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Vol. 59. Issue 2.
Pages 154-164 (February 2006)
DOI: 10.1016/S1885-5857(06)60124-2
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Concerning the Significance of Paraoxonase-1 and SR-B1 Genes in Atherosclerosis
Sobre los genes paraoxonasa-1 y SR-B1, y su importancia en la aterosclerosis
Francisco Rodríguez Esparragóna, Yaridé Hernández Trujilloa, Antonio Macías Reyesa, Enrique Hernández Ortegab, Alfonso Medinab, José C Rodríguez Pérezc
a Unidad de Investigación, Hospital Universitario de Gran Canaria Doctor Negrín, Universidad de Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, España,
b Servicios de Cardiología, Hospital Universitario de Gran Canaria Doctor Negrín, Universidad de Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, España,
c Unidad de Investigación, Hospital Universitario de Gran Canaria Doctor Negrín, Universidad de Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, España, Nefrología, Hospital Universitario de Gran Canaria Doctor Negrín, Universidad de Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gra
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Tables (3)
Figure 2. A. Significant reduction in paraoxonase activity in 68 diabetic men versus 93 nondiabetic men adjusted for age. B. Significant reduction in paraoxonase activity in 161 men after an acute coronary event and versus 184 age-adjusted controls.123 The bars represent mean and standard deviation. The comparison was made with the Student t test.
Figure 3. A. Differing protection against oxidation of L-1-palmitoyl-2-arachidonyl- sn-glycero-3-phosphorylcholine and hydroperoxyoctadecadienoic acid afforded by high-density lipoproteins (HDL) according to different isoforms of paraoxonase. The HDL samples were isolated by precipitation and adjusted with saline buffer to 20 units of arylesterase.107,108 The experiments were done by free cell assay (J Lipid Res. 2001;42:1308-17). B. Differing behavior of HDL with respect to preventing their own oxidation according to different paraoxonase isoforms. Determination of lipid peroxidation was done by the Xylenol Orange method (FOX) (Biochem J. 1996;313:781-6). All experiments were done in the presence of phenylmethylsulfonyl fluoride (PMSF).107,108
Figure 4. A: Mean concentration of total plasma homocysteine (tHcy) according to the PON1 genotypes Gln192 Arg RR (Arg/Arg); QR (Gln/Arg); QQ (Gln/Gln) in a control group of 243 healthy men not receiving pharmacological treatment.107 ,108 B: Mean concentration of total plasma homocysteine according to the PON1 genotype Gln192 Arg in a group of 20 patients treated with statins.107,108
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La lipoproteína de alta densidad (HDL) constituye un factor de protección independiente de enfermedad cardiovascular. La enzima paraoxonasa-1 (PON-1) contribuye a las propiedades antiaterogénicas asociadas al HDL. Estudios in vitro muestran que posee una gran heterogeneidad de sustratos, algunos de los cuales participan en la progresión de las lesiones ateroscleróticas. Se han desarrollado modelos animales que muestran su papel ateroprotector. En humanos, las variantes PON-1 Gln192Arg y Met55Leu parecen asociarse con una mayor susceptibilidad cardiovascular, con diferentes actividades y concentración de la proteína PON-1. El gen CLA-1 (CD36 and Lysosomal integral membrana protein-II Analogous-1) es el homólogo humano del gen SR-B1 (Scavenger Receptor class B type 1) y constituye el primer receptor de alta afinidad de HDL bien caracterizado. El receptor CLA-1 participa en el transporte reverso de colesterol a través de la entrada selectiva de ésteres de colesterol nativos y oxidados, y su papel ateroprotector se ha deducido de los estudios en animales genéticamente manipulados. En humanos, el gen CLA-1 es polimórfico y algunas de sus variantes han sido previamente asociadas con cambios fenotípicos en lipoproteínas plasmáticas. Ambos genes participan en el complejo metabolismo del HDL y, presumiblemente, en los mecanismos de defensa frente a estrés oxidativo.
Palabras clave:
Ésteres de colesterol
Estrés oxidativo
High-density lipoprotein (HDL) is an independent protective factor against cardiovascular disease. The enzyme paraoxonase-1 (PON-1) contributes to the anti-atherogenic effects of HDL. In vitro studies have demonstrated that paraoxonase's substrates are highly heterogeneous and that some contribute to the development of atherosclerotic lesions. The atheroprotective role of PON-1 was established in genetically engineered animal models. In humans, the PON-1 Gln192Arg and Met55Leu polymorphisms appear to be associated with increased susceptibility to cardiovascular disease and with different PON-1 activity levels and concentrations. The CLA-1 (CD36 and Lysosomal integral membrane protein-II Analogous-1) gene is the human homologue of the murine SR-B1 (Scavenger Receptor class B type 1) gene. SR-B1 was the first high-affinity HDL receptor to be identified at the molecular level. The CLA-1 receptor plays a pivotal role in HDL-mediated reverse cholesterol transport by mediating the selective uptake of free cholesterol as well as of native and oxidized cholesteryl esters. Its atheroprotective role has also been established in transgenic mice studies. Several polymorphic variants of the CLA-1 gene have been described, some of which are associated with phenotypic changes in plasma lipoproteins. Both genes participate in the complex HDL metabolic pathway and, presumably, also in defense mechanisms against oxidative stress.
Cholesteryl esters
Oxidative stress
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According to the oxidation hypothesis of atherogenesis, increased generation of free radicals and reactive oxygen species, possibly associated with weakened antioxidant defense mechanisms, is responsible for atherosclerosis.1 Oxidized low-density lipoproteins (LDL) and derivative products generated in association with these oxidative processes can accumulate in the arterial wall and accelerate the atherosclerotic process.1,2 In principle, any enzymatic system that generates free radicals could be implicated in the oxidation of LDL particles, for example, the NADPH oxidase system, the myeloperoxidase system, the P450 system, the mitochondrial electron transport chain, the xanthine oxidase system, and the lipoxygenase system. The importance of lipoxygenase was first investigated in studies carried out in vitro,3-5 although several in vivo studies have since corroborated the in vitro findings.6-10 The role of lipoxygenase has been further confirmed by experiments with apolipoprotein E and 12/15-lipooxygenase double knockout (apoE-­-/­/L-12LO-­/-­) mice, in which atherosclerotic lesions decreased substantially,11,12 although contradictory findings have been reported.13

