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  Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity

Costantino, S., Paneni, F., Virdis, A., Hussain, S., Mohammed, S. A., Capretti, G., et al. (2017). Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity. European Heart Journal, 40, 383-391. doi:org/10.1093/eurheartj/ehx615.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-AF58-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-C295-7
Genre: Journal Article

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 Creators:
Costantino, Sarah1, Author
Paneni, Francesco1, Author
Virdis, Agostino1, Author
Hussain, Shafaat1, Author
Mohammed, Shafeeq Ahmed1, Author
Capretti, Giuliana1, Author
Akhmedov, Alexander1, Author
Dalgaard, Kevin2, Author
Chiandotto, Sergio1, Author
Pospisilik, John Andrew2, Author              
Jenuwein, Thomas2, Author              
Giorgio, Marco1, Author
Volpe, Massimo1, Author
Taddei, Stefano1, Author
Lüscher, Thomas F1, Author
Cosentino, Francesco1, Author
Affiliations:
1External Organizations, ou_persistent22              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              

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Free keywords: Epigenetics, Chromatin remodeling, Vascular disease, Oxidative stress, Endothelial dysfunction, Obesity
 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.

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Language(s): eng - English
 Dates: 2017-10
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: org/10.1093/eurheartj/ehx615
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Title: European Heart Journal
  Other : Eur. Heart J.
Source Genre: Journal
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Publ. Info: Amsterdam : No longer published by Elsevier
Pages: - Volume / Issue: 40 Sequence Number: - Start / End Page: 383 - 391 Identifier: ISSN: 0195-668X
CoNE: https://pure.mpg.de/cone/journals/resource/954925625319