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(Circulation. 2000;101:2252.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Smoking Is Associated With Reduced Serum Paraoxonase Activity and Concentration in Patients With Coronary Artery Disease
From the Lipid Laboratory (R.W.J., I.L.), Division of Endocrinology and Diabetology (A.R.), Cardiology Division, Faculty of Medicine, University Hospital, Geneva, Switzerland.
Correspondence to Dr Richard W. James, Lipid Laboratory, Division of Endocrinology and Diabetology, University Hospital, 1211 Geneva 14, Switzerland. E-mail Richard.James{at}hcuge.ch
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Abstract |
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Background—Paraoxonase is an HDL-associated enzyme that protects lipoproteins from oxidative modifications. Smoking is a major cardiovascular risk factor that promotes lipid peroxidation. Cigarette smoke has been shown in vitro to inhibit paraoxonase. The present study examined the hypothesis that smoking is associated with modulated serum activities and concentrations of paraoxonase.
Methods and Results—Coronary artery disease was assessed with the use of coronary arteriography in participants recruited from a hospital cardiology division. Medical and lifestyle data were obtained, and a fasting blood sample was provided. Three smoking categories were established (never, ex-smokers, and current smokers), and serum paraoxonase variables were compared among them. The activities and concentrations of paraoxonase were significantly lower in current than in never smokers. Ex-smokers had values comparable to those of never smokers. Ex-smokers who had recently stopped (<3 months) had activities and concentrations comparable to those of current smokers; values returned to the levels of never smokers within 2 years of cessation of smoking. Smoking status was an independent determinant of paraoxonase activity and concentration in multivariate analysis. Finally, lower paraoxonase was associated with more severe coronary disease and a reduced capacity to protect LDL from oxidation.
Conclusions—Smoking is independently associated with significant decreases in serum paraoxonase activities and concentrations, which normalize within a relatively short time of cessation. Lower serum paraoxonase is linked to more severe coronary artery disease and a lower antioxidant capacity. The data are consistent with the hypothesis that smoking modifies serum paraoxonase such that there is an increased risk of coronary artery disease due to a diminished capacity to protect lipoproteins from oxidative stress.
Key Words: lipoproteins • smoking • coronary disease • antioxidants • risk factors
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Introduction |
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Paraoxonase (PON) is a serum enzyme that is entirely complexed to HDL.1 A recent hypothesis suggests an antioxidant role for PON in the protection of LDL from oxidative modifications.2 Substantial in vitro evidence supports such a function.2 3 4 This is complemented by studies of a recently developed PON knockout mouse model that demonstrated greater susceptibility of the lipoproteins to oxidation.5 The mice also developed more extensive atherosclerotic plaques, which is consistent with the hypothesis that oxidized lipoproteins play a major role in atherosclerosis.6 In humans, we identified PON as an independent, genetic risk factor for coronary artery disease (CAD).7 8 The observation has been confirmed in independent studies9 10 11 12 13 although not uniformly.14 15
Smoking is firmly established as 1 of the principal cardiovascular risk factors. Oxidative stress is considered to be the major, pathological mechanism associated with smoking, leading notably to lipid peroxidation.16 17 18 Several studies have demonstrated increased susceptibility of LDL to oxidation and higher levels of oxidized LDL in smokers.18 19 20 21 This would provide an important causal mechanism that links smoking with vascular disease given the numerous pathological effects of oxidized LDL.22 23
Smoking may enhance oxidative stress not only through the production of reactive oxygen radicals in smoke but also through weakening of the antioxidant defense mechanisms. In this context, a recent in vitro study showed that extracts of cigarette smoke inhibited the enzymatic activity of PON.24 Given its hypothesized, antioxidant role, this could also contribute to the increased oxidation of LDL in smokers. The present study examined the hypothesis that smoking is associated with lower serum PON activity and examined the possible consequences of lower PON levels with respect to the protection of LDL from oxidation and the severity of vascular disease.
