title: Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart.
abstract: Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After myocardial infarction, activated cardiac fibroblasts deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate, and new molecular targets are needed.
  
  
  
  Herein we report that glycogen synthase kinase-3β (GSK-3β) is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using 2 fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a profibrotic myofibroblast phenotype in isolated cardiac fibroblasts, in post-myocardial infarction hearts, and in mouse embryonic fibroblasts deleted for GSK-3β. Mechanistically, GSK-3β inhibits profibrotic transforming growth factor-β1/SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the significant increase of SMAD-3 transcriptional activity. This pathway is central to the pathology because a small-molecule inhibitor of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling.
  
  
  
  These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction.
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Firdos
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Jibin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Justine E
authors.initials: JE
authors.lastname: Yu
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Vagnozzi
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Yuanjun
authors.initials: Y
authors.lastname: Guo
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Tsai
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: James
authors.initials: J
authors.lastname: Woodgett
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.). thomas.force@temple.edu Hind.lal@temple.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000368:Aged; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: fibroblasts; fibrosis; glycogen synthase kinase 3 beta; hypertrophy; myocardial infarction