Seeding Mechanism

The action of 15- and 12-lipoxygenases on arachidonic and linoleic acid generates mainly hydroperoxyoctadecadienoic acid (HPODE) and hydroperoxyeicosatetraenoic acid (HPETE). Several experimental findings support, at least partially, a mechanism of formation of mildly oxidized LDL whereby phospholipids derived from arachidonic acid are oxidized and these metabolic products of lipoxygenases, particularly HPODE and HPETE, are taken up by different LDL lipids.14 However, LDL particles also need to be seeded with reactive oxygen species for extensive oxidation to occur.14,15 High-density lipoproteins (HDL) and their main structural component, apolipoprotein A1, can prevent oxidation of LDL.1 A number of molecular mechanisms may arise after transfer of cholesterol ester hydroperoxides (CEOOH) from LDL to HDL, in a process partially determined by the enzymatic activity of the cholesterol ester transfer protein (CETP).16 Nevertheless, the role of CETP is potentially atherogenic and CETP inhibitors (JTT-705 and torcetrapib) have been shown to afford protection in several clinical trials.17,18 It should, however, be remembered that the mechanism of cholesterol ester transfer from HDL to apolipoprotein B lipoproteins (in a process that leads to the exchange of triglycerides), operates both ways and depends on the concentration of triglyceride-rich lipoproteins.16,19 The renovation of HDL rather than a high concentration of HDL is thought to be most relevant to vascular protection. In particular, the action of CETP in HDL facilitates esterification by lecithin-cholesterol acyltransferase (LCAT) and therefore, the efflux of cholesterol. In turn, the combined action of CETP and hepatic lipase on mature HDL (HDL2) generates HDL fractions that contain lower concentrations of lipids and that are better cholesterol acceptors.17,20

The mechanism of formation of mildly oxidized LDL comprises at least 3 steps.14,15 The first consists of the aforementioned seeding of LDL particles with the metabolic products of arachidonic acid and with CEOOH.14 In the second step, LDL crosses the subendothelial space, where there is an additional accumulation of reactive oxygen species. The third step involves oxidation of LDL phospholipids on reaching a threshold concentration of reactive oxygen species.15 The enzymatic activity of paraoxonase presumably intervenes in the first of these steps. The mechanisms covered by this review are represented schematically in Figure 1.

Figure 1. Schematic representation of high-density lipoprotein (HDL) metabolism and its protective role against oxidation of low-density lipoproteins (LDL).

Measuring Oxidized Phospholipids and Hydroperoxides in Plasma

The method used for measuring lipid hydroperoxides in plasma depends on whether total concentrations or concentrations in subfractions are determined. The wide variety of techniques used has led to discrepancies in the measurement of the normal content of peroxides in healthy subjects. Bowry et al,21 using high performance liquid chromatography with chemoluminescence detection, found that HDL in both plasma and isolated lipoproteins (HDL and LDL) carried 85% of the total content of CEOOH and phospholipid hydroperoxides, detected as hydroperoxides of phosphatidylcholine. In contrast, Nourooz-Zadeh et al22 analyzed the total content of lipid hydroperoxides and found that they resided mainly in LDL particles and not in HDL ones.

