Inhibition of DNA methylation reverses norepinephrine-induced cardiac hypertrophy in rats

Daliao Xiao, Chiranjib Dasgupta, Man Chen, Kangling Zhang, John Buchholz, Zhice Xu, Lubo Zhang

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

AimsThe 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 resultsMale 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.ConclusionsThe 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.

Original languageEnglish (US)
Pages (from-to)373-382
Number of pages10
JournalCardiovascular research
Volume101
Issue number3
DOIs
StatePublished - Mar 1 2014
Externally publishedYes

Keywords

  • Failure
  • Heart
  • Hypertrophy
  • Methylation
  • Proteomic

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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