Epigenetic regulation in heart failure

Abstract

Purpose of review: This article provides an overview, highlighting recent findings, of a major mechanism of gene regulation and its relevance to the pathophysiology of heart failure.

Recent findings: The syndrome of heart failure is a complex and highly prevalent condition, one in which the heart undergoes substantial structural remodeling. Triggered by a wide range of disease-related cues, heart failure pathophysiology is governed by both genetic and epigenetic events. Epigenetic mechanisms, such as chromatin/DNA modifications and noncoding RNAs, have emerged as molecular transducers of environmental stimuli to control gene expression. Here, we emphasize metabolic milieu, aging, and hemodynamic stress as they impact the epigenetic landscape of the myocardium.

Summary: Recent studies in multiple fields, including cancer, stem cells, development, and cardiovascular biology, have uncovered biochemical ties linking epigenetic machinery and cellular energetics and mitochondrial function. Elucidation of these connections will afford molecular insights into long-established epidemiological observations. With time, exploitation of the epigenetic machinery therapeutically may emerge with clinical relevance.

Figure 1

Epigenetic mechanisms transduce environmental cues into transcriptional reprogramming during HF. Aging and metabolic stress are associated with changes in the cardiac environment -- excess circulating FA, insulin resistance, and oxidative stress -- that lead to alterations in myocardial metabolism. Dysregulated cellular metabolism, in turn, provokes changes in metabolic intermediates, including NAD⁺, acetyl-CoA, β-hydroxybutyrate (β-OHB), S-adenosylmethionine (SAM), and α-ketoglutarate, each of which is also a key cofactor/substrate for the enzymatic actions of epigenetic editors. In addition, whereas a range of signaling events alters the abundance of the epigenetic editing proteins, these changes in metabolic intermediates alter the activity of the enzymes, as well. The resulting changes in the epigenetic landscape contribute significantly to HF-related reprogramming of the myocardium, working synergistically with hormonal and cytokine stimuli (which activate transcription factors that recruit epigenetic editors to specific loci) to promote pathological remodeling in HF.