to background (S/B) ratio were 0.74 and 5.4, respectively. Among the 7000 compounds, 4 hits (XHN22, XHN26, XHN27 and triptoquinone A) were found to inhibit aromatase with IC 50 values of 1.60±0.07, 2.76±0.24, 0.81±0.08 and 45.8±11.3 μmol /L, respectively. The hits XHN22, XHN26 and XHN27 shared the same chemical scaffold of 4-imidazolyl quinoline. Moreover, the most potent hit XHN27 at 10 and 50 μmol/L inhibited the proliferation of T47D cells by 45.3% and 35.2%, respectively. The docking study revealed that XHN27 docked within the active site of aromatase and might form a hydrogen bond and had a π-cation interaction with amino acid residues of the protein.Conclusion: XHN27, an imidazolyl quinoline derivative of flavonoid, is a potent aromatase inhibitor with anti-proliferation activity against breast cancer in vitro. The established assay can be used in HTS for discovering novel aromatase inhibitor.Keywords: aromatase; breast cancer; imidazolyl quinoline; triptoquinone A; homogeneous time-resolved fluorescence assay; highthroughput screening; molecular docking; drug discovery Acta Pharmacologica Sinica (2014Sinica ( ) 35: 1082Sinica ( -1092 doi: 10.1038/aps.2014 [12,13] . Previous studies have demonstrated that AIs provide an increased survival benefit compared with other therapies and have acceptable toxicity profiles with decreased virginal bleeding and thromboembolism and increased rash, diarrhea and vomiting [14,15] . As AIs sometimes have more severe bone, brain and heart side effects, research for alternative compounds is necessary [15][16][17] .Natural products, extracted from traditional medicines and foods, may be helpful for discovering novel AIs that may selectively target aromatase in the breast and reduce systemic toxicity [18] . Among these compounds, flavonoids [19] are the most commonly investigated agents due to their prominent aromatase inhibitory activity and high breast selectivity [18] . Moreover, flavonoids may modulate the multi-step process of carcinogenesis through cellular and molecular mechanisms [19] . Biochanin A (BCA), isolated from red clover (Trifolium pretense), is a common isoflavone product that can inhibit aromatase activity and cell growth in MCF-7 cells [20] . Furthermore, cyp19a1 mRNA abundance was significantly reduced by BCA through promoter regulation in SK-BR-3 cells [20] .The classical tritiated water release assay [21,22] is ...

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Involvement of estrogen receptor-β in farrerol inhibition of rat thoracic aorta vascular smooth muscle cell proliferation

Cited by 45 publications

References 38 publications

IQGAP1 modulates the proliferation and migration of vascular smooth muscle cells in response to estrogen

IQGAP1 modulates the proliferation and migration of vascular smooth muscle cells in response to estrogen

Alpha-Lipoic Acid Protects Human Aortic Endothelial Cells Against H2O2-Induced Injury and Inhibits Atherosclerosis in Ovariectomized Low Density Lipoprotein Receptor Knock-Out Mice

Discovery of novel aromatase inhibitors using a homogeneous time-resolved fluorescence assay

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