title: High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Atorvastatin Preferentially Reduces LDL-Associated Platelet-Activating Factor Acetylhydrolase Activity in Dyslipidemias of Type IIA and Type IIB Clinical and Genetic Association of Serum Paraoxonase and Arylesterase Activities With Cardiovascular Risk Anthocyanin supplementation improves HDL-associated paraoxonase 1 activity and enhances cholesterol efflux capacity in subjects with hypercholesterolemia. Simvastatin treatment prevents oxidative damage to DNA in whole blood leukocytes of dyslipidemic type 2 diabetic patients Paraoxonase-1 activity, malondialdehyde and glutathione peroxidase in non-alcoholic fatty liver disease and the effect of atorvastatin. ADMINISTRATION OF EXOGENOUS ERYTHROPOIETIN β AFFECTS LIPID PEROXIDATION AND SERUM PARAOXONASE‐1 ACTIVITY AND CONCENTRATION IN PREDIALYSIS PATIENTS WITH CHRONIC RENAL DISEASE AND ANAEMIA Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. Effect of Simvastatin Therapy on Paraoxonase Activity and Related Lipoproteins in Familial Hypercholesterolemic Patients Decreased in vitro oxidizability of low‐density lipoprotein in hypercholesterolaemic patients treated with 3‐hydroxy‐3‐methyIgIutaryl‐CoA reductase inhibitors Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol. Effect of rosuvastatin versus atorvastatin treatment on paraoxonase-1 activity in men with established cardiovascular disease and a low HDL-cholesterol Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage The effects of rosuvastatin alone or in combination with fenofibrate or omega 3 fatty acids on inflammation and oxidative stress in patients with mixed dyslipidemia Antioxidant effect of atorvastatin is independent of PON1 gene T(–107)C, Q192R and L55M polymorphisms in hypercholesterolaemic patients A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin. Simvastatin Modulates Expression of the PON1 Gene and Increases Serum Paraoxonase: A Role for Sterol Regulatory Element–Binding Protein-2 The effect of atorvastatin therapy on lecithin:cholesterol acyltransferase, cholesteryl ester transfer protein and the antioxidant paraoxonase. Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia Dose-dependent Effect of Rosuvastatin Treatment on HDL-subfraction Phenotype in Patients With Primary Hyperlipidemia
abstract: The British Regional Heart Study ( BRHS ) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol ( HDLC ) and incidence of coronary heart disease was eliminated by covariance adjustment . Using the proportional hazards model and adjusting for age , blood pressure , smoking , body mass index , and low-density lipoprotein cholesterol , we analyzed this relation separately in the Framingham Heart Study ( FHS ) , Lipid Research Clinics Prevalence Mortality Follow-up Study ( LRCF ) and Coronary Primary Prevention Trial ( CPPT ) , and Multiple Risk Factor Intervention Trial ( MRFIT ) . In CPPT and MRFIT ( both r and omized trials in middle-age high-risk men ) , only the control groups were analyzed . A 1-mg/dl ( 0.026 mM ) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2 % in men ( FHS , CPPT , and MRFIT ) and 3 % in women ( FHS ) . In LRCF , where only fatal outcomes were documented , a 1-mg/dl increment in HDLC was associated with significant 3.7 % ( men ) and 4.7 % ( women ) decrements in cardiovascular disease mortality rates . The 95 % confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably , and all contained the range 1.9 - 2.9 % . HDLC levels were essentially unrelated to non-cardiovascular disease mortality . When differences in analytic methodology were eliminated , a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies Human plasma platelet-activating factor acetylhydrolase ( PAF-AH ) is a phospholipase A2 that is primarily associated with low density lipoprotein ( LDL ) . PAF-AH activity has also been found in high density lipoprotein ( HDL ) , although it has recently been indicated that there is no PAF-AH protein in HDL . Plasma paraoxonase 1 ( PON1 ) is an HDL-associated esterase , which also exhibits PAF-AH – like activity . The effect of atorvastatin ( 20 mg per day for 4 months ) on PAF-AH and PON1 activities in patients with dyslipidemia of type IIA ( n=55 ) or type IIB ( n=21 ) was studied . In both patient groups , atorvastatin significantly reduced plasma PAF-AH activity because of the decrease in LDL plasma levels and the preferential decrease in PAF-AH activity on dense LDL subfractions ( LDL-4 and LDL-5 ) . Drug therapy did not affect HDL-associated PAF-AH activity or serum PON1 activities toward paraoxon and phenylacetate in either patient group . However , because of the reduction in LDL cholesterol levels , the ratios of HDL-associated PAF-AH and serum PON1 activities to LDL cholesterol levels were significantly increased after drug administration . The reduction of the LDL-associated PAF-AH activity and the elevation in the ratios of HDL-associated PAF-AH and PON1 activities to LDL plasma levels may represent a new dimension in the antiatherogenic effect of atorvastatin Objective —Diminished serum paraoxonase and arylesterase activities ( measures of paraoxonase-1 [ PON-1 ] function ) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk . The clinical prognostic use of measuring distinct PON-1 activities has not been established , and the genetic determinants of PON-1 activities are not known . Methods and Results —We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospect ively followed for major adverse cardiovascular events ( MACE= death , myocardial infa rct ion , stroke ) over 3 years . Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE , with arylesterase activity showing greatest prognostic value ( quartile 4 versus quartile 1 ; hazard ratio 2.63 ; 95 % CI , 1.97–3.50 ; P<0.01 ) . Arylesterase remained significant after adjusting for traditional risk factors , C-reactive protein , and creatinine clearance ( hazard ratio , 2.20 ; 95 % CI , 1.60–3.02 ; P<0.01 ) , predicted future development of MACE in both primary and secondary prevention population s , and reclassified risk categories incrementally to traditional clinical variables . A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase ( 1.18 × 10 - 303 ) or arylesterase ( 4.99 × 10−116 ) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort ( n=2136 ) or history of either coronary artery disease or myocardial infa rct ion in the Coronary Artery Disease Genome-Wide Replication and Meta- Analysis consortium ( n≈80 000 subjects ) . Conclusion —Diminished serum arylesterase activity , but not the genetic determinants of PON-1 functional measures , provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE CONTEXT AND OBJECTIVE Paraoxonase 1 ( PON1 ) , an enzyme associated with high-density lipoprotein ( HDL-PON1 ) , is reported to have antioxidant and cardioprotective properties . The aim of the present study was to investigate the effects of anthocyanins on the HDL-PON1 activity and cholesterol efflux capacity in hypercholesterolemic subjects . DESIGN AND PARTICIPANTS A total of 122 hypercholesterolemic subjects were given 160 mg of anthocyanins twice daily or placebo ( n = 61 of each group ) for 24 weeks in a double-blind , r and omized , placebo-controlled trial . Participants and investigators were masked to treatment allocation . RESULTS Anthocyanin consumption significantly increased HDL cholesterol and decreased low -density lipoprotein cholesterol concentrations compared with placebo ( P < .018 and P < .001 , respectively ) . Anthocyanin supplementation also increased the activity of HDL-PON1 compared with placebo ( P < .001 ) . Furthermore , cholesterol efflux capacity was increased more in the anthocyanin group ( 20.0 % increase ) than in the placebo group ( 0.2 % increase ) ( P < .001 ) . The negative correlations established between HDL-PON1 activity and the levels of lipid hydroperoxides associated with HDL confirm the relationship between PON1 activity and lipid peroxidation of lipoproteins . Furthermore , a strong positive correlation was noted between increased HDL-PON1 activity and improved cholesterol efflux capacity both before and after adjustment for HDL cholesterol and apolipoprotein AI in anthocyanin-treated subjects ( both P < .001 ) . Inhibition of HDL-PON1 activity strongly prevented the antioxidant ability of HDL and attenuated the cholesterol efflux capacity of subjects from anthocyanin group . CONCLUSIONS Our observations suggest that the alterations of PON1 activity by anthocyanin observed in hypercholesterolemic HDL reflect a shift to an improvement of cholesterol efflux capacity of HDL and may provide a link between anthocyanin and cardioprotective effects Type 2 diabetes ( T2D ) is associated with increased oxidative stress as indicated by elevated levels of lipid peroxidation and protein oxidation products . Since reactive oxygen species ( ROS ) can cause damage to biological macromolecules including DNA , this study investigated oxidative damage to DNA using the alkaline ( pH > 13 ) comet assay in peripheral whole blood leukocytes sample d from 15 dyslipidemic T2D patients treated with simvastatin ( 20 mg/day ) , 15 dyslipidemic T2D patients not treated with simvastatin , 20 non‐dyslipidemic T2D patients , and 20 healthy individuals ( controls ) . Our results showed a greater DNA migration in terms of damage index ( DI ) ( p < 0.01 ) in the dyslipidemic T2D patients not treated with statin ( DI = 67.70 ± 10.89 ) when compared to the dyslipidemic T2D patients under statin treatment ( DI = 47.56 ± 7.02 ) , non‐dyslipidemic T2D patients ( DI = 52.25 ± 9.14 ) , and controls ( DI = 13.20 ± 6.40 ) . Plasma malondialdehyde ( MDA ) and C‐reactive protein ( CRP ) levels were also increased and total antioxidant reactivity ( TAR ) and paraoxonase activity ( PON1 ) decreased in non‐dyslipidemic T2D patients and dyslipidemic T2D non‐treated with simvastatin . We also found that DI was inversely correlated with TAR ( r = −0.61 , p < 0.05 ) and PON1 ( r = −0.67 , p < 0.01 ) . In addition , there was a significant positive correlation between DI and CRP ( r = 0.80 , p < 0.01 ) . Our results therefore indicate that simvastatin treatment plays a protective role on oxidative damage to DNA in dyslipidemic T2D patients probably reflecting a general decrease in oxidative stress in these patients . Copyright © 2010 John Wiley & Sons , BACKGROUND AND STUDY AIMS The prevalence of non-alcoholic fatty liver disease ( NAFLD ) appears to be increasing . The aim of the present study was to investigate the relationship between hepatic antioxidant paraoxonase 1 ( PON1 ) activity , lipid peroxidation and antioxidant enzymes in patients with NAFLD and the effect of atorvastatin . PATIENTS AND METHODS This study was conducted on 50 patients with NAFLD and 20 normal subjects matched for age and sex . All of them were subjected to the following investigations : abdominal ultrasonography , serum PON1 activity level , liver function tests , serum lipid profile , fasting and postpr and ial blood glucose and serum levels of malondialdehyde ( MDA ) and glutathione peroxidase ( GP ) .  NAFLD patients were further r and omly classified into two groups ( 25 patients each ) , groups Ia and Ib . Only group Ia received atorvastatin 40 mg tablet for 8months . RESULTS Obesity , dyslipidaemia and impaired glucose tolerance were prevalent in group I. There was a significant decrease in serum PON1 activity with a significant increase in MDA and GP activity ( i.e. , there is a significant increase in lipid peroxidation rate ) in group I compared with group II . After atorvastatin therapy , there was a significant increase in serum PNO1 activity and significant decrease in serum MDA levels . CONCLUSION Patients with NAFLD show enhanced oxidative stress which may lead to non-alcoholic steatohepatitis ( NASH ) . Reduced PON1 activity and increased MDA could be considered a biochemical marker for lipid peroxidation , which require follow-up in patients with NAFLD . Atorvastatin may have a role in prevention of , or delay , the transformation of liver steatosis into NASH 1 Patients with advanced chronic renal disease and anaemia have decreased serum paraoxonase‐1 ( PON1 ) activity and an increased degree of oxidative stress compared with normal subjects . The present study investigated the effects of treatment of anaemia with exogenous recombinant erythropoietin ( EPO ) β and iron on levels of antibodies against oxidized low‐density lipoproteins ( ox‐LDL ) , as well as on serum PON1 activity and concentration , in predialysis patients with chronic renal disease . 2 Forty‐nine patients with chronic renal failure and haemoglobin ( Hb ) < 11 g/dL were treated over a period of 6 months with EPOβ ( 80–120 U/kg per week , s.c . ) and variable doses of iron . Selected biochemical variables were determined before and after treatment . 3 Treatment with EPOβ and iron was associated with a significant increase in mean ( ±SD ) blood Hb concentration compared with pretreatment values ( 12.8 ± 1.5 vs 9.9 ± 0.6 g/dL , respectively ; P < 0.001 ) . The average dose of EPOβ was 6160 ± 3000 U/week . After 6 months of treatment , compared with pretreatment values , the median levels ( 95 % confidence intervals ) of antibodies against ox‐LDL were decreased ( 17.5 ( 10.6–24.4 ) vs 24.8 ( 11.5–38.1 ) U/mL , respectively ; P < 0.001 ) , serum PON1 activity was slightly but significantly increased ( 123.6 ( 76.1–343.6 ) vs 101.0 ( 50.0–332.5 ) U/L , respectively ; P = 0.016 ) and the concentration of PON1 was significantly decreased ( 37.3 ( 11.8–76.2 ) vs 46.7 ( 24.6–98.0 ) mg/L , respectively ; P < 0.001 ) . There were no significant changes in total cholesterol , triglycerides or cholesterol fraction concentrations before and after treatment . 4 We suggest that EPOβ and iron treatment of anaemia promotes significant changes in serum PON1 activity and concentration and has a beneficial effect on oxidative stress in predialysis patients with chronic renal disease The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme ( PON1 ) activity in type 2 diabetic Egyptian patients with or without nephropathy . The present study was carried out on the following groups : control group , which consisted of 30 healthy persons ; Group I , which consisted of 20 type 2 diabetic patients without nephropathy ; and Group II , which consisted of 20 type 2 diabetic patients with nephropathy . All the patients selected were under an antidiabetic regimen of insulin  , and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies . Twenty-two patients ( 15 without nephropathy and seven with nephropathy ) received atorvastatin in individually adjusted oral dosage ( range 10 - 20 mg ) once per day for 12 weeks . All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity , malondialdehyde ( MDA ) , glutathione reductase activity , fasting glucose , total cholesterol , triglycerides , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) , urea , and creatinine . Urine sample s were collected for determination of proteinuria . The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group , with significant difference in their levels between Group II and Group I. MDA , total cholesterol , and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group . Urea , creatinine , and proteinuria levels showed significant increase in Group II when compared to the control group and Group I , with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity , and serum levels of MDA and glutathione reductase activity were significantly decreased and increased , respectively . Also , total cholesterol , triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels . There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level . Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period . PON1 activity showed a significant negative correlation with glucose and LDL , and a significant positive correlation with HDL in all the studied groups . It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia , but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy . More specifically , restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy . Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications CONTEXT Paraoxonase 1 ( PON1 ) is reported to have antioxidant and cardioprotective properties . The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease ( CVD ) risk in humans has not been systematic ally investigated . OBJECTIVE To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans . DESIGN , SETTING , AND PARTICIPANTS The association between systemic PON1 activity measures and a functional polymorphism ( Q192R ) result ing in high PON1 activity with prevalent CVD and future major adverse cardiac events ( myocardial infa rct ion , stroke , or death ) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Clevel and Clinic . Patients were followed up until December 2006 . Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age- , sex- , and race-matched patients and compared with regard to PON1 genotype and activity . MAIN OUTCOME MEASURES Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD . RESULTS The PON1 genotype demonstrated significant dose-dependent associations ( QQ192 > QR192 > RR192 ) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress . Compared with participants with either the PON1 RR192 or QR192 genotype , participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality ( 43/681 deaths [ 6.75 % ] in RR192 and QR192 and 62/584 deaths [ 11.1 % ] in QQ192 ; adjusted hazard ratio , 2.05 ; 95 % confidence interval [ CI ] , 1.32 - 3.18 ) and of major adverse cardiac events ( 88/681 events [ 13.6 % ] in RR192 and QR192 and 102/584 events [ 18.0 % ] in QQ192 ; adjusted hazard ratio , 1.48 ; 95 % CI , 1.09 - 2.03 ; P = .01 ) . The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile ( 23/315 [ 7.3 % ] ) and 235/324 [ 7.7 % ] for paraoxonase and arylesterase , respectively ) compared with those in the lowest activity quartile ( 78/311 [ 25.1 % ] and 75/319 [ 23.5 % ] ; P < .001 for paraoxonase and arylesterase , respectively ) . The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were , for paraoxonase , 3.4 ( 95 % CI , 2.1 - 5.5 ; P < .001 ) and for arylesterase , 2.9 ( 95 % CI , 1.8 - 4.7 ; P < .001 ) and remained independent in multivariate analysis . CONCLUSION This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospect i ve cardiovascular risk , indicating a potential mechanism for the atheroprotective function of PON1 Human paraoxonase ( PON1 ) is a calcium-dependent esterase closely associated with high density lipoprotein (HDL)-containing apolipoprotein AI ( apoAI ) , which has been shown to confer antioxidant properties to HDL . PON1 has been recently implicated in the pathogenesis of atherosclerosis . Low PON1 activities have been found in familial hypercholesterolemia ( FH ) and diabetes mellitus . We have undertaken a study of the effect of the lipid-lowering drug simvastatin on serum PON1 activity ( in relation to paraoxon and arylesterase activity ) , on apoAI-containing and apolipoprotein B (apoB)-containing lipoproteins , and on lipid peroxide concentrations in 64 ( 39 women and 25 men ) unrelated FH patients . We have also analyzed the influence of the PON1 - 192 and PON1 - 55 genetic polymorphisms on the response of PON1 activity to simvastatin therapy . A venous blood sample for a baseline analysis and another after 4 months of simvastatin therapy at a dosage of 20 mg per day were taken . The major effect of simvastatin on lipid traits was to decrease serum cholesterol , low density lipoprotein ( LDL ) cholesterol , and lipid peroxide concentrations by 19.9 % , 26.3 % , and 37.3 % , respectively . There was also a significant decrease in serum apoB , LDL apoB , and triglyceride concentrations ( 20.5 % , 21.1 % , and 15.6 % , respectively ) . Conversely , simvastatin had no significant influence on very low density lipoprotein – lipid content , HDL cholesterol , apoAI concentrations , and lipoprotein AI and AI : AII particles . Remarkably , serum PON1 activity toward paraoxon significantly increased during treatment with simvastatin ( 168.7±100.3 U/L before therapy versus 189.5±116.5 U/L after therapy , P = 0.005 ) . Arylesterase activity displayed only a nonsignificant trend to increase after therapy . Whereas PON1 activity levels were significantly lower in FH patients  before simvastatin therapy compared with those of 124 normolipidemic subjects ( 168.7±100.3 versus 207.6±125.2 U/L , respectively;P < 0.05 ) , this difference disappeared after simvastatin therapy . After simvastatin therapy , a significantly negative correlation between PON1 activity and lipid peroxide concentration was observed ( r = −0.35 , P = 0.028 ) . The latter also strongly correlated with LDL cholesterol concentration ( r = 0.64 , P < 0.001 ) . Serum PON1 activity levels were significantly lower in the low-activity PON1 - 192 QQ and PON1 - 55 M carriers than in R carriers and in LL carriers , respectively . No significant differences were found in the therapeutic response of PON1 activity between genotype groups ( 8.5 % and 11.1 % increase for QQ homozygous and R-carrier FH patients , respectively , and 12.7 % and 9.5 % increase for LL homozygotes and M carriers , respectively ) . We conclude that simvastatin may have important antioxidant properties through increasing serum PON1 activity , perhaps as a consequence of reducing oxidative stress , by a mechanism independent of apoAI-containing lipoprotein concentration and without the influence of PON1 - 192 and PON1 - 55 genetic polymorphisms . Further studies are clearly warranted to clarify the precise mechanism by which simvastatin therapy is associated with increased PON1 activity Abstract . We studied the effects of the 3‐hydroxy‐3‐methylglutaryl‐CoA ( HMG‐CoA ) reductase inhibitors simvastatin and pravastatin on the in vitro susceptibility of low‐density lipoprotein ( LDL ) to oxidation . Twenty‐three hypercholesterolaemic patients ( mean serum cholesterol 9.7 mmol 1‐1 ) were treated with increasing doses of either simvastatin or pravastatin for 18 weeks . No significant differences in effect on lipid levels between the two drugs were found . Treatment result ed in lowering of total cholesterol and LDL‐cholesterol by maximally 30 % and 34 % , respectively . Chemical composition analysis showed that LDL particles contained relatively more protein and less free cholesterol and cholesteryl‐ester after treatment . The LDL cholesterol/protein ratio decreased from 1.24 ± 0.21 to 0.97 ± 0.23 ( n = 20 ) . By continuous monitoring of in vitro oxidation it appeared that LDL was less susceptible to oxidation after drug treatment . Maximal rate of diene production was significantly decreased from 19.7 ± 3.1 to 18.5 ± 3.3 nmol min‐1 mg‐1 LDL ; total diene production decreased significantly from 420.3 ± 67.6 to 380.5 ± 49.1 nmol mg‐1 LDL ; the lag time was unchanged throughout the study . These studies show that HMG‐CoA reductase inhibitors reduce the oxidizability of LDL by altering its composition Paraoxonase ( PON ) is an enzyme carried by high-density lipoprotein cholesterol ( HDL-C ) . Two gene polymorphisms leading to amino acid substitutions of methionine for leucine at position 55 ( M/L55 ) and arginine for glutamine at position 192 ( R/Q192 ) modulate the activity of the enzyme and possibly also lipid and apolipoprotein concentrations . Our purpose was to examine the effect of the PON genotype on HDL-C and apolipoprotein AI ( apo AI ) responses to pravastatin treatment . Fifty-one mildly hypercholesterolemic male subjects ( mean age 35 + /- 4 years ) were enrolled by this prospect i ve , r and omized , double-blind study . Lipid concentrations were measured at baseline and after 6 months of pravastatin ( n = 25 ) or placebo ( n = 26 ) therapy . Low active ( MM , ML or QQ ) and high active ( LL or RQ , RR ) PON genotype groups were related to lipid and apolipoprotein concentration changes . Pravastatin increased the apo AI concentration 12 % ( P = 0.017 , RANOVA ) and tended to increase the HDL-C concentration ( P = 0.095 , RANOVA ) in R allele carriers but not in QQ homozygotes . Significant predictors of the change in apo AI concentration during pravastatin treatment were R/Q192 genotype ( P = 0.002 ) , apo AI concentration at baseline ( P = 0.002 ) and M/L55 genotype ( P = 0.042 ) . Correspondingly , R/Q192 ( P = 0.009 ) and M/L55 ( P = 0.050 ) genotypes were the statistically significant determinants of HDL-C concentration change . The PON genotype thus modifies the effect of pravastatin on serum HDL-C and apo AI concentrations . This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concentration ABSTRACT Objective : Paraoxonase-1 ( PON-1 ) is a high-density lipoprotein ( HDL ) associated enzyme involved in the protective mechanisms of HDL . Our aim was to compare the effect of treatment with rosuvastatin and atorvastatin on serum PON-1 activity . Methods : We performed a prespecified prospect i ve study in 68 patients , part of a larger , multicentre r and omized study – RADAR  ( Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport ) . Patients aged 40–80 years , all men , with established cardiovascular disease and high-density lipoprotein cholesterol ( HDL‑C ) < 1.0 mmol/L ( < 40 mg/dL ) entered a 6-week dietary run-in period before receiving treatment with rosuvastatin 10 mg or atorvastatin 20 mg daily for 6 weeks . Doses were increased after 6 weeks to rosuvastatin 20 mg or atorvastatin 40 mg and after 12 weeks to rosuvastatin 40 mg or atorvastatin 80 mg daily . Serum PON-1 activity and lipid profile were determined at baseline , 6 and 18 weeks . Results : After 18 weeks , the rosuvastatin arm showed a significant increase of PON-1 activity ( 6.39 U/L , p = 0.02 ) whereas this was not observed in the atorvastatin arm ( 1.84 U/L , p = 0.77 ) . The difference between groups did not reach significance ( p = 0.11 ) . Both rosuvastatin and atorvastatin result ed in significant ( p = 0.0001 ) and similar increases in HDL‑C after 6 weeks [ 0.06 mmol/L ( 2.32 mg/dL ) vs. 0.05 mmol/L ( 1.93 mg/dL ) ] and after 18 weeks [ 0.10 mmol/L ( 3.87 mg/dL ) vs. 0.10 mmol/L ( 3.87 mg/dL ) ] . Conclusions : Rosuvastatin treatment result ed in a significant increment of serum PON-1 activity with increasing dose while this was not observed with atorvastatin Objective High-density lipoprotein (HDL)-associated antioxidant paraoxonase ( PON ) may reduce low-density lipoprotein ( LDL ) oxidation and prevent atherosclerosis . The aim of this present study was to investigate the effect of the 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor atorvastatin on hydrogen-peroxide-induced DNA damage by comet assay and the correlation between oxidative DNA damage and antioxidant PON activity . Methods Thirteen type-II/a hyperlipidemic patients were enrolled in the study . We examined the effect of 10 mg/day atorvastatin treatment on lipid levels and the degree of DNA damage in lymphocytes separated from hyperlipidemic patients , nitric oxide ( NO ) , thiobarbituric acid-reactive substances ( TBARS ) , PON levels and activity . Results After 6 months , atorvastatin treatment significantly decreased serum cholesterol and LDL-cholesterol levels . The triglyceride level did not change , and there was no significant change in the HDL cholesterol level . The visual score characteristic to the degree of DNA damage in comet assay was significantly decreased , as well as the TBARS level , while the level of NO was non-significantly increased . PON activity and the PON/HDL ratio were significantly increased after atorvastatin treatment . There was a negative correlation between DNA damage and PON activity , as well as between DNA damage and the PON/HDL ratio before and after atorvastatin treatment . Conclusion 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 Objective : Mixed dyslipidemia , oxidative stress and inflammation are related to a high risk for cardiovascular events . The aim of this open-label r and omized study was to compare the effects of high-dose rosuvastatin , low-dose rosuvastatin plus fenofibrate and low-dose rosuvastatin plus omega 3 fatty acids on inflammation and oxidative stress indices in patients with mixed dyslipidemia . Methods : Ninety patients with mixed dyslipidemia participated in the study . Patients were r and omly allocated to receive rosuvastatin 40 mg ( n = 30 , group R ) , rosuvastatin 10 mg plus fenofibrate 200 mg ( n = 30 , group RF ) or rosuvastatin 10 mg plus omega 3 fatty acids 2 g daily ( n = 30 , group RΩ ) . Plasma and high-density lipoprotein (HDL)-associated lipoprotein-associated phospholipase A2 ( LpPLA2 ) activities , high-sensitivity C reactive protein ( hsCRP ) , plasma isoprostane and paraoxonase ( PON1 ) activities were measured at baseline and after 3 months of treatment . Results : Serum concentrations of non-HDL cholesterol and low-density lipoprotein cholesterol ( LDL-C ) were significantly reduced in all study groups . However , these changes were more pronounced in the rosuvastatin monotherapy group . In all treatment groups a significant reduction in total plasma LpPLA2 activity was observed ( by 41 , 38 and 30 % for groups R , RF and RΩ , respectively ) . This decrease was greater in the R and RF groups compared with the RΩ combination ( p < 0.05 ) . HDL-LpPLA2 activity was increased more in the RF group ( + 43 % ) compared with the R and RΩ groups ( + 18 % and + 35 % , respectively ; p < 0.05 for both comparisons ) . In all treatment groups there was a nonsignificant reduction in plasma 8-iso-PGF2α levels . A 53 % reduction of hsCRP levels was observed in the R group , while in the RF and RΩ groups the reduction was 28 and 23 % , respectively ( p < 0.05 and p < 0.01 for the comparisons of group R with groups RF and RΩ , respectively ) . No significant changes were observed in PON activities in all treatment groups . Conclusion : The greater non-HDL-C- and LDL-C-lowering  efficiency of rosuvastatin monotherapy along with its more potent effect on LpPLA2 activity and hsCRP levels indicate that this regimen is a better treatment option for patients with mixed dyslipidemia ABSTRACT Background : Serum paraoxonase ( PON1 ) , a high density lipoprotein (HDL)-bound antioxidant enzyme , plays a role in atherosclerosis . An increase in PON1 activity has been reported following statin treatment . Objective : In the present study the following factors were evaluated : the influence of PON1 gene Q192R , L55 M and T(–107)C polymorphisms on the response of LDL oxidisability and PON1 activity to atorvastatin treatment . Research design and methods : 205 Sicilian subjects with primary hypercholesterolaemia ( HCh ) and 69 healthy subjects as controls were concurrently enrolled . Hypercholesterolaemic patients were r and omly divided into two groups : an atorvastatin group ( 10 mg/day atorvastatin ) and a placebo group .  