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.
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.
Department of Microbiology, Tulane University School of Medicine, New Orleans, LA, USA.
Naveen K
NK
Somanna
Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA.
Anthony J
AJ
Valente
Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA.
Maike
M
Krenz
Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, USA.
Kerry S
KS
McDonald
Medicine/Cardiology, University of Missouri School of Medicine, Columbia, MO, USA.
Yusuke
Y
Higashi
Molecular Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
Makoto
M
Noda
Medicine/Cardiology, University of Missouri School of Medicine, Columbia, MO, USA.|Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA.
Bysani
B
Chandrasekar
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology*; D020382:Interleukin-18 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*
D001549:Benzamides; D058851:GPI-Linked Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020382:Interleukin-18; D011743:Pyrimidines; C492025:Reck protein, mouse; D000804:Angiotensin II; C012589:trichostatin A; C523184:mocetinostat; D020780:Matrix Metalloproteinase 9