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.

Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease

“…NF-κB activity is upregulated by acetylation mediated by acetyl transferases, like p300, which is also inhibited through deacetylation by Sirt1 [131]. Other polyphenols regulating NADPH oxidase function like caffeic acid, gallic acid, quercetin and myricetin were also shown to regulate HDAC activity [132]. Thus, the role of polyphenols in epigenetic regulation of Nox enzymes is an exciting area of research that needs further exploration.…”

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

“…HDACs are enzymes that remove acetyl group on Lys residues of histone proteins, the following four classes of HDACs are recognized: I (HDAC1, 2, 3, and 8), II (A: HDAC4, 5, 7, and 9; B: HDAC6 and 10), III (SIRT1-7), and IV (HDAC11) ( Figure 2 ) ( 46 ). Given that the HDACs frequently show higher expression levels in cancer cells, small molecules targeting HADCs were first investigated.…”

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

“…Similarly, HDAC inhibitory activity was reported for the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor atorvastatin [50]. A detailed description of the different HDAC inhibitors actually available can be found in excellent recent reviews [49][50] [51].…”

“…Several HDAC inhibitors, of both synthetic and natural origin, such as molecules isolated from bacteria (trichostatin A, FK322), vegetables or marine organisms, are actually available. On the basis of their chemical structure, these inhibitors can be classified into five different groups (Table 2; [49]). With the exception of sirtuin inhibitors, most of them interact with the HDAC Zn 2+ domain through a zinc-binding group connected to a cap and target different HDAC classes (see above) or specific classes/isoforms.…”

“…Two of them (belinostat and panobinostats) belong to the same family of SAHA and TSA, while romidepsin, a cyclic peptide, and chidamide target class I HDACs. Along this line, several other HDAC inhibitors are currently under investigation in clinical trials for the treatment of various cancer types [49].…”