Lipid profile , markers of LDL resistance to in vitro oxidation ( lag-phase , oxidation rate and thiobarbituric acid-reactive substances ) , vitamin E content in LDL , PON1 activity and genotypes in both HCh and control subjects were determined at baseline . The same parameters were measured again after 3 weeks of treatment in both the atorvastatin and placebo groups . Results : HCh subjects showed significantly lower LDL resistance to oxidation , vitamin E content and PON1 activity levels than controls . A strong association was found among PON1 T(–107)C genotypes , LDL susceptibility to oxidation , vitamin E content and PON1 activity . After treatment , the atorvastatin group displayed a significant decrease in total cholesterol , LDL-cholesterol levels , and LDL susceptibility to oxidation , and an increase in vitamin E content and PON1 activity , compared with baseline values . Unlike PON1 activity levels , no difference among PON1 gene polymorphisms and reduction in markers of LDL oxidisability was observed . Conclusions : These results show , for the first time , that atorvastatin is able to improve the resistance to LDL oxidation independently of PON1 gene polymorphism Human serum paraoxonase ( PON1 ) is a high-density lipoprotein (HDL)-associated enzyme that is responsible for the protective effect of HDL against oxidation of low-density lipoprotein ( LDL ) . PON1 has a Glu to Arg polymorphism at codon 192 ( CGA-->CAA ) which is design ated R/Q192 . The R/Q192 polymorphism has been associated with coronary artery disease ( CAD ) in several , but not all , case-control studies . We prospect ively studied the association of the Q/R192 genotypes with the severity , progression and regression of CAD , plasma lipid levels , clinical events and response to treatment with fluvastatin in a well-characterized cohort . Genotypes were determined by polymerase chain reaction ( PCR ) and restriction mapping with AlwI enzyme in 356 subjects in the Lipoprotein and Coronary Atherosclerosis Study ( LCAS ) .  Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following r and omization to fluvastatin or placebo . A total of 177 ( 50 % ) , 142 ( 40 % ) and 37 ( 10 % ) subjects had Q/Q , Q/R and R/R genotypes , respectively . Baseline and final plasma levels of HDL , LDL , triglyceride and other lipoproteins , lesion-specific minimum lumen diameters ( MLD ) , mean MLD , number of coronary lesions and total occlusions at baseline and follow-up and clinical event rates were not significantly different among the genotypes . There was no genotype-treatment interaction with respect to plasma lipid levels and angiographic indices of CAD . The Q/R192 variants of PON1 are not associated with severity , progression or regression of coronary atherosclerosis , plasma lipid levels , clinical events , or response to treatment with fluvastatin .  Thus , the Q/R192 polymorphism is not a major risk factor in susceptibility to CAD in the LCAS population Background —The HDL-associated enzyme paraoxonase protects LDLs from oxidative stress . 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ( statins ) appear to favorably influence the atherosclerotic process by different mechanisms . The present study examined the influence of simvastatin on paraoxonase expression and serum paraoxonase levels . Methods and Results —Simvastatin upregulated in a dose-dependent manner the activity of the promoter of the paraoxonase gene in expression cassettes transfected into HepG2 cells . Upregulation could be blocked by mevalonate and other intermediates of the cholesterol biosynthetic pathway . Simvastatin increased nuclear factors , notably sterol regulatory element – binding protein-2 , capable of binding to the paraoxonase promoter ; this was also blocked by mevalonate . Sterol regulatory element – binding protein-2 upregulated promoter activity in vitro . Patients treated with statin  showed a significant increase in serum concentrations and activities of paraoxonase . Conclusions —The data indicate that simvastatin can modulate expression in vitro of the antioxidant enzyme paraoxonase and is associated with increased serum paraoxonase concentration and activity . It is consistent with effects of simvastatin treatment , which have the potential to influence beneficially antiatherogenic mechanisms at the HDL level . The study provides evidence for 1 molecular mechanism by