title: ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene.
abstract: Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-β/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, 75651 Paris Cedex 13, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Chatzifrangkeskou
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Dour
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Morrow
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Leroy C
authors.initials: LC
authors.lastname: Joseph
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, 75651 Paris Cedex 13, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Beuvin
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Fusako
authors.initials: F
authors.lastname: Sera
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, 75651 Paris Cedex 13, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vignier
authors.affiliation: Sorbonne Universités, UPMC Paris 06, INSERM UMS28 Phénotypage du petit animal, Faculté de Médecine Pierre et Marie Curie, F-75013, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mougenot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, 75651 Paris Cedex 13, France.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.affiliation: FibroGen Inc, San Francisco, CA 94158, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière, 75651 Paris Cedex 13, France Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA a.muchir@institut-myologie.org.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D055513:Connective Tissue Growth Factor / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051785:Smad Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000473:pathology
chemical_list: C526318:CCN2 protein, mouse; D034904:Lamin Type A; C576142:Lmna protein, mouse; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor