Jung, SB and Kim, CS and Kim, YR and Naqvi, A and Yamamori, T and Kumar, S and Kumar, A and Irani, K
(2013)
Redox Factor-1 Activates Endothelial SIRTUIN1 through Reduction of Conserved Cysteine Sulfhydryls in Its Deacetylase Domain.
PLoS ONE, 8 (6).
Abstract
Apurinic/Apyrmidinic Endonuclease 1/Redox Factor-1 (APE1/Ref-1) is a reductant which is important for vascular homeostasis. SIRTUIN1 (SIRT1) is a lysine deacetylase that also promotes endothelium-dependent vasorelaxation. We asked 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. APE1/Ref-1 maintains sulfhydryl (thiol) groups of cysteine residues in SIRT1 in the reduced form and promotes endothelial SIRT1 activity. APE1/Ref-1 stimulates SIRT1 activity by targeting highly conserved vicinal thiols 371 and 374 which form a zinc tetra-thiolate motif in the deacetylase domain of SIRT1. Cysteine residues in the N-terminal redox domain of APE1/Ref-1 are essential for reducing SIRT1 and stimulating its activity. APE1/Ref-1 protects endothelial SIRT1 from hydrogen peroxide-induced oxidation of sulfhydryls and from inactivation. APE1/Ref-1 also promotes lysine deacetylation of the SIRT1 target endothelial nitric oxide synthase (eNOS). SIRT1 mutated at cysteines 371 and 374, which renders it non-reducible by APE1/Ref-1, prevents lysine deacetylation of eNOS by APE1/Ref-1. SIRT1 free thiol (reduced sulfhydryl) content and deacetylase activity are diminished in all examined tissues of APE1/Ref-1+/- mice, including the vasculature. Overexpression of SIRT1 in aortas of APE1/Ref-1+/- mice restores endothelium-dependent vasorelaxation and bioavailable nitric oxide (NO) to levels similar to those observed in wild-type mice. Thus, APE1/Ref-1, by maintaining functionally important cysteine sulfhydryls in SIRT1 in the reduced form, promotes endothelial SIRT1 activity. This reductive activation of endothelial SIRT1 by APE1/Ref-1 mediates the effect of APE1/Ref-1 on eNOS acetylation, promoting endothelium-derived NO and endothelium-dependent vasorelaxation. © 2013 Jung et al.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID  |
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Jung, SB | | | | Kim, CS | | | | Kim, YR | | | | Naqvi, A | ANAQVI@pitt.edu | ANAQVI | | Yamamori, T | | | | Kumar, S | | | | Kumar, A | | | | Irani, K | | | |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID  |
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Editor | Gaetano, Carlo | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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Date: |
3 June 2013 |
Date Type: |
Publication |
Journal or Publication Title: |
PLoS ONE |
Volume: |
8 |
Number: |
6 |
DOI or Unique Handle: |
10.1371/journal.pone.0065415 |
Schools and Programs: |
School of Medicine > Medicine |
Refereed: |
Yes |
Date Deposited: |
15 Jul 2013 20:15 |
Last Modified: |
22 Jun 2021 13:55 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/19210 |
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