Epi-Drugs in Heart Failure

Abstract

Unveiling the secrets of genome's flexibility does not only foster new research in the field, but also gives rise to the exploration and development of novel epigenetic-based therapies as an approach to alleviate disease phenotypes. A better understanding of chromatin biology (DNA/histone complexes) and non-coding RNAs (ncRNAs) has enabled the development of epigenetic drugs able to modulate transcriptional programs implicated in cardiovascular diseases. This particularly applies to heart failure, where epigenetic networks have shown to underpin several pathological features, such as left ventricular hypertrophy, fibrosis, cardiomyocyte apoptosis and microvascular dysfunction. Targeting epigenetic signals might represent a promising approach, especially in patients with heart failure with preserved ejection fraction (HFpEF), where prognosis remains poor and breakthrough therapies have yet to be approved. In this setting, epigenetics can be employed for the development of customized therapeutic approaches thus paving the way for personalized medicine. Even though the beneficial effects of epi-drugs are gaining attention, the number of epigenetic compounds used in the clinical practice remains low suggesting that more selective epi-drugs are needed. From DNA-methylation changes to non-coding RNAs, we can establish brand-new regulations for drug targets with the aim of restoring healthy epigenomes and transcriptional programs in the failing heart. In the present review, we bring the timeline of epi-drug discovery and development, thus highlighting the emerging role of epigenetic therapies in heart failure.

Keywords: cardiovascular diseases; epi-drugs; epigenetics; heart failure; non-coding RNAs.

FIGURE 1

Epigenetic changes potentially involved in the HF and the role of epi-drugs. Throughout life, numerous environmental factors induce epigenetic signals which alter the expression of genes implicated in the development of HF. Alterations in DNA methylation, histone modifications, and ncRNA elicit transcriptional changes leading to cardiac remodeling, fibrosis, and microvascular dysfunction, key hallmarks of the failing heart. Using epi-drugs to target chromatin-modifying enzymes, or employing short oligonucleotides to mimic or antagonize relevant ncRNA appear to be a promising strategy for a personalized management of patients at risk of developing HF. *Ac = acetylation, Ub = ubiquitination, Sum = sumoylation, Me = methylation, P = phosphorylation, HAT = histone acetyltransferase, HMT = histone methyltransferase, HDAC = histone deacetylase, HDM = histone demethylase, DNMT = DNA methyltransferase.

FIGURE 2

The epigenetic network in HF is potentially orchestrated by alterations of DNA methylation, non-coding RNA, and histone modification. These alterations boost transcriptional changes leading to crucial HF features, i.e., diabetes, fibrosis, cardiac remodeling, atherosclerosis, and microvascular dysfunction.