HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes

Abstract

Pharmacological histone deacetylase (HDAC) inhibitors attenuate pathological cardiac remodeling and hypertrophic gene expression; yet, the direct histone targets remain poorly characterized. Since the inhibition of HDAC activity is associated with suppressing hypertrophy, we hypothesized histone acetylation would target genes implicated in cardiac remodeling. Trichostatin A (TSA) regulates cardiac gene expression and attenuates transverse aortic constriction (TAC) induced hypertrophy. We used chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq) to map, for the first time, genome-wide histone acetylation changes in a preclinical model of pathological cardiac hypertrophy and attenuation of pathogenesis with TSA. Pressure overload-induced cardiac hypertrophy was associated with histone acetylation of genes implicated in cardiac contraction, collagen deposition, inflammation, and extracellular matrix identified by ChIP-seq. Gene set enrichment analysis identified NF-kappa B (NF-kB) transcription factor activation with load induced hypertrophy. Increased histone acetylation was observed on the promoters of NFkB target genes (Icam1, Vcam1, Il21r, Il6ra, Ticam2, Cxcl10) consistent with gene activation in the hypertrophied heart. Surprisingly, TSA attenuated pressure overload-induced cardiac hypertrophy and the suppression of NFkB target genes by broad histone deacetylation. Our results suggest a mechanism for cardioprotection subject to histone deacetylation as a previously unknown target, implicating the importance of inflammation by pharmacological HDAC inhibition. The results of this study provides a framework for HDAC inhibitor function in the heart and argues the long held views of acetylation is subject to more flexibility than previously thought.

Roles of HDAC2 and HDAC8 in Cardiac Remodeling in Renovascular Hypertensive Rats and the Effects of Valproic Acid Sodium

“…Cardiac remodeling amelioration reduces cardiac morbidity and mortality [1,23] . To prevent cardiac hypertrophy and fibrosis more effectively and to apply more efficient therapeutic intervention, it is important to explore the factors involved in ventricular growth both at the early and established stage of cardiac remodeling.…”

Role of TRAF3 in neurological and cardiovascular diseases: an overview of recent studies

“…TRAF3 was found to be epigenetically regulated in three conditions: cardiac hypertrophy (25), acute lymphoblastic leukaemia (ALL) (26) and vascular recurrence in patients treated with clopidogrel (22).…”

“…It was observed that cardiac hypertrophy was associated with increased acetylation and activation of TRAF3 and other NF-κβ target genes. HDAC inhibition was associated with an antiinflammatory effect and, therefore, with cardio-protection through histone deacetylation and inactivation of NF-κβ target genes, including TRAF3 (25).…”

“…DNA methylation is usually associated with transcription repression, in contrast with unmethylated DNA, usually associated with active transcription (23)(24)(25).…”

“…The N-terminal tails of histones are modified by histone acetyl transferases (HATs) and histone deacetylases (HDACs), which acetylate and deacetylate, respectively. Acetylation is usually associated with gene activation while deacetylation is usually associated with gene inactivation (25).…”