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Methods |
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Study Population
The present study was undertaken in cardiovascular patients and control subjects recruited from patients attending the Cardiology Division of the University Hospital, Geneva. They gave written, informed consent to participate, and the study was performed according to the requirements of the ethical committee of the medical faculty. All participants underwent a biplane coronary arteriographic examination (standard Judkins technique), and the degree of stenosis was visually interpreted by a panel of experienced senior cardiologists. No other attempt was made to quantify the extent of the lesions. Arteriograms were considered positive for CAD (CAD+) if a stenosis estimated as >20% was detected in 1 major epicardial vessels. Patients were further classified as having 1-, 2-, or 3-vessel disease according to the presence of a stenosis of >70% in 1, 2, or 3 of the major epicardial vessels. Subjects with no detectable stenosis in any artery were considered free of disease (CAD-); patients with myocardial infarction were also excluded from the latter group. An analysis of the relationship of serum PON to disease severity was limited to control subjects with no detectable stenosis and patients with
1 lesion of >70%. The assessment
of lesion severity and quantification of serum PON were completely
independent; cardiologists were not aware of clinical data with respect
to PON, whereas personnel who performed clinical analyses or
interviewed patients were unaware of the arteriographic assessment. Each participant completed questionnaires on lifestyle and personal and family medical history with a qualified interviewer. Patients were asked if they were current smokers or nonsmokers. Nonsmokers were classified as either never smokers or ex-smokers.
Lipoproteins and Oxidation
For studies of lipoprotein oxidation, LDL (
1.019 to 1.063)
and HDL ( 1.063 to 1.21) were isolated with
ultracentrifugation25 26 from fasting
plasma and serum samples provided from a donor pool.
Oxidation of LDL was performed as described previously27 with Cu2+ (5 µmol/L) as the oxidizing agent. Lipid hydroperoxides were quantified28 with the use of hydrogen peroxide to develop the calibration curve (intra-assay and interassay coefficients of variation were 1.0 and 2.2, respectively).
Protection assays were performed as described29 30 31 with the use of HDL that contained PON isolated by ultracentrifugation. Protection was determined in a comparison of lipid hydroperoxides formed in LDL+HDL coincubates (LDL and HDL mixed in a 1:2 protein ratio) with lipid peroxides formed in LDL and HDL incubated individually. PON-free HDL was prepared with the passage of HDL through an affinity column that contained anti-PON antibodies.1 The nonbound fraction was collected and concentrated. It contained >95% of HDL protein and lipids; no PON enzyme activity could be detected in the fraction, and PON protein was absent on Western blotting.1 PON-free HDL was used to dilute PON-enriched HDL to lower the PON activity levels while maintaining lipid and total protein concentrations of HDL.
Analyses
Fasting serum and plasma samples were obtained. Plasma was used
to measure lipid, lipoprotein, and apolipoprotein levels as described
previously.25 26 LDL cholesterol was
calculated with the Friedewald formula.32 Serum samples
were used to quantify PON enzyme activities and mass concentrations, as
described previously.8 33 DNA was extracted from blood
cells and genotyped for polymorphisms 191 and 54 of the
PON1 gene.8
Statistical Analyses
Patients were categorized as never smokers, ex-smokers (stopped
1 week before recruitment), or current smokers. Comparisons between
categories were performed with ANOVA. Variables that influence
serum PON activities and concentrations were analyzed with
forward stepwise regression analysis. Analyses were
performed with the JMP statistical package (SAS Institute).
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Results |
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A total of 596 subjects were included in the study (Table 1
). Mean lipid levels differed
significantly among the 3 defined smoking categories with respect to
HDL cholesterol, apoA-I, and triglyceride
levels. It should be noted that the percentage of women was
significantly higher in the never smoked category, but when men alone
were analyzed, similar results were obtained (results not
shown). The frequency of CAD was significantly lower in the never
smoked group but did not differ between ex-smoker and current smoker
groups (Table 1). Regarding medication, 58% of the population
took aspirin on a regular basis (a similar percentage of never smokers
[49.6%] and current smokers [51.4%] but a higher percentage of
ex-smokers [64.8%]; P<0.02). Lipid-lowering drugs were
used by 33.7% of the population, with similar percentages in the 3
subgroups (never, ex, and current 30.1%, 37.4%, and 29.1%). HMG-CoA
reductase inhibitors were predominantly used (81.3%), with
a similar percentage of users in the 3 groups. Vitamin supplementation
was infrequent (11.7%) and did not differ significantly among smoking
categories (never, ex, and current 14.4%, 10.5%, and 12.0%).
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Table 2 shows the serum activities and
concentrations of PON as a function of smoking category. With both
substrates, enzyme activities were lowest in the current smoker group.
