Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66 Shc transcription and vascular oxidative stress in obesity

Sarah Costantino, Francesco Paneni, Agostino Virdis, Shafaat Hussain, Shafeeq Ahmed Mohammed, Giuliana Capretti, Alexander Akhmedov, Kevin Dalgaard, Sergio Chiandotto, J. Andrew Pospisilik, Thomas Jenuwein, Marco Giorgio, Massimo Volpe, Stefano Taddei, Thomas F. Lüscher, Francesco Cosentino

Research output: Contribution to journalArticlepeer-review

Abstract

Aims Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66Shc contributes to obesity-related vascular disease. Methods and results ROS-driven endothelial dysfunction was observed in visceral fat arteries (VFAs) isolated from obese subjects when compared with normal weight controls. Gene profiling of chromatin-modifying enzymes in VFA revealed a significant dysregulation of methyltransferase SUV39H1 (fold change,-6.9, P< 0.01), demethylase JMJD2C (fold change, 3.2, P<0.01), and acetyltransferase SRC-1 (fold change, 5.8, P< 0.01) in obese vs. control VFA. These changes were associated with reduced di-(H3K9me2) and trimethylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on p66Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice (LepOb/Ob) suppressed p66Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66Shc transcription. Conclusion These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.

Original languageEnglish
Pages (from-to)383-391
Number of pages9
JournalEuropean Heart Journal
Volume40
Issue number4
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Chromatin remodelling
  • Endothelial dysfunction
  • Epigenetics
  • Obesity
  • Oxidative stress
  • Vascular disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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