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Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain
Journal article   Open access   Peer reviewed

Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain

Saet-Byel Jung, Cuk-Seong Kim, Young-Rae Kim, Asma Naqvi, Tohru Yamamori, Santosh Kumar, Ajay Kumar and Kaikobad Irani
PloS one, Vol.8(6), pp.e65415-e65415
2013
DOI: 10.1371/journal.pone.0065415
PMCID: PMC3670896
PMID: 23755229
url
https://doi.org/10.1371/journal.pone.0065415View
Published (Version of record) Open Access

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.
 Sirtuin 1 - metabolism Nitric Oxide - biosynthesis Oxidation-Reduction Signal Transduction Tissue Culture Techniques Humans Gene Expression Regulation Male Mice, Transgenic Endothelium, Vascular - enzymology Nitric Oxide Synthase Type III - genetics Sirtuin 1 - genetics Vasodilation - genetics DNA-(Apurinic or Apyrimidinic Site) Lyase - genetics Animals Diffusion Chambers, Culture DNA-(Apurinic or Apyrimidinic Site) Lyase - metabolism HEK293 Cells Cysteine - metabolism Mice Acetylation Enzyme Activation Nitric Oxide Synthase Type III - metabolism Aorta - enzymology

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