Abstract 302: Neuregulin-1β Inhibits TGFβ-induced Cardiofibroblast to Myofibroblast Transition
Neuregulin (NRG) is a growth and survival factor critical for cardiac development and repair. Our laboratory recently demonstrated decreased fibrosis with NRG treatment in post-infarcted swine. We subsequently hypothesized that NRG inhibits transition of fibroblasts to myofibroblasts (myoFbs), the cells primarily responsible for collagen deposition after cardiac injury. Immunohistochemistry of post-infarcted swine hearts confirmed reduced presence of myoFbs in NRG-treated pig ventricles, compared to untreated animals. Further investigation revealed that NRG acts directly upon primary cultures of rat cardiac fibroblasts, with subsequent phosphorylation of both AKT and p38. Based on quantitative RT-PCR, primary fibroblasts isolated from both rats and mice express ErbB2 and ErbB3, which are known to form heterodimers and thereby transduce the NRG signal. NRG treatment also reduced myoFb percentages by ~40% in primary rat and mouse cardiac cultures, compared to untreated cells, as demonstrated by immunohistochemistry, Western blot, and flow cytometric analyses of the myoFb marker, alpha smooth muscle actin. NRG pre-treatment of cardiac fibroblasts likewise inhibited TGFβ-induced fibroblast-to-myoFb transition, including suppression of SMAD3 phosphorylation and reduction of the down-stream pro-fibrotic proteins, collagen I and periostin. Considered together, these data strongly support the hypothesis that NRG modulates fibroblast signaling directly. These results demonstrate that NRG inhibits the activation of pro-fibrotic cells and suggests a novel mechanism by which NRG treatment might improve cardiac remodeling.
- © 2013 by American Heart Association, Inc.