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Neuregulin‐1β Induces ErbB3‐dependent Proliferation and Survival of Normal Human Cardiac Ventricular Fibroblasts
Author(s) -
Galindo Cristi Lara,
Kirabo Annet,
Gupte Manisha,
Ryzhov Sergey,
Sawyer Douglas B
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.470.2
Subject(s) - pi3k/akt/mtor pathway , neuregulin , neuregulin 1 , protein kinase b , erbb3 , phosphorylation , fibroblast , signal transduction , cancer research , biology , fibrosis , receptor tyrosine kinase , microbiology and biotechnology , medicine , cell culture , genetics
Neuregulin‐1β (NRG‐1β) is critical for cardiac development and repair and is currently being assessed as a possible therapeutic for systolic heart failure. Our laboratory and others have shown that NRG‐1β improves heart function in several animal models of heart disease, and several human trials indicate that it is a promising treatment for human heart disease. We previously demonstrated that NRG‐1β reduces cardiac fibrosis in an animal model of myocardial infarction, suggesting that it might influence cardiac fibroblast signaling. Here we show that NRG‐1β receptors (ErbB2, ErbB3, and ErbB4) are indeed expressed in normal human cardiac ventricular (NHCV) fibroblasts. Treatment of NHCV fibroblasts with exogenous 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 (TY)1248 and TY1289 respectively. RNASeq analysis of NRG‐1β‐treated cardiac fibroblasts obtained from three different donor hearts 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. These novel findings suggest a role for NRG‐1β in the regulation of cardiac ventricular fibroblast growth and survival via ErbB2/ErbB3 receptor phosphorylation with subsequent activation of the PI3K‐AKT signaling pathway. Support or Funding Information This work was supported in part by National Institutes of Health grants 1K01HL13049701(Kirabo) and K01HL121045 (Galindo). VANTAGE is supported in part by CTSA Grant (5UL1 RR024975‐03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956).