Paraoxonases 1, 2, and 3 (PON-1, PON-2, and PON-3)

Human paraoxonase/arylesterase (PON-1) (EC is a calcium-dependent glycoprotein that is present bound to HDL particles. Investigators have attempted to demonstrate that serum paraoxonase decreases the risk of coronary artery disease by destroying proinflammatory molecules involved in the initiation and progression of atherosclerotic lesions.23 The antiatherogenic potential of paraoxonase is derived from its capacity to hydrolyze oxidized lipids, phospholipids, and CEOOH, thus preventing them from accumulating in LDL particles. In vitro studies have shown that paraoxonase activity prevents oxidation of LDL particles24 and even oxidation of the HDL particles themselves.25 PON-1 can act in a similar fashion in vivo.26-28 PON-1 is also characterized by hydrolyzing different carboxylic acid esters and some organophosphates. Although the actual physiological substrate of the PON-1 enzyme is not well known, it has been possible to determine its serum activity using paraoxon as a substrate. Determination of this activity has shown that serum levels of paraoxonase vary from individual to individual but remain relatively constant in a given individual.23 A range of physiopathological situations linked to increased oxidative stress and environmental factors can lower serum paraoxonase activity.29-34 Moreover, increased oxidative stress has been reported in PON1 knockout mice and in apo E/PON1 double-knockout mice--models in which a different response to macrophage expression of PON2 and PON3 was reported.35,36

Binding between paraoxonase and HDL particles may explain the inverse relationship between HDL levels and coronary artery disease reported in a number of population studies.23 The antioxidant activity could be responsible for the protective role of paraoxonase. Such activity would be conserved even in the process of reverse cholesterol transport. Thus, esterification of excess cholesterol occurs on the surface of the HDL particles and is mediated by LACT activity, which is particularly sensitive to lipid hydroperoxides.37,38 It is important to remember that the enzymatic activity of paraoxonase is limited to certain subfractions of HLD39 and that apolipoprotein A1 is required to stabilize the enzyme.40

The human gene PON1 maps to the long arm of chromosome 7 (7q21-q22)41 and exhibits interesting polymorphims.42 The Gln192 Arg (Q/R) polymorphism is responsible for the PON1 A (Q) and PON1 B (R) alleles, which are associated with different levels of enzymatic activity according to the substrate. The Met55 Leu polymorphism is responsible for the appearance of the L (55 leucine) and M (55 methionine) alleles. The Met55 Leu variant is the one that modifies serum concentrations, but not the enzymatic activity of paraoxonase.43

The Gln192 Arg polymorphism of the PON1 gene has been associated with vascular disease in diabetic subjects44-47 and nondiabetic subjects.46 However, not all groups have found such an association.48-50 Some meta-analyses have been published that show a weak association between this variant and cardiovascular disease.34,51,52 Although other nongenetic determinants are partly responsible for interindividual variability of PON-1 activity, some authors think it appropriate to consider genotypes and PON-1 activity together in studies of association.34,53 Moreover, the fact that the association does not appear in all populations studied suggests that the variant does not correspond to a functional mutation but is rather a marker of another mutation in the PON1 gene itself or another nearby gene.54 There may also be interactions between the genotype and environment that have yet to be well characterized or that have a low prevalence in certain populations but that would be important for these studies.55,56

The possibility that the Met55 Leu polymorphism is a genetic risk factor for cardiovascular disease was assessed by Garin et al,43 who found that Leu55 homozygosis was an independent risk factor for cardiovascular disease in subjects with diabetes.

