Abstract 13264: Inhibition of Class I HDACs Suppresses Fibrogenesis by Repressing Tgf-β1-induced Smad Activation in Cardiac Fibroblasts
Introduction: Cardiac fibrosis is a hallmark feature of pathological cardiac remodeling, contributing to contractile dysfunction and arrhythmogenesis. We have shown previously that HDACs (histone deacetylases) participate in myocardial fibrogenesis, and HDAC inhibition (e.g. with Trichostatin A, TSA) suppresses afterload-triggered cardiac fibrosis. Here, we tested the hypothesis that HDAC activity is required for cardiac fibrosis and defined underlying mechanisms.
Methods: Neonatal rat cardiac fibroblasts (NRCFs) were isolated and exposed in vitro to recombinant TGF-β1 to stimulate collagen biosynthesis. HDAC activity was inhibited pharmacologically or by RNAi-dependent protein knockdown.
Results: Treatment of NRCFs with TSA, valproic acid, or the class I-specific HDAC inhibitor, apicidin, blunted TGF-β1-stimulated collagen I protein and mRNA levels, as well as levels of CTGF (connective tissue growth factor). Targeted knockdown of HDAC1, HDAC2, or HDAC3 individually had no effect, but combined knockdown of all three isoforms significantly blunted collagen I production and CTGF levels, pointing to functional redundancy among these protein isoforms. Repression of class I HDACs, however, did not impair TGF-β1-induced differentiation of fibroblasts into myofibroblasts. To address underlying mechanisms, we focused on the Smad signaling pathway. In these experiments, we found that apicidin significantly suppressed Smad2 phosphorylation induced by TGF-β1.
Conclusions: Our data suggest, for the first time, that class I HDACs are required for collagen biosynthesis in response to TGF-β1. Evidence to date suggests that suppression of TGF-β1-induced activation of the Smad pathway is involved. Together, these data suggest strongly that class I HDACs participate in stress-induced cardiac fibrogenesis, and that pharmacological suppression of these enzymes has potential to limit fibrosis after cardiac injury. Also, these data uncover cardiac fibroblasts as a novel target of therapeutic intervention in heart disease.
- © 2013 by American Heart Association, Inc.