Abstract
Re-induction of fetal genes and/or re-expression of postnatal genes represent hallmarks of pathological cardiac remodeling, and are considered important in the progression of the normal heart towards heart failure (HF). Whether epigenetic modifications are involved in these processes is currently under investigation. Here we hypothesized that histone chromatin modifications may underlie changes in the gene expression program during pressure overload-induced HF. We evaluated chromatin marks at the promoter regions of the sarcoplasmic reticulum Ca2+ATPase (SERCA-2A) and β-myosin-heavy chain (β-MHC) genes (Atp2a2 and Myh7, respectively) in murine hearts after one or eight weeks of pressure overload induced by transverse aortic constriction (TAC). As expected, all TAC hearts displayed a significant reduction in SERCA-2A and a significant induction of β-MHC mRNA levels. Interestingly, opposite histone H3 modifications were identified in the promoter regions of these genes after TAC, including H3 dimethylation (me2) at lysine (K) 4 (H3K4me2) and K9 (H3K9me2), H3 trimethylation (me3) at K27 (H3K27me3) and dimethylation (me2) at K36 (H3K36me2). Consistently, a significant reduction of lysine-specific demethylase KDM2A could be found after eight weeks of TAC at the Atp2a2 promoter. Moreover, opposite changes in the recruitment of DNA methylation machinery components (DNA methyltransferases DNMT1 and DNMT3b, and methyl CpG binding protein 2 MeCp2) were found at the Atp2a2 or Myh7 promoters after TAC. Taken together, these results suggest that epigenetic modifications may underlie gene expression reprogramming in the adult murine heart under conditions of pressure overload, and might be involved in the progression of the normal heart towards HF.
Highlights
Heart failure (HF) represents an end-stage phenotype of a number of cardiovascular diseases, frequently anticipated by cardiac hypertrophy, the earliest and general response of the heart to injury or increased workload [1,2]
To investigate the mechanism(s) involved in left ventricular (LV) gene expression re-programming during cardiac hypertrophy and failure, we analyzed a well-known murine model of cardiac pressure overload induced by transverse aortic constriction (TAC) [4] at two time points: one week (1w) or eight weeks (8w) after surgery, and we focused our study on two representative genes, Atp2a2 and Myh7, whose reprogramming in cardiac hypertrophy and failure is well established [1]
To further investigate whether epigenetic mechanisms may mark gene expression reprogramming occurring in the progression of the normal heart towards HF, we analyzed several different chromatin marks associated with transcriptional activation or repression at the Atp2a2 and Myh7 gene promoters
Summary
Heart failure (HF) represents an end-stage phenotype of a number of cardiovascular diseases, frequently anticipated by cardiac hypertrophy, the earliest and general response of the heart to injury or increased workload [1,2]. In response to cardiac overload, changes in the gene transcription program are required to obtain de novo synthesis of contractile, structural or regulatory proteins [5,6], but are associated to the re-induction of fetal genes including Myh, the gene encoding for b-myosin-heavy chain (b-MHC), and the repression of post-natal genes such as Atp2a2, the gene encoding for sarcoplasmic reticulum Ca2+ ATPase (SERCA-2A) [7,8] Such gene expression reprogramming is considered a hallmark of pathological hypertrophy and HF, and its inhibition through different approaches in different animal models has been shown to reduce cardiac hypertrophy and ameliorate cardiac dysfunction [5,9]. Class II histone de-acetylases (HDACs) 5 and 9 exert anti-hypertrophic effects by inhibiting the expression of prohypertrophic genes [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
