2007 Fiscal Year Final Research Report Summary
The Role of Sirtl in Vascular Senescence and Funcrion
| Project/Area Number |
18590801
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
AKISHITA Masahiro The University of Tokyo, Geriatric Medicine, Associate Professor (00261975)
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| Co-Investigator(Kenkyū-buntansha) |
ETO Masato The University of Tokyo, Geriatric Medicine, Lecturer (80282630)
IJIMA Katsuya The University of Tokyo, Geriatric Medicine, Lecturer (00334384)
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| Project Period (FY) |
2006 – 2007
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| Keywords | senescence / aging / Sir2 / Sirt1 / cardiovascular disease / atherosclerosis / endothelial dysfunction |
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| Research 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 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. 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. Next, we found that cilostazol, a phosphodiesterase 3 inhibitor, exerted protective effects against premature senescence-like phenotype of HUVEC, and NO-dependent Sirt1 expression plays a key role in its effects. We conclude that Sirt1 may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence.
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