Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc

Sarah Costantino, Francesco Paneni, Katharyn Mitchell, Shafeeq A. Mohammed, Shafaat Hussain, Christos Gkolfos, Liberato Berrino, Massimo Volpe, Colin Schwarzwald, Thomas Felix Lüscher, Francesco Cosentino

Research output: Contribution to journalArticle

Abstract

Aims: Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66Shc contributes to persistent myocardial dysfunction despite IGC. Methods and results: p66Shc expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66Shc upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66Shc, performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66Shc promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66Shc promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66Shc expression and ROS generation. Conclusions: In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66Shc transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy.

Original languageEnglish
Pages (from-to)179-186
Number of pages8
JournalInternational Journal of Cardiology
Volume268
DOIs
Publication statusPublished - Oct 1 2018

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Keywords

  • Diabetic cardiomyopathy
  • Epigenetics
  • miR-218
  • miR-34a
  • miRNAs
  • Oxidative stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Costantino, S., Paneni, F., Mitchell, K., Mohammed, S. A., Hussain, S., Gkolfos, C., Berrino, L., Volpe, M., Schwarzwald, C., Lüscher, T. F., & Cosentino, F. (2018). Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc. International Journal of Cardiology, 268, 179-186. https://doi.org/10.1016/j.ijcard.2018.04.082