This was paralleled by significantly lower mass concentrations of
PON in the smoker group (Table 2). Ex-smokers had values
intermediate between those of never and current smokers. In a
complementary evaluation, activities and concentrations were
analyzed as a function of the time since ex-smokers had stopped
smoking. Ex-smokers (n=75) who had stopped between 0.25 and 24 months
before entry into the study showed a significant, positive, albeit
weak, correlation between duration of nonsmoking and PON activity
(phenylacetate, r=0.25, P=0.032) and
concentration (r=0.25, P=0.033). Mean activities
and concentrations were subsequently compared in ex-smokers who had
stopped between 0.25 and 3 months (n=40, mean 1.4 months) and those who
had stopped between 3 and 24 months (n=35, mean 12.4 months). In a
comparison of current smokers (n=142), ex-smokers (<3 months),
ex-smokers (3 to 24 months), and never smokers (n=139), there were
significant differences in activity with phenylacetate (83.3 [1.7]
versus 81.5 [2.6] versus 91.6 [4.7] versus 92.3 [2.7] U/mL;
P=0.012) and for concentration (97.5 [1.6] versus 98.7
[3.2] versus 104.6 [3.1] versus 104.4 [2.0] µg/mL;
P=0.028). With paraoxon as substrate, the respective mean
values were 248.4 (13.4) versus 314.1 (29.5) versus 352.3 (30.9) versus
291.5 (16.1) U/mL (P=0.009). Those who had stopped smoking
for a longer period again showed higher activities. The higher
activities with paraoxon in the ex-smoker groups compared with the
never smokers reflects the higher percentage of BB homozygotes in the
ex-smokers (15.0% versus 8.6%), with the B isoform showing increased
activity with paraoxon. These results are consistent with
smoking having a short-term rather than a long-term influence on serum
PON.
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Factors independently associated with variations in serum enzyme
activities and concentrations of PON were analyzed with the use
of stepwise regression analysis. These analyses also
took into account polymorphisms 191 and 54 of the human PON gene,
which have strong associations with serum PON activities and
concentrations.8 34 Table 3
shows the best models that emerged from these analyses. Smoking
status was significantly associated with variations in enzyme activity
(phenylacetate) and concentration independent, notably, of sex, age,
cardiovascular status (CAD+ or CAD-), and PON
polymorphisms. Activity with paraoxon was also significantly and
independently associated with smoking status when polymorphism 191
was not included in the model (P=0.01, results not shown)
but was of borderline significance with the 191 polymorphism
included (P=0.06, Table 3).
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To gauge the potential importance of our observations, 2 final
analyses were performed. The first analysis was an
examination of disease severity as a function of PON. This
analysis was limited to the subgroups of ex-smokers and current
smokers (who had a similar prevalence of vascular disease; Table 1
). Patients within these subgroups with normal coronary
arteries or with <70% stenoses were also excluded. Results
are shown in Table 4. Patients with
3-vessel disease had significantly lower serum activities of PON with
both substrates tested and significantly lower serum concentrations of
the enzyme. The second study was an analysis of the
physiological relevance of the reduction in serum
PON with respect to its hypothesized role of protecting LDL from
oxidation. The Figure, A, shows lipid hydroperoxides
generated in LDL incubated with HDL containing increasing
concentrations of PON, up to 20% of its mean normal concentration.
There was a continual decrease in lipid hydroperoxides measured in LDL,
showing that incremental changes in the PON content of HDL, of the
order of differences in serum concentrations between never and current
smokers, influence the ability of HDL to protect LDL from oxidation.
The Figure, B, shows the protective capacity of HDL differing in
PON concentrations by 10%. There were significantly higher levels of
lipid hydroperoxides (P<0.02) in LDL incubated with the HDL
containing lower concentrations of PON. Thus, control HDL (normal PON
concentration) reduced LDL hydroperoxides by 50.0±3.5% after a 3-hour
incubation, whereas HDL with lower PON reduced hydroperoxide levels by
35.6±3.6%. The difference was evident after longer incubation periods
(Figure, B), reflecting previous studies that showed a more
pronounced effect of PON as greater concentrations of lipid
hydroperoxides are generated.30 35
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Discussion |
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Cigarette smoking is firmly established as a primary risk factor for atherosclerotic, cardiovascular disease. Increased oxidative stress is 1 of the principal mechanisms by which it may exert its pathological influence.17 Available data furnish persuasive arguments for an antioxidant function of PON,2 3 4 which would represent an antiatherogenic potential of particular importance. In this context, the results presented here are highly consistent with the hypothesis that modifications of serum PON could be a mechanism by which smoking accelerates the atherogenic process. Serum PON activities assayed with 2 distinct substrates were significantly lower in current smokers compared with those in nonsmokers. Although there is debate concerning the extent to which activities measured with exogenous substrates (particularly paraoxon) reflect the activity of PON toward its physiological substrate,34 35 36 37 our demonstration that there also were significantly lower serum concentrations of PON in current smokers appears to eliminate