Estrogen Receptor Alpha as a Key Target of Red Wine Polyphenols Action on the Endothelium
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{"title"=>"Estrogen receptor alpha as a key target of red wine polyphenols action on the endothelium", "type"=>"journal", "authors"=>[{"first_name"=>"Matthieu", "last_name"=>"Chalopin", "scopus_author_id"=>"36007073300"}, {"first_name"=>"Angela", "last_name"=>"Tesse", "scopus_author_id"=>"6508226004"}, {"first_name"=>"Maria Carmen", "last_name"=>"Martínez", "scopus_author_id"=>"55335137700"}, {"first_name"=>"Didier", "last_name"=>"Rognan", "scopus_author_id"=>"7004226067"}, {"first_name"=>"Jean François", "last_name"=>"Arnal", "scopus_author_id"=>"35241961200"}, {"first_name"=>"Ramaroson", "last_name"=>"Andriantsitohaina", "scopus_author_id"=>"35557791300"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-77649123355", "pui"=>"358372407", "doi"=>"10.1371/journal.pone.0008554", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"77649123355", "pmid"=>"20049322"}, "id"=>"6b5ffdf8-2278-39c2-a0bc-bdf61ee93acb", "abstract"=>"BACKGROUND: A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERalpha) could be involved in the transduction of the vascular benefits of polyphenols.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: Here, we used ERalpha deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERalpha. Indeed, Provinols, delphinidin and ERalpha agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERalpha Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERalpha completely prevented the effects of Provinols and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERalpha activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERalpha deficient mice.\\n\\nCONCLUSIONS/SIGNIFICANCE: This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits via ERalpha activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.", "link"=>"http://www.mendeley.com/research/estrogen-receptor-alpha-key-target-red-wine-polyphenols-action-endothelium", "reader_count"=>52, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>5, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>2, "Other"=>6, "Student > Master"=>2, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>2, "Unspecified"=>2}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>5, "Researcher"=>12, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>2, "Other"=>6, "Student > Master"=>2, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>2, "Unspecified"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>27, "Medicine and Dentistry"=>6, "Neuroscience"=>2, "Sports and Recreations"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>1, "Chemistry"=>2, "Psychology"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>2}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>27}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Canada"=>2, "Belgium"=>1, "United Kingdom"=>1, "Italy"=>1, "France"=>2}, "group_count"=>0}

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  • {"files"=>["https://ndownloader.figshare.com/files/431513"], "description"=>"<div><h3>Background</h3><p>A greater reduction in cardiovascular risk and vascular protection associated with diet rich in polyphenols are generally accepted; however, the molecular targets for polyphenols effects remain unknown. Meanwhile evidences in the literature have enlightened, not only structural similarities between estrogens and polyphenols known as phytoestrogens, but also in their vascular effects. We hypothesized that alpha isoform of estrogen receptor (ERα) could be involved in the transduction of the vascular benefits of polyphenols.</p><h3>Methodology/Principal Findings</h3><p>Here, we used ERα deficient mice to show that endothelium-dependent vasorelaxation induced either by red wine polyphenol extract, Provinols™, or delphinidin, an anthocyanin that possesses similar pharmacological profile, is mediated by ERα. Indeed, Provinols™, delphinidin and ERα agonists, 17-beta-estradiol and PPT, are able to induce endothelial vasodilatation in aorta from ERα Wild-Type but not from Knock-Out mice, by activation of nitric oxide (NO) pathway in endothelial cells. Besides, silencing the effects of ERα completely prevented the effects of Provinols™ and delphinidin to activate NO pathway (Src, ERK 1/2, eNOS, caveolin-1) leading to NO production. Furthermore, direct interaction between delphinidin and ERα activator site is demonstrated using both binding assay and docking. Most interestingly, the ability of short term oral administration of Provinols™ to decrease response to serotonin and to enhance sensitivity of the endothelium-dependent relaxation to acetylcholine, associated with concomitant increased NO production and decreased superoxide anions, was completely blunted in ERα deficient mice.