Abstract 97: Histone Deacetylase Inhibition Prevents Cardiac Remodeling in Mice Carrying the Disruption of Guanylyl Cyclase/natriuretic Peptide Receptor-A Gene
Regulation of gene expression plays an obligatorily role in the modification of chromatin structure that dynamically attenuates cardiac hypertrophy. In order to culminate the role of epigenetic regulators in the heart tissue, the current study was undertaken to elucidate the effect of histone deacetylase (HDAC) inhibitor, sodium butyrate (SB) in cardiac remodeling process of Npr1 (coding for GC-A/NPRA) gene-targeted mice. Wild type (Npr1+/+, 2-copy), gene-disrupted (Npr1+/-, 1-copy), and gene-duplicated (Npr1++/+-, 3-copy) mice were administered intraperitoneally with SB (0.5 mg/kg/day) for 2 weeks (8 mice/group). Mice with gene-disruption (Npr1+/-, 1-copy) exhibited the increase in cardiac hypertrophy, heart weight/body weight (HW/BW) ratio (6.9 ± 0.2), and systolic blood pressure (SBP, 121.5 ± 4 mmHg) compared with 2-copy (HW/BW, 5.1 ± 0.2; SBP; 100.9 ± 6 mmHg) and 3-copy (HW/BW, 4.7 ± 0.1; SBP, 89.4 ± 2 mmHg) mice. In addition, an increased activity of HDAC (3-fold, p<0.01) and decreased activity of histone acetyltransferases (HAT) (2.5-fold, p<0.01) were found in untreated 1-copy mice hearts. Whereas, 1-copy mice treated with SB showed reduced HW/BW ratio (5.7 ± 0.3), SBP (SB, 101.2 ± 2), HDAC activity (p<0.01) and improved HAT activity (3-fold, p<0.001). Also, a stimulatory effect on HAT activity was observed in SB treated 2-copy (30%, p<0.01) and 3-copy (50%, p<0.01) mice. Furthermore, Npr1+/- mice showed a significant increase in the expression of hypertrophic marker genes such as β-myosin heavy chain (β-MHC, 2-fold), α-skeletal actin (α-SK, 2-fold), c-fos (2.5-fold), and c-jun (3-fold) compared to untreated 2-copy and 3-copy mice. A substantial attenuation in the expression of hypertrophic markers (β-MHC, 2.5-fold; α-SK, 2.4-fold) and matrix genes (MMP-2, p<0.01; MMP-9, p<0.01) was found in SB-treated Npr1+/- mice. The basal expression levels of matrix proteins were also significantly reduced in 2-copy and 3-copy mice hearts. The results show that sodium butyrate-dependent inhibition of HDAC activity attenuates cardiac hypertrophy and fibrosis by improving HAT activity suggesting that chromatin modification can prevent cardiac remodeling process in a Npr1 gene-dose-dependent manner.
- © 2013 by American Heart Association, Inc.