Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats.
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Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats. / Stenzig, Justus; Schneeberger, Yvonne; Löser, Alexandra; Peters, Barbara; Schäfer, Andreas; Zhao, Rongrong; Ng, Shi Ling; Höppner, Grit; Geertz, Birgit; Hirt, Marc; Tan, Wilson; Wong, Eleanor; Reichenspurner, Hermann; Foo, Roger; Eschenhagen, Thomas.
In: J MOL CELL CARDIOL, Vol. 120, 07.2018, p. 53-63.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Pharmacological inhibition of DNA methylation attenuates pressure overload-induced cardiac hypertrophy in rats.
AU - Stenzig, Justus
AU - Schneeberger, Yvonne
AU - Löser, Alexandra
AU - Peters, Barbara
AU - Schäfer, Andreas
AU - Zhao, Rongrong
AU - Ng, Shi Ling
AU - Höppner, Grit
AU - Geertz, Birgit
AU - Hirt, Marc
AU - Tan, Wilson
AU - Wong, Eleanor
AU - Reichenspurner, Hermann
AU - Foo, Roger
AU - Eschenhagen, Thomas
N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.
PY - 2018/7
Y1 - 2018/7
N2 - BACKGROUND: Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes.METHODS AND RESULTS: Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5 mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4 weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were "cardiac hypertrophy", "cell death" and "xenobiotic metabolism signalling". Among these, "cardiac hypertrophy" was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated.CONCLUSIONS: DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification.
AB - BACKGROUND: Heart failure is associated with altered gene expression and DNA methylation. De novo DNA methylation is associated with gene silencing, but its role in cardiac pathology remains incompletely understood. We hypothesized that inhibition of DNA methyltransferases (DNMT) might prevent the deregulation of gene expression and the deterioration of cardiac function under pressure overload (PO). To test this hypothesis, we evaluated a DNMT inhibitor in PO in rats and analysed DNA methylation in cardiomyocytes.METHODS AND RESULTS: Young male Wistar rats were subjected to PO by transverse aortic constriction (TAC) or to sham surgery. Rats from both groups received solvent or 12.5 mg/kg body weight of the non-nucleosidic DNMT inhibitor RG108, initiated on the day of the intervention. After 4 weeks, we analysed cardiac function by MRI, fibrosis with Sirius Red staining, gene expression by RNA sequencing and qPCR, and DNA methylation by reduced representation bisulphite sequencing (RRBS). RG108 attenuated the ~70% increase in heart weight/body weight ratio of TAC over sham to 47% over sham, partially rescued reduced contractility, diminished the fibrotic response and the downregulation of a set of genes including Atp2a2 (SERCA2a) and Adrb1 (beta1-adrenoceptor). RG108 was associated with significantly lower global DNA methylation in cardiomyocytes by ~2%. The differentially methylated pathways were "cardiac hypertrophy", "cell death" and "xenobiotic metabolism signalling". Among these, "cardiac hypertrophy" was associated with significant methylation differences in the group comparison sham vs. TAC, but not significant between sham+RG108 and TAC+RG108 treatment, suggesting that RG108 partially prevented differential methylation. However, when comparing TAC and TAC+RG108, the pathway cardiac hypertrophy was not significantly differentially methylated.CONCLUSIONS: DNMT inhibitor treatment is associated with attenuation of cardiac hypertrophy and moderate changes in cardiomyocyte DNA methylation. The potential mechanistic link between these two effects and the role of non-myocytes need further clarification.
U2 - https://doi.org/10.1016/j.yjmcc.2018.05.012
DO - https://doi.org/10.1016/j.yjmcc.2018.05.012
M3 - SCORING: Journal article
C2 - 29792884
VL - 120
SP - 53
EP - 63
JO - J MOL CELL CARDIOL
JF - J MOL CELL CARDIOL
SN - 0022-2828
ER -
