title: G protein-coupled estrogen receptor protects from atherosclerosis.
abstract: Coronary atherosclerosis and myocardial infarction in postmenopausal women have been linked to inflammation and reduced nitric oxide (NO) formation. Natural estrogen exerts protective effects on both processes, yet also displays uterotrophic activity. Here, we used genetic and pharmacologic approaches to investigate the role of the G protein-coupled estrogen receptor (GPER) in atherosclerosis. In ovary-intact mice, deletion of gper increased atherosclerosis progression, total and LDL cholesterol levels and inflammation while reducing vascular NO bioactivity, effects that were in some cases aggravated by surgical menopause. In human endothelial cells, GPER was expressed on intracellular membranes and mediated eNOS activation and NO formation, partially accounting for estrogen-mediated effects. Chronic treatment with G-1, a synthetic, highly selective small molecule agonist of GPER, reduced postmenopausal atherosclerosis and inflammation without uterotrophic effects. In summary, this study reveals an atheroprotective function of GPER and introduces selective GPER activation as a novel therapeutic approach to inhibit postmenopausal atherosclerosis and inflammation in the absence of uterotrophic activity.
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Meyer
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Fredette
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Howard
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Chelin
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA.
authors.forename: Chinnasamy
authors.initials: C
authors.lastname: Ramesh
authors.affiliation: Pathologisches Institut, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.affiliation: Pathologisches Institut, Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.affiliation: Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM, USA.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Arterburn
authors.affiliation: Molecular Internal Medicine, University of Zürich, Zürich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Barton
authors.affiliation: Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008078:Cholesterol, LDL / Q000235:genetics / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D017698:Postmenopause / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D008078:Cholesterol, LDL; D003517:Cyclopentanes; C109584:GPER1 protein, human; D011804:Quinolines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide