Epigenetic therapies in heart failure

Abstract

Heart failure (HF) is a dominant cause of morbidity and mortality in the developed world, with available pharmacotherapies limited by high rates of residual mortality and a failure to directly target the changes in cell state that drive adverse cardiac remodeling. Pathologic cardiac remodeling is driven by stress-activated cardiac signaling cascades that converge on defined components of the chromatin regulatory apparatus in the nucleus, triggering broad shifts in transcription and cell state. Thus, studies focusing on how cytosolic signaling pathways couple to the nuclear gene control machinery has been an area of therapeutic interest in HF. In this review, we discuss current concepts pertaining to the role of chromatin regulators in HF pathogenesis, with a focus on specific proteins and RNA-containing macromolecular complexes that have shown promise as druggable targets in the experimental setting.

Fig. 1

Stress-activated cardiac signaling cascades converge on defined components of the chromatin regulatory apparatus. These events trigger activation of stress-associated gene programs, Pol II pause release, cardiomegaly, fibrosis, and ultimately heart failure (HF). Chromatin regulators in HF that can be pharmacologically targeted with demonstration of translational potential include the histone methyltransferase G9a, members of the Bromo- and Extra- Terminal (BET) domain family, and certain long non-coding RNA (IncRNA) molecules, in unstressed CMs, G9a binds to and represses the transcriptional activity of MEF2C. Following stress, BET bromodomain inhibition with JQ1 suppresses stress-dependent transcriptional elongation in the heart and potently blocks pathological remodeling in vivo. CM-enriched IncRNAs such as Mhrt, Chast and Chaer play important roles during maladaptive cardiac remodeling. In contrast, the IncRNA Wisper is a cardiac fibroblast-enriched IncRNA that regulates cardiac fibrosis after injury. FB = Fibroblast. myoFB = Myofibroblast. CM = Cardiomyocyte. ASOs = Antisense Oligonucleotides.