Histone deacetyltransferase inhibitors Trichostatin A and Mocetinostat differentially regulate MMP9, IL-18 and RECK expression, and attenuate Angiotensin II-induced cardiac fibroblast migration and proliferation

• Published in: Hypertension research Vol. 39; no. 10; pp. 709 - 716
• Main Authors: Somanna, Naveen K, Valente, Anthony J, Krenz, Maike, McDonald, Kerry S, Higashi, Yusuke, Noda, Makoto, Chandrasekar, Bysani
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2016
• Subjects: Angiotensin II - pharmacology; Animals; Benzamides - pharmacology; Cell Death - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; GPI-Linked Proteins - metabolism; Heart - drug effects; Histone Deacetylase Inhibitors - pharmacology; Hydroxamic Acids - pharmacology; Interleukin-18 - metabolism; Matrix Metalloproteinase 9 - metabolism; Mice; Myocardium - cytology; Myocardium - metabolism; Pyrimidines - pharmacology
• ISSN: 0916-9636; 1348-4214
• DOI: 10.1038/hr.2016.54

Histone acetylation/deacetylation plays a key role in the epigenetic regulation of multiple pro-fibrotic genes. Here we investigated the effects of histone deacetyltransferase (HDAC) inhibition on angiotensin (Ang)-II-induced pro-fibrotic changes in adult mouse cardiac fibroblasts (CF). CF express class I HDACs 1 and 2, and Ang-II induces their activation. Notably, silencing HDAC1 or HDAC2 attenuated Ang-II induced CF proliferation and migration. Under basal conditions, HDAC1 dimerizes with HDAC2 in CF and Ang-II reversed this interaction. Treatment with Trichostatin A (TSA), a broad-spectrum HDAC inhibitor, restored their physical association, and attenuated Ang-II-induced MMP9 expression, IL-18 induction, and extracellular matrix (collagen I, collagen III and fibronectin) production. Further, TSA inhibited Ang-II-induced MMP9 and Il18 transcription by blocking NF-κB and AP-1 binding to their respective promoter regions. By inhibiting Sp1 binding to RECK promoter, TSA reversed Ang-II-induced RECK suppression, collagen and fibronectin expression, and CF migration and proliferation. The class I-specific HDAC inhibitor Mocetinostat (MGCD) recapitulated TSA effects on Ang-II-treated CF. Together, these results demonstrate that targeting HDACs attenuates the pro-inflammatory and pro-fibrotic effects of Ang-II on CF.