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PMID:17916362

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Citation

Ota, H, Akishita, M, Eto, M, Iijima, K, Kaneki, M and Ouchi, Y (2007) Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J. Mol. Cell. Cardiol. 43:571-9

Abstract

Yeast Sir2 plays critical roles in gene silencing, stress resistance and longevity. Mammalian Sirt1 NAD(+)-dependent protein deacetylase, the closest homolog of Sir2, regulates cell cycle, cellular senescence, apoptosis and metabolism, by functional interactions with a number of biological molecules such as p53. To investigate a role of Sirt1 in endothelial dysfunction and premature senescence, we examined the effects of Sirt1 inhibition in human umbilical vein endothelial cells (HUVEC). Sirt1 inhibition by sirtinol, which is a 2-hydroxy-1-napthaldehyde derivative, or siRNA for Sirt1-induced premature senescence-like phenotype, as judged by increased senescence-associated beta-galactosidase (SA-beta-gal) activity, sustained growth arrest and enlarged and flattened cell morphology at 10 days after the treatment. Sixty-four percent of sirtinol (60 mumol/L)-treated HUVEC was SA-beta-gal-positive, whereas only 17% of vehicle-treated cells were positive. Sirt1 inhibition by sirtinol or Sirt1 siRNA increased PAI-1 expression and decreased both protein expression and activity of eNOS. Treatment with sirtinol or Sirt1 siRNA increased acetylation of p53, while p53 expression was unaltered. Impaired epidermal growth factor-induced activation of mitogen-activated protein kinases was associated with Sirt1 inhibition-induced senescence-like growth arrest. Conversely, overexpression of Sirt1 prevented hydrogen peroxide-induced SA-beta-gal activity, morphological changes and deranged expression of PAI-1 and eNOS. These results showed that Sirt1 inhibition increased p53 acetylation and induced premature senescence-like phenotype in parallel with increased PAI-1 and decreased eNOS expression. Our data suggest that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of PAI-1 and eNOS.

Links

PubMed Online version:10.1016/j.yjmcc.2007.08.008

Keywords

Cell Aging/genetics; Cell Division/physiology; Cells, Cultured; Endothelium, Vascular/enzymology; Endothelium, Vascular/physiology; Humans; Nitric Oxide Synthase/metabolism; Phenotype; RNA, Small Interfering/genetics; Recombinant Proteins/metabolism; Sirtuin 1; Sirtuins/antagonists & inhibitors; Sirtuins/genetics; Sirtuins/physiology; Transfection; Umbilical Veins; beta-Galactosidase/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SIRT1

involved_in

GO:0071441: negative regulation of histone H3-K14 acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIRT1

involved_in

GO:2000619: negative regulation of histone H4-K16 acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIRT1

involved_in

GO:0090400: stress-induced premature senescence

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIRT1

involved_in

GO:1901984: negative regulation of protein acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIRT1

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

involved_in

GO:0010629: negative regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

involved_in

GO:0071441: negative regulation of histone H3-K14 acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

involved_in

GO:1901984: negative regulation of protein acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

involved_in

GO:0090400: stress-induced premature senescence

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

involved_in

GO:2000619: negative regulation of histone H4-K16 acetylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SIR1

GO:0071441: negative regulation of histone H3-K14 acetylation

ECO:0000315:

P

Figure 1A: Inhibition of this protein with sirtinol increased acetylation of histone H3 (Lys14).

complete
CACAO 9497

HUMAN:SIR1

GO:2000619: negative regulation of histone H4-K16 acetylation

ECO:0000315:

P

Figure 1A: Inhibition with sirtinol increased the acetylation of histone H4 (Lys16)

complete
CACAO 9498

HUMAN:SIR1

GO:0044154: histone H3-K14 acetylation

ECO:0000315:

P

Figure 1A & 1D: Knockdown with Sirt1 siRNA led to increased acetylation of H3 (Lys14).

complete
CACAO 9499

HUMAN:SIR1

GO:0043983: histone H4-K12 acetylation

ECO:0000315:

P

Figure 1A and 1D: Knockdown with Sirt1 siRNA increased acetylation of H4 (Lys 16).

complete
CACAO 9500

HUMAN:SIR1

GO:0042127: regulation of cell proliferation

ECO:0000315:

P

Figure 1B: Knockdown with Sirt1 siRNA decreased cellular proliferation, but not to the same extent of that by inhibition with sirtinol.

complete
CACAO 9502

HUMAN:SIR1

GO:0006260: DNA replication

ECO:0000315:

P

Figure 1C: Knockdown of Sirt1 with Sirt1 siRNA decreased DNA replication as measured by BrdU incorporation to a lesser extent than by inhibition with sirtinol.

complete
CACAO 9504

HUMAN:SIR1

GO:0090400: stress-induced premature senescence

ECO:0000315:

P

Figure 2A: Knockdown with Sirt1 siRNA caused cells to exhibit senescent-like morophological changes (enlarged and flattened shapes).

complete
CACAO 9508

HUMAN:SIR1

GO:1901984: negative regulation of protein acetylation

ECO:0000315:

P

Figure 3A, 3C: Inhibition by sirtinol increased the acetylation of p53 after 3 days.

complete
CACAO 9509

HUMAN:SIR1

GO:0006473: protein acetylation

ECO:0000315:

P

Figure 3A, 3C & 3D: Knockdown with Sirt1 siRNA increased the acetylation of p53 after 3 days.

complete
CACAO 9510

HUMAN:SIR1

GO:0010629: negative regulation of gene expression

ECO:0000315:

P

Figure 3A, 3C: Inhibition by sirtinol increased the expression of p53 after 5 days.

complete
CACAO 9511

HUMAN:SIR1

GO:0010468: regulation of gene expression

ECO:0000315:

P

Figure 3A, 3C & 3D: Knockdown with Sirt1 siRNA increased the expression of p53 after 5 days.

complete
CACAO 9512

See also

References

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