which paraoxonase gene expression could be regulated OBJECTIVES The aim of our study was to examine the influence of atorvastatin on lipid parameters , particularly on HDL , and on the activity of LCAT and CETP and how they affect the activity of the HDL-associated antioxidant enzyme paraoxonase . DESIGN AND METHODS Thirty-three patients with types II.a and II.b primary hyperlipoproteinemia were enrolled into our study . The patients received atorvastatin , 20 mg daily , for 3 months . We measured the serum paraoxonase activity and concentration , oxidized LDL , LCAT and CETP activities . RESULTS Atorvastatin significantly reduced the levels of cholesterol , triglyceride , LDL-C and apoB , while it did not influence the levels of HDL-C and apo A-I. The increases in serum PON-specific activity , PON/HDL ratio and LCAT activity were significant , while oxLDL and CETP activities were significantly decreased . CONCLUSION Atorvastatin may influence the composition and function of HDL , thereby possibly increasing the activity of paraoxonase and preventing atherosclerosis SUMMARY Objective : High-density lipoprotein (HDL)-associated paraoxonase ( PON ) activity may play an important role in the inhibition of low-density lipoprotein ( LDL ) oxidation . Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease . The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia . Research design and methods : A prospect i ve , non-blinded , single-group , cross-over , comparative trial was performed . Following an 8-week dietary run-in period , 49 patients ( 23 men and 26 women , mean age : 59.8 ± 7.9 years ) with Fredrickson type IIa . and IIb . hyperlipoproteinaemias were r and omized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months . Following an 8-week washout period , patients were crossed-over to receive the other drug for a further 3 months . Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate . Results : Simvastatin treatment significantly reduced serum cholesterol , LDL-cholesterol ( LDL-C ) and apolipoprotein ( apo ) B levels ( p < 0.001 ) . Atorvastatin had a more pronounced cholesterol , LDL-C- and apo B-lowering effect ( p < 0.001 ) compared with simvastatin . Both statins also significantly reduced serum triglyceride levels  ( p < 0.01 ) . Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol ( HDL-C ) and apo A1 . HDL-associated PON activity did not change significantly after simvastatin therapy , but significantly increased after atorvastatin treatment ( p < 0.05 ) . Conclusions : Short-term administration of simvastatin did not increase PON activity  . Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON Although the raising effect of rosuvastatin on high-density lipoprotein cholesterol is well-established , there is a paucity of data regarding the effect of this statin on the high-density lipoprotein subfraction phenotype . A total of 150 participants without evidence of cardiovascular disease were r and omized to therapeutic lifestyle modification ( nonstatin-treated group ) or to therapeutic lifestyle modification plus rosuvastatin at 10 mg/d ( RSV10 group ) or 20 mg/d ( RSV20 group ) . We assessed the effect of rosuvastatin on the cholesterol mass of high-density lipoprotein subfractions at baseline as well as after 12 weeks post-treatment . Rosuvastatin treatment dose-dependently increased the high-density lipoprotein cholesterol ( 3.4 % vs 5.3 % in the RSV10 and RSV20 groups , respectively , P = .02 ) . A dose-related rosuvastatin-induced increase in the cholesterol concentration of large high-density lipoprotein particles was also noted ( by 11.4 % in RSV10 group vs 22.0 % in the RSV20 group , P = .01 ) . Rosuvastatin treatment increases the high-density lipoprotein cholesterol by increasing the cholesterol mass only of the larger high-density lipoprotein particles in a dose-dependent manner
target: RESULTS Meta- analysis suggested that statin therapy is associated with a significant elevation of PON1 paraoxonase and arylesterase activities , but not PON1 protein concentration .
  The PON1-enhancing effects of statins were robust in the sensitivity analyses and were independent of statin dose , treatment duration and changes in plasma low-density lipoprotein cholesterol concentration .
  CONCLUSION The increase of paraoxonase and arylesterase activities with statins is a pleiotropic lipid-independent clinical benefit that may partly explain the putative effects of statins in preventing cardiovascular outcomes
background: BACKGROUND Decreased activity of the enzyme paraoxonase-1 ( PON1 ) has been demonstrated in cardiovascular diseases .
  Statins , the forefront of pharmacotherapy for dyslipidemia , have been shown to enhance PON1 activity but clinical findings have not been conclusive .
  OBJECTIVE To systematic ally review the clinical findings on the impact of statin therapy on PON1 status ( protein concentrations and activities of paraoxonase and arylesterase ) and calculate an effect size for the mentioned effects through meta- analysis of available data .