title: Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice.
abstract: OBJECTIVE
  Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases and promotes inflammation. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated. We examined the role of Bsg in cardiac hypertrophy and failure in mice and humans.
  
  
  RESULTS
  We performed transverse aortic constriction in Bsg(+/-) and in wild-type mice. Bsg(+/-) mice showed significantly less heart and lung weight and cardiac interstitial fibrosis compared with littermate controls after transverse aortic constriction. Both matrix metalloproteinase activities and oxidative stress in loaded left ventricle were significantly less in Bsg(+/-) mice compared with controls. Echocardiography showed that Bsg(+/-) mice showed less hypertrophy, less left ventricular dilatation, and preserved left ventricular fractional shortening compared with littermate controls after transverse aortic constriction. Consistently, Bsg(+/-) mice showed a significantly improved long-term survival after transverse aortic constriction compared with Bsg(+/+) mice, regardless of the source of bone marrow (Bsg(+/+) or Bsg(+/-)). Conversely, cardiac-specific Bsg-overexpressing mice showed significantly poor survival compared with littermate controls. Next, we isolated cardiac fibroblasts and examined their responses to angiotensin II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion, and extracellular signal-regulated kinase/Akt/JNK activities in Bsg(+/+) cardiac fibroblasts, all of which were significantly less in Bsg(+/-) cardiac fibroblasts. Consistently, extracellular and intracellular Bsg significantly promoted cardiac fibroblast proliferation. Finally, serum levels of Bsg were significantly elevated in patients with heart failure and predicted poor prognosis.
  
  
  CONCLUSIONS
  These results indicate the crucial roles of intracellular and extracellular Bsg in the pathogenesis of cardiac hypertrophy, fibrosis, and failure in mice and humans.
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kota
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Shohei
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sunamura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Otsuki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Taijyu
authors.initials: T
authors.lastname: Satoh
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Junichi
authors.initials: J
authors.lastname: Omura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurosawa
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Masamichi
authors.initials: M
authors.lastname: Nogi
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Numano
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sugimura
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Aoki
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tatebe
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyata
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.).
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: From the Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (K.S., K.S., S.I., S.S., T.O., T.S., N.K., J.O., R.K., M.N., K.N., K.S., T.A., S.T., H.S.); Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston (R.M.); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia (F.G.S.); and Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K.). shimo@cardio.med.tohoku.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001018:Aortic Diseases / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D040542:Mechanotransduction, Cellular; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016277:Ventricular Function, Left
chemical_list: C497886:BSG protein, human; D001798:Blood Proteins; C497887:Bsg protein, mouse; C079432:Bsg protein, rat; D018836:Inflammation Mediators; D000804:Angiotensin II; D051926:Basigin; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases
keywords: angiotensin II; cytokines; heart failure; hypertrophy; inflammation