Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage

Harangi, Mariann; Serés, I.; Varga, Zsuzsa; Emri, Gabriella; Szilvássy, Zoltán; Paragh, György; Remenyik, Éva

doi:10.1007/s00228-004-0820-6

Cited by 79 publications

(64 citation statements)

References 38 publications

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“…These results suggest that these genotypes are not associated with physiological responses to atorvastatin, which has been observed by others [8,16]. However, we found that the PON1 T(-107)C polymorphism significantly influences the levels of oxidative stress parameters after atorvastatin treatment, which is in contrast with a previous report [41].…”

Section: Discussioncontrasting

confidence: 96%

“…Atorvastatin is a drug of choice for reducing lipids in hypercholesterolemic patients. Many studies have demonstrated that atorvastatin induces a significant reduction in total cholesterol, LDL-C, and triglycerides levels, but the effect of atorvastatin on HDL-C remains unchanged [16,20,31,36,41]. Similarly to previous studies, we found that atorvastatin significantly reduces total cholesterol (24.5%), LDL-C (25.4%) and triglyceride (24.4%) levels; however, there were insignificant changes in HDL-C levels.…”

Section: Discussionsupporting

confidence: 83%

“…The mechanism involved in this phenomenon may be the ability of atorvastatin to reduce the production of reactive oxygen species [34,39,40,45]. On the other hand, atorvastatin may play a role in protecting LDL, and HDL from oxidation by increasing antioxidant activity of the HDL-associated enzyme, PON1 [16,20,31,36,41]. However, the outcome and consistency of the effect of atorvastatin on PON1 activity varies in the literature.…”

Section: Discussionmentioning

confidence: 99%

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Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Nagila

Permpongpaiboon

Tantrarongroj

et al. 2009

Pharmacological Reports

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Abstract:It has been proposed that paraoxonase1 (PON1), a high density lipoprotein (HDL)-associated esterase/lactonase, has antiatherosclerotic properties. The activity of PON1 is influenced by PON1 polymorphisms. However, the influence of PON1 polymorphisms on PON1 activity and oxidative stress in response to lipid-lowering drugs remains poorly understood. The objective of the present study was to investigate the effects of atorvastatin on PON1 activity and oxidative status. The influence of PON1 polymorphisms on PON1 activity and oxidative status in response to atorvastatin treatment was also evaluated. In total, 22 hypercholesterolemic patients were treated with atorvastatin at a dose of 10 mg/day for 3 months. Lipid profile, lipid oxidation markers (malondialdehyde (MDA), conjugated diene (CD), total peroxides (TP)), total antioxidant substance (TAS), oxidative stress index (OSI), and paraoxonase1 activity were determined before and after treatment. L55M, Q192R, and T(-107)C PON1 polymorphisms were also determined. Atorvastatin treatment significantly reduced the levels of total cholesterol (24.5%), low density lipoprotein (LDL) cholesterol (25.4%), triglycerides (24.4%), CD (4.4%), MDA (15.2%), TP (13.0%) and OSI (24.0%), and significantly increased the levels of TAS (27.3%), and PON1 activity (14.0%). Interestingly, the increase in PON1 activity and the reduction in oxidative stress in response to atorvastatin were influenced only by the PON1 T-107C polymorphism. Atorvastatin treatment improved the lipid profile, lipid oxidation, and oxidative/antioxidative status markers including the activity of PON1 towards paraoxon. These beneficial effects may be attributed to the antioxidant properties of statins and the increase in PON1 activity. The increase in PON1 activity was enhanced by the PON1 T-107C polymorphism.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Nagila

Permpongpaiboon

Tantrarongroj

et al. 2009

Pharmacological Reports

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“…PON1 activity was increased inversely proportionally to decreased lipid peroxides caused by ROS. It was shown that atorvastatin increased PON1 activities in different clinical and experimental studies, in line with our study (28)(29)(30)(31)(32), whereas some others failed to find any changes in serum paraoxonase activity following simvastatin or atorvastatin administration (16). Deakin et al (33) explained that patients with the -108C allele, who already have higher PON1 levels, may further benefit from treatment with statins, indicating the importance of gene polymorphism among individuals.…”

Section: Discussionsupporting

confidence: 89%

The effects of atorvastatin on antioxidant/antiinflammatory propertiesof HDLs in hypercholesterolemics

Çiftçi¹,

Ertorun²,

Akalın³

et al. 2015

Turk J Med Sci

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Background/aim: Hypercholesterolemia is characterized by changes in lipid profile, nitric oxide pathway, and oxidative stress markers, but functions of high-density lipoprotein (HDL) were not well established in hypercholesterolemic subjects treated with atorvastatin. In this study, we aimed to evaluate effects of atorvastatin treatment on functionality of HDL, oxidative stress, and endothelial functions in hypercholesterolemic subjects. Materials and methods:Thirty patients (20 females, 10 males) aged from 40 to 60 years and diagnosed as hypercholesterolemic were included. Patients were treated with 10 mg/day atorvastatin for 3 months. Markers of endothelial functions, namely asymmetric dimethylarginine (ADMA), homocysteine, and nitric oxide (NO), and markers of oxidative status, namely malondialdehyde (MDA), antioxidant potential (AOP), paraoxonase 1 (PON1), and arylesterase, were measured. Before and after atorvastatin treatment, glucose, lipid parameters, and antioxidant/antiinflammatory HDL levels were also measured.Results: ADMA and homocysteine levels were decreased whereas NO levels were increased with atorvastatin therapy. MDA levels were decreased but AOP, PON1, and arylesterase levels and antiinflammatory characteristics of HDLs were increased. Furthermore, lipid profiles of the patients improved with atorvastatin therapy. Conclusion:Hypercholesterolemia is a cause of oxidative stress, endothelial dysfunction, and proinflammatory HDL levels. Atorvastatin is a beneficial pharmacological modulator of impaired antiinflammatory HDL-C levels, endothelial functions, and oxidative status against atherosclerosis indicating pleiotropic effects of statins.

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“…More recently, statins have been reported to reduce DNA damage in vitro and also in vivo, after a variety of insults. There are multiple mechanisms by which statins might reduce DNA damage, including reduction of oxidative stress, [12][13][14][15] inhibition of prenylation of proteins involved in inducing DNA damage, 16 and inhibition of downstream signaling from damaged DNA. 17,18 We, therefore, examined the effect of statin treatment on DNA damage and repair pathways in human VSMCs.…”

mentioning

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

125

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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Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage

Abstract: These findings show that atorvastatin treatment favorably affected the lipid profile, increasing the activity of HDL-associated PON and decreasing the cytotoxic effect of oxidative stress.

Cited by 79 publications

References 38 publications

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

The effects of atorvastatin on antioxidant/antiinflammatory propertiesof HDLs in hypercholesterolemics

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

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