Abstract
Abstract 470: Redox Rgulation of SIRTUIN1 in Endothelium-Dependent Vascular Function
Arteriosclerosis, thrombosis, and vascular biology, Vol.32(suppl_1)
05/2012
DOI: 10.1161/atvb.32.suppl_1.A470
Abstract
Objective:
The DNA repair enzyme/reducing protein Apurinic/Apyrmidinic Endonuclease 1/Redox Factor-1 (APE/Ref-1) maintains normal endothelial function, as mice heterozygous for APE1/Ref-1 (+/-) have impaired endothelium-dependent vasorelaxation and are hypertensive. APE1/Ref-1 maintains many redox sensitive transcription factors in their reduced active form. The SIRTUIN1 (SIRT1) protein deacetylase also promotes endothelial nitric oxide (NO) production and endothelium-dependent vasorelaxation. Although SIRT1 activity is subject to redox regulation, whether it is governed by APE1/Ref-1 is not known. The purpose of this study is to determine if APE1/Ref-1 governs the redox state and activity of SIRT1, and whether SIRT1 mediates the effect of APE1/Ref-1 on endothelium-dependent vascular function.
Methods and results:
In endothelial cells APE1/Ref-1 maintains cysteine (thiol) residues in SIRT1 in the reduced (free) form and is obligatory for endothelial SIRT1 activity. In vitro APE1/Ref-1 increases the free thiol content of SIRT1, targeting functionally critical cysteine residues in the catalytic domain of SIRT1 for reduction, and activates SIRT1. Cysteine residues in the N-terminal redox domain of APE1/Ref-1 are essential for activating SIRT1 and for increasing free thiol content of SIRT1. APE1/Ref-1 protects endothelial SIRT1 from hydrogen peroxide-induced oxidation and inactivation. Moreover, APE1/Ref-1 stimulates lysine deacetylation of nitric oxide synthase, a target of SIRT1 in endothelial cells. When compared to wild-type mice, APE1/Ref-1(+/-) mice have lower free thiol content of SIRT1, and diminished SIRT1 activity in tissues. Overexpression of SIRT1 in aortas of APE1/Ref-1 (+/-) mice restores endothelium-dependent vasorelaxation and vascular bioavailable NO to levels similar to those observed in wild-type mice.
Conclusions:
APE1/Ref-1 maintains endothelial SIRT1 in the reduced form, and is required for maintaining SIRT1 activity. This relationship between SIRT1 and APE1/Ref-1 is an important mechanism responsible for APE1/Ref-1-stimulated endothelium-dependent vasorelaxation.
Details
- Title: Subtitle
- Abstract 470: Redox Rgulation of SIRTUIN1 in Endothelium-Dependent Vascular Function
- Creators
- Cuk-Seong Kim - Chungnam National UniversitySaet-Byel Jung - Medicine, Chungnam National Univ, Daejeon, Korea, Republic ofTimothy A Hoffman - Medicine, Univ of Pittsburgh Med Cntr, Pittsburgh, PAAsma Narqvi - Medicine, Univ of Pittsburgh Med Cntr, Pittsburgh, PAKaikobad Irani - University of Pittsburgh
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.32(suppl_1)
- DOI
- 10.1161/atvb.32.suppl_1.A470
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2012
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984315652002771
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