Epigenetic modifications in cardiac fibrosis: recent evidence of new pharmacological targets

Abstract

Cardiac fibrosis (CF) is characterized by the excessive deposition of collagen types I (COI I) and III (COI III), primarily mediated by cardiac fibroblasts (CFB). Recent advances in epigenetic research have enhanced our understanding of the molecular mechanisms underlying CF and have facilitated the identification of novel therapeutic strategies targeting key proteins and signaling pathways involved in its progression. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), are structural and chemical alterations that regulate gene expression and cellular responses without changing the DNA sequence. Investigating the role of epigenetic enzymes in CF may reveal promising pharmacological targets. This review summarizes current evidence on epigenetic modifications implicated in CF and discusses their potential as therapeutic targets for modulating this pathological process.

Keywords: DNA methylation; cardiac fibroblasts; cardiac fibrosis; cardiovascular epigenetics; epigenetic modifications; non-coding RNA.

FIGURE 1

In response to cardiac injury, CFBs become activated, proliferate, and differentiate into cardiac myofibroblasts (myoFIBs). This phenotypic transition is associated with the upregulation of fibrotic markers, including COI I, COI III, alpha-smooth muscle actin (α-SMA), and fibronectin. Accumulating evidence indicates that various epigenetic modifications play a key role in regulating the activation, proliferation, and fibrogenic behavior of CFBs, as well as the expression of proteins that characterize the fibrotic cardiac phenotype.

FIGURE 2

Epigenetic mechanisms involved in the progression of CF. Following myocardial injury, CFBs become activated and differentiate into myoFIBs, leading to excessive ECM deposition and the development of CF. This process is regulated by several epigenetic mechanisms, including: (a) Histone modifications, mediated by enzymes such as HDAC8, KDM5B, PRMT5, Dot1L, and p300, which influence the expression of key genes including MMP12, TCF3, TGF-β1/Smad3, FOXP3, and Smad2. (b) DNA methylation, regulated by DNA methyltransferases (DNMTs), affects genes such as RASSF1, SOCS3, sFRP3, and microRNAs like miR-152-3p. (c) m6A RNA modification, controlled by METTL3, FTO, WTAP, and IGF2BP3, impacts the expression of GAS5, TNC, Drp1, Mettl1, and TGF-β1/SMAD2/3. (d) Non-coding RNAs, including microRNAs (miR-223, miR-10a, miR-99b-3p, miR-331, miR-29a-3p, miR-129-5p), lncRNAs (NEAT1, GAS5), and circRNAs (circNSD1), which modulate signaling pathways involved in fibroblast activation and tissue remodeling, such as RAS, Wnt/β-catenin, TGF-β/Smad3, and NLRP3 inflammasome. These epigenetic regulators represent promising therapeutic targets for the development of innovative antifibrotic strategies in cardiovascular disease.