</p><h3>Conclusions/Significance</h3><p>This study provides evidence that red wine polyphenols, especially delphinidin, exert their endothelial benefits <em>via</em> ERα activation. It is a major breakthrough bringing new insights of the potential therapeutic of polyphenols against cardiovascular pathologies.</p></div>", "links"=>[], "tags"=>["estrogen", "receptor", "alpha", "polyphenols", "endothelium"], "article_id"=>145154, "categories"=>["Chemistry", "Physiology", "Medicine"], "users"=>["Matthieu Chalopin", "Angela Tesse", "Maria Carmen Martinez", "Didier Rognan", "Jean-François Arnal", "Ramaroson Andriantsitohaina"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008554"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Estrogen_Receptor_Alpha_as_a_Key_Target_of_Red_Wine_Polyphenols_Action_on_the_Endothelium/145154", "title"=>"Estrogen Receptor Alpha as a Key Target of Red Wine Polyphenols Action on the Endothelium", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-01-01 01:25:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/869411"], "description"=>"<p>Concentration-effect curves to increasing concentrations of PPT (A), 17-β estradiol (E<sub>2</sub>) (B), Provinols™ (C) or delphinidin (D) in aortic rings, with functional endothelium precontracted with U46619, taken from ERα Wild Type (open circles) and Knock-Out (filled circles) mice (n = 5–6). **<i>P</i><0.01, ***<i>P</i><0.001.</p>", "links"=>[], "tags"=>["mediates", "endothelium-dependent", "relaxation", "induced"], "article_id"=>539865, "categories"=>["Chemistry", "Physiology", "Medicine"], "users"=>["Matthieu Chalopin", "Angela Tesse", "Maria Carmen Martinez", "Didier Rognan", "Jean-François Arnal", "Ramaroson Andriantsitohaina"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008554.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ER_945_mediates_endothelium_dependent_relaxation_induced_by_agonists_Provinols_8482_and_delphinidin_/539865", "title"=>"ERα mediates endothelium-dependent relaxation induced by agonists, Provinols™ and delphinidin.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-01 02:44:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/869539"], "description"=>"<p>NO production induced by Provinols™, delphinidin, PPT and 17-β estradiol (E<sub>2</sub>) in endothelial cells and consequences of ERα pathway inhibition with either Fulvestrant or siRNA directed against ERα (siRNA). EaHy 926 cells (A and B) or aortic endothelial cells from either ERα Wild-Type (WT) mice (C), ERα Knock-Out (KO) mice (D) or from Swiss mice (E) were treated for 10 minutes with Provinols™ (10<sup>−2</sup> g/L), delphinidin (10<sup>−2</sup> g/L), PPT (10<sup>−5</sup> M) or E<sub>2</sub> (10<sup>−5</sup> M) and this in the presence or in the absence of either Fulvestrant (30 nM) (hatched bars) or after knocking down the receptor with siRNA (siRNA) (striped bars). Then NO production was assessed by electronic paramagnetic resonance. In panel A, insert shows Western blot for ERα in the control (lane 1) or ERα siRNA (lane 2)-treated Eahy endothelial cells. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001 <i>vs</i> non treated; #<i>P</i><0.05, ##<i>P</i><0.01 <i>vs</i> Provinols™, delphinidin (A, C and D), PPT or E<sub>2</sub> alone (B and D), (n = 4–6).</p>", "links"=>[], "tags"=>["activation", "induces", "endothelial"], "article_id"=>539993, "categories"=>["Chemistry", "Physiology", "Medicine"], "users"=>["Matthieu Chalopin", "Angela Tesse", "Maria Carmen Martinez", "Didier Rognan", "Jean-François Arnal", "Ramaroson Andriantsitohaina"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008554.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ER_945_activation_induces_endothelial_NO_release_/539993", "title"=>"ERα activation induces endothelial NO release.