Key result
Treatment with the DNA-demethylating agent 5-aza-2'-deoxycytidine completely reversed norepinephrine-induced left ventricular hypertrophy and reduced contractility in rats.
Why the study?
Does 5-aza-2'-deoxycytidine reverse norepinephrine-induced cardiac hypertrophy and reduced contractility in male adult rats?
Does 5-aza-2'-deoxycytidine reverse norepinephrine-induced cardiac hypertrophy and reduced contractility in male adult rats?
p-value: p=<0.05
Inhibition of DNA methylation reverses norepinephrine-induced cardiac hypertrophy and impaired contractility in a rat model, suggesting a potential therapeutic target.
Not ready for clinical translation in hypertrophy; leaves open epigenetic demethylation as a target for future mechanistic studies.
AIMS: The mechanisms of heart failure remain largely elusive. The present study determined a causative role of DNA methylation in norepinephrine-induced heart hypertrophy and reduced cardiac contractility. METHODS AND RESULTS: Male adult rats were subjected to norepinephrine infusion for 28 days, some of which were treated with 5-aza-2'-deoxycytidine for the last 6 days of norepinephrine treatment. At the end of the treatment, hearts were isolated and left ventricular morphology and function as well as molecular assessments was determined. Animals receiving chronic norepinephrine infusion showed a sustained increase in blood pressure, heightened global genomic DNA methylation and changes in the expression of subsets of proteins in the left ventricle, left ventricular hypertrophy, and impaired contractility with an increase in the susceptibility to ischaemic injury. Treatment of animals with 5-aza-2'-deoxycytidine for the last 6 days of norepinephrine infusion reversed norepinephrine-induced hypermethylation, corrected protein expression patterns, and rescued the phenotype of heart hypertrophy and failure. CONCLUSIONS: The findings provide novel evidence of a causative role of increased DNA methylation in programming of heart hypertrophy and reduced cardiac contractility, and suggest potential therapeutic targets of demethylation in the treatment of failing heart and ischaemic heart disease.
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Xiao et al. (2013) studied Norepinephrine-induced cardiac hypertrophy (n=25). 5-aza-2'-deoxycytidine vs. Norepinephrine alone or saline control was evaluated on Left ventricular hypertrophy and cardiac contractility (p=<0.05). Treatment with the DNA-demethylating agent 5-aza-2'-deoxycytidine completely reversed norepinephrine-induced left ventricular hypertrophy and reduced contractility in rats.
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