Oxidative DNA damage by t‐butyl hydroperoxide causes DNA single strand breaks which is not linked to cell lysis. A mechanistic study in freshly isolated rat hepatocytes

Latour, Isabelle; Demoulin, Jean‐Baptiste; Buc-Calderon, Pedro

doi:10.1016/0014-5793(95)01065-m

Cited by 63 publications

(43 citation statements)

References 31 publications

(29 reference statements)

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“…t-BHP induces DNA breaks in many cell types 20,21 and can induce both "stress-induced premature senescence," and accelerate telomere shortening of human VSMCs. 2 t-BHP increased oxidant stress, DNA breaks and P-ATM and ␥-H2AX expression in normal VSMCs to levels seen in plaque VSMCs, suggesting that plaque VSMCs might be subject to chronic oxidant stress (data not shown).…”

Section: Atorvastatin Accelerates Dna Repair In Human Vsmcsmentioning

confidence: 99%

Statins Use a Novel Nijmegen Breakage Syndrome-1–Dependent Pathway to Accelerate DNA Repair in Vascular Smooth Muscle Cells

Mahmoudi

Gorenne

Mercer

et al. 2008

Circulation Research

122

132

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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. H uman atherosclerotic plaques demonstrate evidence of DNA damage, including expression of oxidized guanosine residues, DNA strand breaks, and activation of DNA repair enzymes. 1,2 Although DNA damage is seen in both vascular smooth muscle cells (VSMCs) and macrophages, the mechanisms underlying DNA damage and its biological consequences are unknown. For example, DNA damage can promote apoptosis and premature cell senescence (reviewed elsewhere 3 ), both of which are prominent in VSMCs in human atherosclerosis. 2,4 Conversely, accelerating DNA repair may prevent or reduce accumulated DNA damage, preventing apoptosis or cell senescence.DNA damage induces a cascade of activated proteins that act as sensors and effectors of the damage response, to stall the cell cycle allowing repair to occur, to promote repair, or to induce apoptosis if damage is severe. DNA damage activates Nijmegen breakage syndrome (NBS)-1, a ubiquitously expressed 754-aa protein and key regulator of the MRE11/RAD-50/NBS-1 (MRN) complex. 5,6 MRN promotes early processing of double-strand breaks (DSBs) via DNA binding and nuclease activities, functions as a DSB sensor, and also recruits the ataxia telangiectasia-mutated (ATM) protein to DSBs, followed by ATM activation. 7-9 ATM is normally present as inactive dimers, but DSB exposure induces autophosphorylation at Ser1981, dimer dissociation, and kinase activation. ATM has multiple downstream substrates that me...

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Section: Atorvastatin Accelerates Dna Repair In Human Vsmcsmentioning

confidence: 99%

Statins Use a Novel Nijmegen Breakage Syndrome-1–Dependent Pathway to Accelerate DNA Repair in Vascular Smooth Muscle Cells

Mahmoudi

Gorenne

Mercer

et al. 2008

Circulation Research

122

132

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“…We next examined oxidative stress in plaque and normal VSMCs, in normal VSMCs at replicative senescence, and after treatment of VSMCs with tert-butylhydroperoxide (t-BHP), an inducer of hydrogen peroxide 21 that can induce DNA single-strand breaks. 22,23 Flow cytometric analysis of fluorescence of the redox-sensitive dye H 2 -DCFDA showed significantly increased oxidative stress in plaque versus normal VSMCs and also in normal VSMCs at replicative senescence. These changes paralleled a significant increase in mitochondrial mass in plaque and senescent VSMCs (supplemental Figure II).…”

Section: Matthews Et Al Atherosclerosis and Telomere Shortening 159mentioning

confidence: 99%

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Matthews

Gorenne²,

Scott³

et al. 2006

Circulation Research

537

434

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Abstract-Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. (VSMCs), and intracellular and extracellular lipids. Plaque disruption results in acute myocardial infarction and stroke, whereas repeated rounds of subclinical rupture and repair also promote plaque growth. Although VSMC proliferation occurs in atherogenesis, most proliferating cells are macrophages, and VSMC mitotic rates are lower in advanced plaques than early lesions, even after plaque rupture, 1 suggesting that plaque VSMCs may exhibit senescence.Cellular senescence can be defined as cell cycle arrest accompanying the exhaustion of replicative potential. 2 Senescent cells display a characteristic morphology (vacuolated, flattened cells) and gene expression, including markers such as senescence-associated ␤-galactosidase (SA␤G). 3 Senescence may be triggered by 2 broadly different mechanisms. In most primary cells, the telomeres of chromosomes shorten at each cell division because of incomplete chromosomal replication. Replicative senescence may be induced at critical telomere lengths or structures, such as telomeric fusion or dicentrics or loss of telomere-bound factors. 4,5 Cells also undergo "stress-induced premature senescence" (SIPS), for example, in response to activated oncogenes (eg, Ha-Ras) and suboptimal culture conditions. 6 Although telomere loss occurs with replication, both premature senescence and telomere breaks may be induced by oxidative DNA damage. Reactive oxygen species (ROS), particularly superoxide anions, hydrogen peroxide, and hydroxyl radicals, can produce a large variety of DNA damage, including DNA strand breaks and DNA base modifications. ROS can accelerate telomere loss during replication in some cell types 7 but also induces premature senescence independently of telomere shortening. 8 Increased levels of ROS are Original

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“…In particular, 3 is a rare substance on which only one study has reported. 7) Compound 4 was assigned to be eriodictyol-7-O-b-D-glucopyranoside on the basis of UV, MS, 1 H-NMR and 13 C-NMR spectral data. 8) The CD spectrum of 4 showed a positive Cotton eŠect at 292 nm and a negative Cotton eŠect at 333 nm.…”

mentioning

confidence: 99%

“…This system involves the bacteria receiving fatal damage through lipid peroxidation of the membranes, and the DNA single strand breaking. 13) Table 1 shows the protective activity of the isolated compounds against the peroxyl radical. The present study demonstrates that orientin and isoorientin signiˆcantly protected bacteria from the bactericidal action of peroxyl radicals, although their activities were lower than that of epigallocatechin gallate.…”

mentioning

confidence: 99%

Antioxidative Compounds fromCrotalaria sessiliflora

Mun’im

Negishi

Ozawa

2003

Bioscience, Biotechnology, and Biochemistry

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Seven antioxidative compounds were isolated from the EtOAc extract of the aerial part of C. sessili‰ora (Japanese name, tanukimame) by activity-guided fractionation with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Among the isolated compounds, hydroxyeucomic acid showed the strongest free radical-scavenging activity, which was almost identical to that of epigallocatechin gallate, against DPPH. Orientin and isoorientin showed strong anti-peroxidative activities toward linoleic acid and protective eŠects against the bactericidal action of the tert-butyl peroxyl radical. Their activities were nearly equal to that of epigallocatechin gallate.

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Oxidative DNA damage by t‐butyl hydroperoxide causes DNA single strand breaks which is not linked to cell lysis. A mechanistic study in freshly isolated rat hepatocytes

Cited by 63 publications

References 31 publications

Statins Use a Novel Nijmegen Breakage Syndrome-1–Dependent Pathway to Accelerate DNA Repair in Vascular Smooth Muscle Cells

Statins Use a Novel Nijmegen Breakage Syndrome-1–Dependent Pathway to Accelerate DNA Repair in Vascular Smooth Muscle Cells

Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis

Antioxidative Compounds fromCrotalaria sessiliflora

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