Olafur Pall Olafsson
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 Posted: Sat Oct 04, 2008 4:28 pm Post subject: Statins may delay cell senescence and promote DNA repair in |
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This study may explain some of the beneficial effects of statins. It
adds further support to the use of HMG-CoA reductase inhibitors for
life-extension, as long as CoQ10 is also taken along with them of
course to offset any reduction in its synthesis.
Circ Res. 2008 Sep 26;103(7):717-25. Epub 2008 Aug 21.
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Statins use a novel Nijmegen breakage syndrome-1-dependent pathway
to accelerate DNA repair in vascular smooth muscle cells.
Mahmoudi M, Gorenne I, Mercer J, Figg N, Littlewood T, Bennett M.
Division of Cardiovascular Medicine, University of Cambridge,
Cambridge, United Kingdom.
Although the hydroxymethylglutaryl-coenzyme A reductase inhibitors
(statins) are widely used in atherosclerosis to reduce serum
cholesterol, statins have multiple other effects, including direct
effects on cells of the vessel wall. Recently, DNA damage, including
telomere shortening, has been identified in vascular smooth muscle
cells (VSMCs) in human atherosclerosis. Although statins reduce DNA
damage in vitro, the mechanisms by which they might protect DNA
integrity in VSMCs are unknown. We show that human atherosclerotic
plaque VSMCs exhibit increased levels of double-stranded DNA breaks
and basal activation of DNA repair pathways involving ataxia
telangiectasia-mutated (ATM) and the histone H2AX in vivo and in
vitro. Oxidant stress induced DNA damage and activated DNA repair
pathways in VSMCs. Statin treatment did not reduce oxidant stress or
DNA damage but markedly accelerated DNA repair. Accelerated DNA repair
required both the Nijmegen breakage syndrome (NBS)-1 protein and the
human double minute protein Hdm2, accompanied by phosphorylation of
Hdm2, dissociation of NBS-1 and Hdm2, inhibition of NBS-1 degradation,
and accelerated phosphorylation of ATM. Statin treatment reduced VSMC
senescence and telomere attrition in culture, accelerated DNA repair
and reduced apoptosis in vivo after irradiation, and reduced ATM/ATR
(ATM and Rad3-related) activity in atherosclerosis. We conclude that
statins activate a novel mechanism of accelerating DNA repair,
dependent on NBS-1 stabilization and Hdm2. Statin treatment may delay
cell senescence and promote DNA repair in atherosclerosis.
Publication Types:
* Research Support, Non-U.S. Gov>t
PMID: 18723444 [PubMed - in process]
Related Articles
* Vascular smooth muscle cells undergo telomere-based
senescence in human atherosclerosis: effects of telomerase and
oxidative stress. [Circ Res. 2006]
* ATM phosphorylation of Nijmegen breakage syndrome protein is
required in a DNA damage response. [Nature. 2000]
* UV-induced ataxia-telangiectasia-mutated and Rad3-related
(ATR) activation requires replication stress. [J Biol Chem. 2004]
* Nbs1 is required for ATR-dependent phosphorylation events.
[EMBO J. 2005]
* Distinct functions of Nijmegen breakage syndrome in ataxia
telangiectasia mutated-dependent responses to DNA damage. [Mol Cancer
Res. 2003]
* » See all Related Articles...
Free full text: http://circres.ahajournals.org/cgi/content/abstract/103/7/717 |
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