title: Anti-remodeling and anti-fibrotic effects of the neuregulin-1β glial growth factor 2 in a large animal model of heart failure.
abstract: BACKGROUND
  Neuregulin-1β (NRG-1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG-1β improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post-MI swine, as well as potential mechanisms for anti-remodeling effects.
  
  
  RESULTS
  MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post-MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post-MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end-diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2-treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2-treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG-1β reduces myoFbs, and suppresses TGFβ-induced phospho-SMAD3 as well as αSMA expression.
  
  
  CONCLUSIONS
  These results suggest that GGF2/NRG-1β prevents adverse remodeling after injury in part via anti-fibrotic effects in the heart.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Ehab
authors.initials: E
authors.lastname: Kasasbeh
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Abigail
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryzhov
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Sean
authors.initials: S
authors.lastname: Lenihan
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Farhaan A
authors.initials: FA
authors.lastname: Ahmad
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Philip
authors.initials: P
authors.lastname: Williams
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Amy
authors.initials: A
authors.lastname: Nunnally
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Jamie
authors.initials: J
authors.lastname: Adcock
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, TN (Y.S., F.E.H.).
authors.forename: Yanna
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Biostatistics, Vanderbilt University, Nashville, TN (Y.S., F.E.H.).
authors.forename: Frank E
authors.initials: FE
authors.lastname: Harrell
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Truc-Linh
authors.initials: TL
authors.lastname: Tran
authors.affiliation: Acorda Therapeutics, Ardsley, NY (T.J.P., J.I., A.G., A.O.C.).
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Parry
authors.affiliation: Acorda Therapeutics, Ardsley, NY (T.J.P., J.I., A.G., A.O.C.).
authors.forename: Jen
authors.initials: J
authors.lastname: Iaci
authors.affiliation: Acorda Therapeutics, Ardsley, NY (T.J.P., J.I., A.G., A.O.C.).
authors.forename: Anindita
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Igor
authors.initials: I
authors.lastname: Feoktistov
authors.affiliation: Ingram Cancer Center, Vanderbilt University, Nashville, TN (M.K.S.).
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Stephenson
authors.affiliation: Acorda Therapeutics, Ardsley, NY (T.J.P., J.I., A.G., A.O.C.).
authors.forename: Anthony O
authors.initials: AO
authors.lastname: Caggiano
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN (J.H.C.).
authors.forename: John H
authors.initials: JH
authors.lastname: Cleator
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism; D013552:Swine; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000235:genetics
chemical_list: D000199:Actins; D020890:Neuregulin-1; D051900:Smad3 Protein
keywords: extracellular matrix; fibroblasts; fibrosis; myocardial infarction; neuregulin