title: G Protein-Coupled Estrogen Receptor 1 Mediates Acute Estrogen-Induced Cardioprotection via MEK/ERK/GSK-3β Pathway after Ischemia/Reperfusion.
abstract: Three types of estrogen receptors (ER) exist in the heart, Esr1, Esr2 and the G protein-coupled estrogen receptor 1, Gper1. However, their relative importance in mediating estrogen protective action is unknown. We found that, in the male mouse ventricle, Gper1 transcripts are three- and seventeen-fold more abundant than Esr1 and Esr2 mRNAs, respectively. Analysis of the three ER knockouts (Esr1-/-, Esr2-/- and Gper1-/-) showed that only the Gper1-/- hearts lost their ability to be protected by 40 nM estrogen as measured by heart function, infarct size and mitochondrial Ca2+ overload, an index of mitochondrial permeability transition pore (mPTP) activity. Analysis of Akt, ERK1/2 and GSK-3β salvage kinases uncovered Akt and ERK1/2 transient activation by estrogen whose phosphorylation increased during the first 5 min of non-ischemic perfusion. All these increase in phosphorylation effects were abrogated in Gper1-/-. Inhibition of MEK1/2/ERK1/2 (1 μM U0126) and PI-3K/Akt (10 μM LY294002) signaling showed that the MEK1/2/ERK1/2 pathway via GSK-3β exclusively was responsible for cardioprotection as an addition of U0126 prevented estrogen-induced GSK-3β increased phosphorylation, resistance to mitochondrial Ca2+-overload, functional recovery and protection against infarction. Further, inhibiting PKC translocation (1 μM chelerythrin-chloride) abolished estrogen-induced cardioprotection. These data indicate that estrogen-Gper1 acute coupling plays a key role in cardioprotection against ischemia/reperfusion injury in male mouse via a cascade involving PKC translocation, ERK1/2/GSK-3β phosphorylation leading to the inhibition of the mPTP opening.
authors.affiliation: Department of Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, TX 78229, United States of America.
authors.forename: Mohammad E
authors.initials: ME
authors.lastname: Kabir
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, United States of America.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States of America.
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Olde
authors.affiliation: Department of Experimental Medical Science, Lund University, 22184 Lund, Sweden.
authors.forename: L M Fredrik
authors.initials: LM
authors.lastname: Leeb-Lundberg
authors.affiliation: Department of Physiology, School of Medicine, University of Texas Health Science Center at San Antonio, TX 78229, United States of America.
authors.forename: Jean Chrisostome
authors.initials: JC
authors.lastname: Bopassa
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D008954:Models, Biological; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D002316:Cardiotonic Agents; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; C532507:GPER1 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3; D002118:Calcium