any doubt arising from the use of possibly inappropriate substrates. Associations do not prove cause and effect, but several observations favor a direct relationship between smoking and serum PON. First, the associations were independent of other factors, notably diabetes, vascular disease, and sex. Diabetes may be associated with a lower activity of serum PON,38 whereas other studies39 40 (albeit not confirmed41 ) suggested a lower activity of serum PON in patients with myocardial infarction. PON is tightly linked to HDL and shows significant correlations with apoA-I concentrations.8 33 Diabetes and myocardial infarction are also associated with lower serum levels of HDL, whereas there is a well-established sex difference in HDL concentrations. Hence, variations in HDL associated with these factors could explain differences in PON activities. This does not appear to be the case, because smoking status was an independent predictor of PON activity variations in the presence of these factors and, more important, when HDL and apoA-I were included in the models. Vitamin supplementation, which could conceivably protect PON through augmentation of the overall antioxidant capacity, was low and similar among the 3 groups and thus would not appear to influence the results. There also was no significant difference between current and never smokers groups with respect to the use of aspirin and lipid-lowering medication. Second, smoking status was associated with PON (arylesterase) activity and concentration independent of genetic polymorphisms 191 and 54. The association was of borderline significance for paraoxon, but the hugely predominant effect of the 191 polymorphism on this activity (76% of the variation) should be underscored. Third, in ex-smokers, activity and concentration values tended to revert to those of never smokers. Reduced activities and concentrations were present in ex-smokers who had recently stopped smoking (<3 months) but were recovered within 2 years. Finally, there is in vitro evidence of a direct inhibitory effect of cigarette smoke on PON enzyme activity,24 which is consistent with our observations.
The results of the present study further suggest that activity differences do not arise from the inhibition of enzyme activity alone. There was a decrease in PON protein; concentrations were significantly different in current smokers compared with never smokers, whereas ex-smokers had intermediate levels. In addition, we observed no significant differences in specific activities (enzyme activities per unit mass PON) among the 3 smoker categories, although values tended to be lower in current smokers (results not shown).
The evident question is whether the observations are of relevance to the occurrence of cardiovascular disease. Smoking has such a powerful impact on the risk of disease that it is difficult to dissociate a risk factor that may interact with it. As 1 approach, we analyzed PON in patients with differing severities of CAD, excluding never smokers. The rationale was that if serum PON were of relevance, lower levels could be observed in more severe cases of disease. The analysis demonstrated that enzyme activities and concentrations were significantly lower in patients with 3-vessel disease. Although this does not provide proof of a causal relationship, it is consistent with the accentuation of the risk of disease by a lower serum PON level. Of interest in this respect is a recent study that suggests that the link we previously demonstrated between the PON B allele and the risk of vascular disease7 may be exacerbated by smoking.13
More important, perhaps, we demonstrate that differences in PON concentrations, on the order of those observed in the present study, can influence the ability of HDL to protect LDL from oxidation. Thus, incremental increases in HDL PON are associated with incremental decreases in the level of LDL hydroperoxides generated under oxidization conditions. To complement this analysis, we also show that lowering the PON content of HDL by 10% was associated with a significantly higher concentration of LDL hydroperoxides. The studies were performed with PON-free HDL, which allowed us to maintain HDL protein and lipid concentrations while varying its PON content. We consider this important because several studies have shown that there are HDL-associated antioxidant activities that are independent of PON.42 43 44 45 The PON-enriched HDL subfraction removed through immunoaffinity chromatography contains only 2 other peptides (apoA-I and clusterin [apoJ],1 of which minor quantities were removed), and neither has been shown to have antioxidant enzymic activity.
In vitro studies are providing a wealth of data on the functions of PON, but observations that concern the clinical consequences of modifications to serum PON are less abundant. A limited number of studies have reported lower PON activities in pathologies associated with a higher risk of vascular disease. PON has also been identified as a genetic risk factor for vascular disease. The present study extends these observations by showing (1) an association between smoking, a prooxidant phenomenon with a demonstrated inhibitory effect on PON, and serum PON activities and concentrations and (2) that recuperation of normal PON activities and concentrations coincides with the cessation of smoking. Our data also indicate that lower serum PON levels are associated with increased severity of CAD and reduced capacity to protect LDL from oxidation. They are consistent with the hypothesis that smoking modifies serum PON such that there is an increased risk of CAD, which may be due to a diminished capacity to protect lipoproteins from oxidative stress.
