Epigenetics of the failing heart

Abstract

With the impressive advancement in high-throughput 'omics' technologies over the past two decades, epigenetic mechanisms have emerged as the regulatory interface between the genome and environmental factors. These mechanisms include DNA methylation, histone modifications, ATP-dependent chromatin remodeling and RNA-based mechanisms. Their highly interdependent and coordinated action modulates the chromatin structure controlling access of the transcription machinery and thereby regulating expression of target genes. Given the rather limited proliferative capability of human cardiomyocytes, epigenetic regulation appears to play a particularly important role in the myocardium. The highly dynamic nature of the epigenome allows the heart to adapt to environmental challenges and to respond quickly and properly to cardiac stress. It is now becoming evident that histone-modifying and chromatin-remodeling enzymes as well as numerous non-coding RNAs play critical roles in cardiac development and function, while their dysregulation contributes to the onset and development of pathological cardiac remodeling culminating in HF. This review focuses on up-to-date knowledge about the epigenetic mechanisms and highlights their emerging role in the healthy and failing heart. Uncovering the determinants of epigenetic regulation holds great promise to accelerate the development of successful new diagnostic and therapeutic strategies in human cardiac disease.

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…On the other hand, DNA methylation is believed responsible for the gene promoter methylation and hypermutability of cardiac genes (Meurs & Kuan, 2011). Altered methylation patterns and extent of target genes are known to correlate with heart failure, as evidenced by the genome-wide DNA methylation analysis of human hearts, which revealed significantly lowered global promoter methylation for genes associated with heart failure (Cao et al, 2014;Marin-Garcia & Akhmedov, 2015). Hypomethylation of long interspersed nucleotide elements was also evident in elderly patients with ischemic heart diseases (Cao et al, 2014;Webster et al, 2013).…”

“…Given that adult cardiomyocytes are terminally differentiated with limited proliferative capacity, epigenetic regulation may modulate adaptive and reversible hypertrophy to meet the higher hemodynamic requirements in response to physiological stimuli (Udali et al, 2013). A number of histonemodifying and chromatin remodeling enzymes as well as ncRNAs are demonstrated to have essential roles in cardiac development and function, while their dysregulation along with the complex interplay with genetic mechanisms promote the onset and development of pathological changes in the heart (Marin- Garcia & Akhmedov, 2015). Adaptive cardiac hypertrophy turns out to be maladaptive and irreversible under pathological conditions such as myocardial infarction, obesity, hypertension, aging and diabetes (Marin-Garcia & Akhmedov, 2015).…”

“…A number of histonemodifying and chromatin remodeling enzymes as well as ncRNAs are demonstrated to have essential roles in cardiac development and function, while their dysregulation along with the complex interplay with genetic mechanisms promote the onset and development of pathological changes in the heart (Marin- Garcia & Akhmedov, 2015). Adaptive cardiac hypertrophy turns out to be maladaptive and irreversible under pathological conditions such as myocardial infarction, obesity, hypertension, aging and diabetes (Marin-Garcia & Akhmedov, 2015). Pathological cardiac hypertrophy is associated with dramatic alterations in genetic and epigenetic signaling associated with contractile apparatus and metabolism, resulting in cardiac hypertrophy and heart failure (Schiano et al, 2015).…”

Are Epigenetic Features Essential in Advance of Heart Failure Phenotypes?

“…Epigenetics are referred a modification of the non-DNA sequences related heritable changes in gene expression of target cells that is currently recognized as a key to understanding of pathogenesis CV diseases [29] . Epigenetic modifications are based on different molecular mechanisms, which affect DNA methylation and deactylation, ATP-dependent chromatin remodeling, histone modifications, and microRNA regulation ( Figure 1).…”

In situ nuclear DNA methylation in dilated cardiomyopathy: an endomyocardial biopsy study

“…Clinical and experimental studies suggest epigenetic mechanisms play a pivotal role in the regulation of cardiac gene expression patterns and in the progression of cardiac hypertrophy and heart failure . DNA methylation and histone modification are the most common mechanisms underlying epigenetic modulation of gene expression.…”