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-01 02:46:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/869636"], "description"=>"<p>Activation of NO pathway induced by Provinols™, delphinidin, PPT and 17-β estradiol (E<sub>2</sub>) in endothelial cells and consequences of ERα pathway inhibition with either Fulvestrant or siRNA directed against ERα (siRNA). EaHy 926 cells were treated for 10 minutes with Provinols™ (10<sup>−2</sup> g/L), delphinidin (10<sup>−2</sup> g/L), PPT (10<sup>−5</sup> M) or E<sub>2</sub> (10<sup>−5</sup> M) and this in the presence or in the absence of either Fulvestrant (30 nM) (hatched bars) or after knocking down the receptor with siRNA (siRNA) (striped bars). Then cells were lysed to perform Western Blot analysis. *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001 <i>vs</i> non treated; #<i>P</i><0.05, ##<i>P</i><0.01 <i>vs</i> Provinols™, delphinidin (A, B, C and D), PPT or E<sub>2</sub> alone (E, F, G and H), (n = 4–6).</p>", "links"=>[], "tags"=>["activation", "induces", "phosphorylation", "signaling"], "article_id"=>540089, "categories"=>["Chemistry", "Physiology", "Medicine"], "users"=>["Matthieu Chalopin", "Angela Tesse", "Maria Carmen Martinez", "Didier Rognan", "Jean-François Arnal", "Ramaroson Andriantsitohaina"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008554.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ER_945_activation_induces_phosphorylation_of_NO_signaling_proteins_/540089", "title"=>"ERα activation induces phosphorylation of NO signaling proteins.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-01 00:01:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/869760"], "description"=>"<p>Binding mode of 17-β estradiol (E<sub>2</sub>) (panel A, X-ray structure) and delphinidin (panel B, docking model) to the ligand-binding domain of the ERα (1a52 PDB entry). The receptor backbone is displayed by solid ribbons. Ligand-contacting side chains are displayed by white ball and sticks. Carbon atoms of receptor-bound E<sub>2</sub> and delphinidin are in yellow and green, respectively. In panel C, the ligand-receptor interactions for both compounds are encoded by an interaction fingerprint converting into a 7 bit string the interaction of the ligand with each residue of the binding site using the following color-coding: blue, apolar contact; green: aromatic interaction; red: hydrogen-bond. Eventually, D represents results of a binding assay of delphinidin on ERα. E<sub>2</sub> was used as control agonist for ERα and delphinidin was used at concentration exerting endothelial effects shown before (10<sup>−2</sup> g/L).</p>", "links"=>[], "tags"=>["assay", "docking", "delphinidin", "activator"], "article_id"=>540213, "categories"=>["Chemistry", "Physiology", "Medicine"], "users"=>["Matthieu Chalopin", "Angela Tesse", "Maria Carmen Martinez", "Didier Rognan", "Jean-François Arnal", "Ramaroson Andriantsitohaina"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008554.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Binding_assay_and_docking_show_direct_interaction_between_delphinidin_and_ER_945_activator_site_/540213", "title"=>"Binding assay and docking show direct interaction between delphinidin and ERα activator site.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-01 00:03:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/869880"], "description"=>"<p>Concentration-effect curves to increasing concentrations of serotonin (5-HT) in aortas, with endothelium, from ERα Wild Type (WT) (A) or Knock-Out (KO) (B) mice treated either with control diet (open circles) or diet containing Provinols™ for 2 weeks at 20 mg/kg/day (filled circles, ***<i>P</i><0.001, n = 6). Concentration-effect curves to increasing concentrations of acetylcholine (Ach) in aortas with endothelium, pre-contracted at 80% of the maximal contraction with U46619 from ERα WT (C) or KO (D) mice treated either with control diet (open circles) or diet containing Provinols™ for 2 weeks at 20 mg/kg/day (filled circles) (*<i>P</i><0.05, n = 6). Quantification of NO (E) and O<sub>2</sub><sup>−</sup> production (F) in mesenteric arteries from ERα WT or KO mice receiving either standard diet or diet containing Provinols™ (*<i>P</i><0.05 <i>vs</i> control diet; #<i>P</i><0.05 KO <i>vs</i> WT; n = 5).</p>", "links"=>[], "tags"=>["vascular", "induced"], "article_id"=>540335, "categories"=>["Chemistry", "Physiology", "Medicine"], "users"=>["Matthieu Chalopin", "Angela Tesse", "Maria Carmen Martinez", "Didier Rognan", "Jean-François Arnal", "Ramaroson Andriantsitohaina"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008554.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Involvement_of_ER_945_in_vascular_effects_induced_by_an_oral_treatment_with_Provinols_8482_/540335", "title"=>"Involvement of ERα in vascular effects induced by an oral treatment with Provinols™.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-01 00:05:35"}

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