Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Atherosclerosis / drug therapy*
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Atherosclerosis / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cells, Cultured
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Cellular Senescence / drug effects
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Cellular Senescence / genetics
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Cholesterol / metabolism
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DNA Breaks, Double-Stranded / drug effects
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DNA Repair / drug effects*
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DNA Repair / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Endothelium, Vascular / metabolism
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Histones / genetics
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Histones / metabolism
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Mice
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Muscle, Smooth, Vascular / metabolism*
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Myocytes, Smooth Muscle / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxidative Stress / drug effects
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Oxidative Stress / genetics
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Rabbits
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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H2AX protein, human
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H2AX protein, mouse
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Histones
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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NBN protein, human
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Nijmegen breakage syndrome 1 protein, mouse
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Nuclear Proteins
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Tumor Suppressor Proteins
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Cholesterol
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Atr protein, mouse
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases