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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. doi:org/10.1093/eurheartj/ehx615.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0000-AF58-9 Version Permalink: https://hdl.handle.net/21.11116/0000-0000-AF59-8
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, J 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: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: org/10.1093/eurheartj/ehx615
 Degree: -

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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: - Sequence Number: - Start / End Page: - Identifier: ISSN: 0195-668X
CoNE: https://pure.mpg.de/cone/journals/resource/954925625319