DNA methylation in cardiac fibrosis: new advances and perspectives

Cardiac fibrosis is characterized by net accumulation of extracellular matrix (ECM) proteins in the cardiac interstitium, and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. More specifically, cardiac fibroblasts are activated by a variety of pathological stimuli, thereby undergoing proliferation, differentiation to myofibroblasts, and production of various cytokines and ECM proteins. Thus, understanding the biological processes of cardiac fibroblasts will provide novel insights into the underlying mechanisms of cardiac fibrosis. DNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. The aberrant methylation of CpG island promoters of selected genes is the prominent epigenetic mechanism by which gene transcription can be effectively silenced. Aberrant hypermethylation of a few selected genes such as RASSF1A plays an important role in facilitating fibrotic fibroblast activation and in driving fibrosis. In this review we will discuss the mechanisms of DNA methylation and their implications for cardiac fibroblasts activation and fibrosis. Control of DNA methylation may serve as a new strategy for anti-fibrotic therapy.