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Acknowledgments |
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The study was supported by grants from the Swiss National Research Foundation, the Swiss Cardiology Society, the Stanley Thomas Johnson Foundation, and the AR&J Leenaards Foundation. The expert technical assistance of Marie-Claude Meynet Brulhart, Barbara Kalix, Silvana Bioletto, and Katia Galan was greatly appreciated. We particularly thank Prof A. Morabia for continual advice on statistical analyses.
Received August 6, 1999; revision received November 15, 1999; accepted December 10, 1999.
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D. M. Shih, H. R. Kast-Woelbern, J. Wong, Y.-R. Xia, P. A. Edwards, and A. J. Lusis A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids J. Lipid Res., February 1, 2006; 47(2): 384 - 392. [Abstract] [Full Text] [PDF]
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T. M. van Himbergen, M. Roest, J. de Graaf, E. H. J. M. Jansen, H. Hattori, J. J. P. Kastelein, H. A. M. Voorbij, A. F. H. Stalenhoef, and L. J. H. van Tits Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia J. Lipid Res., March 1, 2005; 46(3): 445 - 451. [Abstract] [Full Text] [PDF]
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S. D. Nguyen and D.-E. Sok Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids J. Lipid Res., December 1, 2004; 45(12): 2211 - 2220. [Abstract] [Full Text] [PDF]
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 A. F Hernndez, B. Mackness, L. Rodrigo, O. Lopez, A. Pla, F. Gil, P. N Durrington, G. Pena, T. Parron, J. L Serrano, et al. Paraoxonase activity and genetic polymorphisms in greenhouse workers with long term pesticide exposure Human and Experimental Toxicology, November 1, 2003; 22(11): 565 - 574. [Abstract] [PDF]
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S. Deakin, I. Leviev, S. Guernier, and R. W. James Simvastatin Modulates Expression of the PON1 Gene and Increases Serum Paraoxonase: A Role for Sterol Regulatory Element-Binding Protein-2 Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2083 - 2089. [Abstract] [Full Text] [PDF]
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G. P. Jarvik, T. S. Hatsukami, C. Carlson, R. J. Richter, R. Jampsa, V. H. Brophy, S. Margolin, M. Rieder, D. Nickerson, G. D. Schellenberg, et al. Paraoxonase Activity, But Not Haplotype Utilizing the Linkage Disequilibrium Structure, Predicts Vascular Disease Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1465 - 1471. [Abstract] [Full Text] [PDF]
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P.N. Durrington, B. Mackness, and M.I. Mackness The Hunt for Nutritional and Pharmacological Modulators of Paraoxonase Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1248 - 1250. [Full Text] [PDF]
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G. P. Jarvik, N. T. Tsai, L. A. McKinstry, R. Wani, V. H. Brophy, R. J. Richter, G. D. Schellenberg, P. J. Heagerty, T. S. Hatsukami, and C. E. Furlong Vitamin C and E Intake Is Associated With Increased Paraoxonase Activity Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1329 - 1333. [Abstract] [Full Text] [PDF]
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 A. Tward, Y.-R. Xia, X.-P. Wang, Y.-S. Shi, C. Park, L. W. Castellani, A. J. Lusis, and D. M. Shih Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice Circulation, July 23, 2002; 106(4): 484 - 490. [Abstract] [Full Text] [PDF]
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M. Tomas, R. Elosua, M. Senti, L. Molina, J. Vila, R. Anglada, M. Fito, M. I. Covas, and J. Marrugat Paraoxonase1-192 polymorphism modulates the effects of regular and acute exercise on paraoxonase1 activity J. Lipid Res., May 1, 2002; 43(5): 713 - 720. [Abstract] [Full Text] [PDF]
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J. E. Hokanson Gene-Environment Interaction in the Expression of Antioxidant Status : A Role for Genes in the Relationship Between Smoking and Coronary Disease Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1102 - 1103. [Full Text] [PDF]
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I. Leviev, S. Deakin, and R. W. James Decreased stability of the M54 isoform of paraoxonase as a contributory factor to variations in human serum paraoxonase concentrations J. Lipid Res., April 1, 2001; 42(4): 528 - 535. [Abstract] [Full Text]
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M. Navab, J. A. Berliner, G. Subbanagounder, S. Hama, A. J. Lusis, L. W. Castellani, S. Reddy, D. Shih, W. Shi, A. D. Watson, et al. HDL and the Inflammatory Response Induced by LDL-Derived Oxidized Phospholipids Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 481 - 488. [Abstract] [Full Text] [PDF]
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A. S. Whitehead and G. A. FitzGerald Twenty-First Century Phox: Not Yet Ready for Widespread Screening Circulation, January 2, 2001; 103(1): 7 - 9. [Full Text] [PDF]
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