Abstract
Abstract 14746: Dynamic SIRTUIN1-modulated Lysine Acetylation of P66shc Governs Vascular Endothelial Oxidative Stress and Dysfunction of Diabetes
Circulation (New York, N.Y.), Vol.130(suppl_2)
11/25/2014
DOI: 10.1161/circ.130.suppl_2.14746
Abstract
The SIRTUIN1 lysine deacetylase (SIRT1) ameliorates diabetic vascular dysfunction by epigenetically suppressing endothelial expression of the oxidative stress protein p66shc. However, whether SIRT1 modulates the oxidative function of p66shc by directly targeting it for lysine deacetylation is not known. Here we show that the oxidative function of p66shc is dynamically modulated by lysine acetylation. Mass spectroscopy identified lysine 81 in the unique CH2 domain of p66shc as the residue targeted by SIRT1. High glucose and SIRT1 knockdown stimulates acetylation of lysine 81 of endothelial p66shc. Compared to WT p66shc, non-acetylatable (K81R) p66shc is significantly handicapped in promoting endothelial hydrogen peroxide production stimulated by high glucose. Compared to WT p66shc, K81R p66shc is also less prone to serine 36 phosphorylation by high glucose, which is essential for the oxidative function of p66shc. Moreover, in contrast to WT p66shc which worsens endothelial dysfunction, expression of K81R p66shc does not impair endothelial function in wild type mice and rescues endothelium dysfunction of diabetic db+/db+ mouse aortas . These findings show that lysine 81 acetylation promotes the oxidative role of p66shc in hyperglycemic conditions, and is essential for p66shc-mediated endothelial dysfunction.
Details
- Title: Subtitle
- Abstract 14746: Dynamic SIRTUIN1-modulated Lysine Acetylation of P66shc Governs Vascular Endothelial Oxidative Stress and Dysfunction of Diabetes
- Creators
- Santosh Kumar - University of IowaYoung Rae Kim - University of IowaAjit Vikram - University of IowaAsma Naqvi - Immunology, Univ of Pittsburgh, Pittsburgh, PAAjay Kumar - Med-Cardiothoracic Surgery, Univ of Pittsburgh, Pittsburgh, PAMarkus Bachschmid - Medicine, Boston Univ, Boston, MAJulia S Jacobs - Internal Medicine, Univ of Iowa, Iowa City, IAKaikobad Irani - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.130(suppl_2)
- DOI
- 10.1161/circ.130.suppl_2.14746
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/25/2014
- Academic Unit
- Internal Medicine; Radiation Oncology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984314283102771
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