title: Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts.
abstract: Neuregulin-1β (NRG-1β) is critical for cardiac development and repair, and recombinant forms are currently being assessed as possible therapeutics for systolic heart failure. We previously demonstrated that recombinant NRG-1β reduces cardiac fibrosis in an animal model of cardiac remodeling and heart failure, suggesting that there may be direct effects on cardiac fibroblasts. Here we show that NRG-1β receptors (ErbB2, ErbB3, and ErbB4) are expressed in normal human cardiac ventricular (NHCV) fibroblast cell lines. Treatment of NHCV fibroblasts with recombinant NRG-1β induced activation of the AKT pathway, which was phosphoinositide 3-kinase (PI3K)-dependent. Moreover, the NRG-1β-induced PI3K/AKT signaling in these cells required phosphorylation of both ErbB2 and ErbB3 receptors at tyrosine (Tyr)1248 and Tyr1289 respectively. RNASeq analysis of NRG-1β-treated cardiac fibroblasts obtained from three different individuals revealed a global gene expression signature consistent with cell growth and survival. We confirmed enhanced cellular proliferation and viability in NHCV fibroblasts in response to NRG-1β, which was abrogated by PI3K, ErbB2, and ErbB3 inhibitors. NRG-1β also induced production and secretion of cytokines (interleukin-1α and interferon-γ) and pro-reparative factors (angiopoietin-2, brain-derived neurotrophic factor, and crypto-1), suggesting a role in cardiac repair through the activation of paracrine signaling.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States. Electronic address: Annet.Kirabo@Vanderbilt.Edu.
authors.forename: Annet
authors.initials: A
authors.lastname: Kirabo
authors.affiliation: Maine Medical Research Institute, 81 Research Drive, Scarborough, ME 04074, United States. Electronic address: SRyzhoh@mmc.org.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ryzhov
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States. Electronic address: Manisha.Gupte@Vanderbilt.edu.
authors.forename: Manisha
authors.initials: M
authors.lastname: Gupte
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States. Electronic address: Ss5w@mtmail.mtsu.edu.
authors.forename: Seng
authors.initials: S
authors.lastname: Sengsayadeth
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States; Department of Pathology, Immunology, and Microbiology, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States. Electronic address: Richard.Gumina@Vanderbilt.Edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gumina
authors.affiliation: Maine Medical Research Institute, 81 Research Drive, Scarborough, ME 04074, United States. Electronic address: DSawyer@mmc.org.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Sawyer
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States. Electronic address: Cristi.L.Galindo@Vanderbilt.Edu.
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
mesh_terms: D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism*; D020890:Neuregulin-1 / Q000378:metabolism*; D019899:Paracrine Communication; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020890:Neuregulin-1; D002118:Calcium
keywords: Cardiac fibroblast; ErbB3; Neuregulin; RNASeq; Survival