Food Bioactive HDAC Inhibitors in the Epigenetic Regulation of Heart Failure

Abstract

Approximately 5.7 million U.S. adults have been diagnosed with heart failure (HF). More concerning is that one in nine U.S. deaths included HF as a contributing cause. Current HF drugs (e.g., β-blockers, ACEi) target intracellular signaling cascades downstream of cell surface receptors to prevent cardiac pump dysfunction. However, these drugs fail to target other redundant intracellular signaling pathways and, therefore, limit drug efficacy. As such, it has been postulated that compounds designed to target shared downstream mediators of these signaling pathways would be more efficacious for the treatment of HF. Histone deacetylation has been linked as a key pathogenetic element for the development of HF. Lysine residues undergo diverse and reversible post-translational modifications that include acetylation and have historically been studied as epigenetic modifiers of histone tails within chromatin that provide an important mechanism for regulating gene expression. Of recent, bioactive compounds within our diet have been linked to the regulation of gene expression, in part, through regulation of the epi-genome. It has been reported that food bioactives regulate histone acetylation via direct regulation of writer (histone acetyl transferases, HATs) and eraser (histone deacetylases, HDACs) proteins. Therefore, bioactive food compounds offer unique therapeutic strategies as epigenetic modifiers of heart failure. This review will highlight food bio-actives as modifiers of histone deacetylase activity in the heart.

Keywords: HDAC; HDAC inhibitors; food bio-actives; heart failure; histone deacetylase; phytochemicals.

Figure 1

Schematic for HDAC classes dividing zinc-dependent HDACs from NAD⁺-dependent HDACs.

Figure 2

Model demonstrating that food bioactives (phytochemicals) inhibit histone deacetylase (HDAC) activity as a cardio-protective mechanism. HDACs catalyze the removal of acetyl groups from lysine residues on histone tails. Deacetylation of histones leads to changes in electrostatic interactions between DNA and histone proteins that lead to chromatin condensation and gene repression. Conversely, histone acetyl transferases (HATs) add acetyl marks contributing to relaxed chromatin and gene expression. Increased HDAC activity is linked to cardiac dysfunction while inhibition of HDACs is cardio-protective. Thus, food bioactive HDAC inhibitors promote heart health via epigenetic regulation of gene expression.