Raloxifene Increases Proliferation and Up-regulates Telomerase Activity in Human Umbilical Vein Endothelial Cells

Doshida, Masakazu; Ohmichi, Masahide; Tsutsumi, Seiji; Koyama, Jun; Takahashi, Toshifumi; Du, Botao; Mori-Abe, Akiko; Ohta, Tsuyoshi; Saitoh-Sekiguchi, Maki; Takahashi, Kazuhiro; Kurachi, Hirohisa

doi:10.1074/jbc.m513251200

Cited by 30 publications

(19 citation statements)

References 42 publications

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“…119 Raloxifene, a selective estrogen receptor modulator, also upregulates telomerase activity in human umbilical ECs (HUVECs). 120 In accordance with these findings, Imanishi et al found that estrogen reduces EPC senescence by increasing TERT levels in a phosphatidylinositol 3-kinase/Aktdependent manner. 121 Furthermore, estrogen stimulates in vascular ECs the production of nitric oxide, 118 which also induces telomerase activity and delays EC senescence.…”

Section: Fuster and Andrés Telomeres And Cardiovascular Diseasesupporting

confidence: 55%

Telomere Biology and Cardiovascular Disease

Fuster

Andrés

2006

Circulation Research

217

206

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Abstract-Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease. Key Words: telomeres Ⅲ telomerase Ⅲ atherosclerosis Ⅲ heart disease Ⅲ oxidative stress Ⅲ hypertension Ⅲ diabetes Ⅲ estrogens T elomeres are special chromatin structures located at the ends of eukaryotic chromosomes that prevent the recognition of chromosomal ends as double-stranded DNA breaks, thereby protecting these regions from recombination and degradation and avoiding a DNA damage cellular response. The telomeric DNA is composed of noncoding doublestranded repeats of G-rich tandem DNA sequences (TTAGGG in vertebrates) that are extended several thousand base pairs (10 to 15 kb in humans and 25 to 40 kb in mice) and end in a 150 to 200 nucleotide 3Ј single-stranded overhang (G-strand overhang) (Figure 1). 1,2 Several specific proteins are associated to telomeric DNA, including telomerase and the telomeric repeat binding factors 1 and 2 (TRF1, TRF2) which directly bind to the TTAGGG repeat and interact with other factors forming large protein complexes that regulate telomere length and structure. Mammalian telomerase consists of a RNA component (telomerase RNA component [TERC]) that serves as a template for the synthesis of new telomeric TTAGGG repeats by the telomerase reverse transcriptase component (TERT). Telomere components and structure has been comprehensively discussed elsewhere. 2

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Section: Fuster and Andrés Telomeres And Cardiovascular Diseasesupporting

confidence: 55%

Telomere Biology and Cardiovascular Disease

Fuster

Andrés

2006

Circulation Research

217

206

View full text Add to dashboard Cite

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“…In some experiments, the membrane-permeable NF-κB transcriptional inhibitor SN50 and its inactive control SN50M (EMD Biosciences) were used to treat EC monolayers at 1 μM, a concentration previously documented to potently block NF-κB transcriptional activation in vascular ECs (Devaraj et al, 2004;Doshida et al, 2006;Iwasaki et al, 2008), including human aortic ECs (Devaraj et al, 2004).…”

Section: Measurement Of Endogenous Nf-κb Transcriptional Activity Andmentioning

confidence: 99%

Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Zhu

Luo

Chen

et al. 2008

Journal of Cell Science

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A physiological membrane-receptor agonist typically stimulates oscillations, of varying frequencies, in cytosolic Ca2+ concentration ([Ca2+]i). Whether and how [Ca2+]i oscillation frequency regulates agonist-stimulated downstream events, such as gene expression, in non-excitable cells remain unknown. By precisely manipulating [Ca2+]i oscillation frequency in histamine-stimulated vascular endothelial cells (ECs), we demonstrate that the gene expression of vascular cell adhesion molecule 1 (VCAM1) critically depends on [Ca2+]i oscillation frequency in the presence, as well as the absence, of histamine stimulation. However, histamine stimulation enhanced the efficiency of [Ca2+]i-oscillation-frequency-regulated VCAM1 gene expression, versus [Ca2+]i oscillations alone in the absence of histamine stimulation. Furthermore, a [Ca2+]i oscillation frequency previously observed to be the mean frequency in histamine-stimulated ECs was found to optimize VCAM1 mRNA expression. All the above effects were abolished or attenuated by blocking histamine-stimulated generation of intracellular reactive oxygen species (ROS), another intracellular signaling pathway, and were restored by supplementary application of a low level of H2O2. Endogenous NF-κB activity is similarly regulated by [Ca2+]i oscillation frequency, as well as its co-operation with ROS during histamine stimulation. This study shows that [Ca2+]i oscillation frequency cooperates with ROS to efficiently regulate agonist-stimulated gene expression, and provides a novel and general strategy for studying [Ca2+]i signal kinetics in agonist-stimulated downstream events.

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“…Existing evidence has shown that ER ligands such as 17β-estradiol (E 2 ), estradiol, and raloxifene play central roles in the proliferation and migration of ERα-positive cells [6,7,8]. Therefore, E 2 was used as a positive control in the present study.…”

Section: Introductionmentioning

confidence: 99%

Biochanin A Promotes Proliferation that Involves a Feedback Loop of MicroRNA-375 and Estrogen Receptor Alpha in Breast Cancer Cells

Chen

Wang

et al. 2015

Cell Physiol Biochem

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Background: Biochanin A and formononetin are O-methylated isoflavones that are isolated from the root of Astragalus membranaceus, and have antitumorigenic effects. Our previous studies found that formononetin triggered growth-inhibitory and apoptotic activities in MCF-7 breast cancer cells. We performed in vivo and in vitro studies to further investigate the potential effect of biochanin A in promoting cell proliferation in estrogen receptor (ER)-positive cells, and to elucidate underlying mechanisms. Methods: ERα-positive breast cancer cells (T47D, MCF-7) were treated with biochanin A. The MTT assay and flow cytometry were used to assess cell proliferation and apoptosis. mRNA levels of ERα, Bcl-2, and miR-375 were quantified using real-time polymerase chain reaction. Compared with the control, low biochanin A concentrations (2-6 μM) stimulated ERα-positive cell proliferation (T47D, MCF-7). The more sensitive T47D cells were used to study the relevant signaling pathway. Results: After treatment with biochanin A, ERα, miR-375, and Bcl-2 expression was significantly upregulated. Additionally, in the in vivo studies, uterine weight in ovariectomized mice treated with biochanin A increased significantly. Conclusion: This study demonstrated that biochanin A promoted ERα-positive cell proliferation through miR-375 activation and this mechanism is possibly involving in a miR-375 and ERα feedback loop.

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Raloxifene Increases Proliferation and Up-regulates Telomerase Activity in Human Umbilical Vein Endothelial Cells

Cited by 30 publications

References 42 publications

Telomere Biology and Cardiovascular Disease

Telomere Biology and Cardiovascular Disease

Ca2+ oscillation frequency regulates agonist-stimulated gene expression in vascular endothelial cells

Biochanin A Promotes Proliferation that Involves a Feedback Loop of MicroRNA-375 and Estrogen Receptor Alpha in Breast Cancer Cells

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