The mechanism by which PON1 polymorphisms increase susceptibility to cardiovascular disease is not known. The presence of the R192 and L55 alleles suggests greater paraoxonase activity towards paraoxon, although these alleles are variants associated with risk in certain populations. This posed an important dilemma for sometime because hydrolysis activity against paraoxon was linked to activity against the real enzyme substrate. Certain theories were put forward to explain this paradox. Reduced paraoxonase enzymatic activity after myocardial infarction,29 in familial hypercholesterolemia,30 in diabetes,31 and in association with renal failure32,33 suggested a direct influence of oxidative stress on the modulation of activity and enzyme concentration (Figure 2). On the other hand, greater hydrolytic activity against paraoxon or other exogenous substrates would not necessarily imply, as had been suggested, a greater antioxidative capacity. This latter insight contributed to the corresponding experimental confirmation in humans. Mackness et al57 found that the capacity of HDL particles to protect against LDL oxidation was greater for the QQ/MM homozygotes than for the RR/LL homozygotes (Figure 3). Cao et al58 observed that the differences in paraoxon hydrolysis resulting from the Gln192 Arg variant did not affect the capacity of the PON-1 protein to protect against oxidation of LDL particles. Aviram et al25 observed that deactivating the (calcium-dependent) PON-1 arylesterase activity did not suppress the capacity of the enzyme to inhibit LDL oxidation. In contrast, inhibitory activity could be suppressed by heating. These authors suggested that different active sites of PON-1, one corresponding to calcium-dependent paraoxonase activity, the other to calcium-independent activity, were responsible for protection against LDL oxidation.58

Figure 2. A. Significant reduction in paraoxonase activity in 68 diabetic men versus 93 nondiabetic men adjusted for age. B. Significant reduction in paraoxonase activity in 161 men after an acute coronary event and versus 184 age-adjusted controls.123 The bars represent mean and standard deviation. The comparison was made with the Student t test.

Figure 3. A. Differing protection against oxidation of L-1-palmitoyl-2-arachidonyl- sn-glycero-3-phosphorylcholine and hydroperoxyoctadecadienoic acid afforded by high-density lipoproteins (HDL) according to different isoforms of paraoxonase. The HDL samples were isolated by precipitation and adjusted with saline buffer to 20 units of arylesterase.107,108 The experiments were done by free cell assay (J Lipid Res. 2001;42:1308-17). B. Differing behavior of HDL with respect to preventing their own oxidation according to different paraoxonase isoforms. Determination of lipid peroxidation was done by the Xylenol Orange method (FOX) (Biochem J. 1996;313:781-6). All experiments were done in the presence of phenylmethylsulfonyl fluoride (PMSF).107,108

After the initial characterization of the PON1 gene, new PON-like genes, PON2 and PON3, were identified, also mapping to 7q21.3.59,60 Unlike PON1, which is mainly expressed in the liver, PON2 is expressed in a variety of tissues.

Mochizuki et al59 identified several forms of mRNA from the PON2 gene produced by alternative splicing or by use of a second transcription start site. Likewise, these authors characterized 2 polymorphisms in the gene coding sequence: Arg148 Gly and Cys311 Ser.

Sanghera et al61 observed that PON1 (Gln192 Arg) and PON2 (Cys311 Ser) polymorphisms both contributed synergistically to cardiovascular risk in Asian Indians.

As discussed earlier, the paraoxonase gene family comprises 3 members: PON1, PON2, and PON3. The physiological role of the corresponding gene products is of increasing interest. So far, the serum paraoxonase/arylesterase PON-1 and the paraoxonase PON-3 from rabbit serum have been characterized.62 Unlike PON-1, PON-3 presents only limited arylesterase activity and complete lack of paraoxonase activity; however, it rapidly hydrolyzes lactones and its protective activity against Cu2+--induced oxidation of LDL particles is greater than that reported for the PON-1 protein.

Which Enzyme Is Mostly Responsible for the Antioxidant Activity of HDL Particles?

The paraoxonase enzyme is not the only one that affords HDL particles protection against oxidation; other enzymes are implicated. The most important of these is platelet-activating factor acetylhydrolase (PAF-AH). Plasma PAF-AH enzymatic activity is responsible for deactivation of platelet-activating factor (PAF), thereby regulating its function and pathophysiological effects.63 Approximately 70% of the plasma activity of PAF-AH is associated with LDL particles and the rests with HDL particles, suggesting an active exchange between the 2 fractions.64 Lipid peroxidases are hydrolyzed by PAF-AH, which acts like phospholipase A2 but not like phospholipase C or D, and its antiatherogenic role is strongly debated.65-68 Marathe et al69 published an excellent study that suggested that PAF-AH and not the enzymatic activity of paraoxonase is responsible for all hydrolase activity of oxidized phospholipids. As discussed earlier, PON-1 is a calcium-dependent enzyme, whereas PAF-AH is not calcium dependent. PAF-AH is a phospholipase A2 that belongs to the serine-esterase family and, as such, its activity can be inhibited by specific inhibitors that block PAF-AH activity but not PON activity. In fact, paraoxonase lacks serine residues at its active site. With this strategy, it has been shown that PAF-AH is the only HDL phospholipase A2 and that PON-1 lacks phospholipase activity against PAF or oxidized phospholipids. Nevertheless, direct evidence suggests that PON-1 should at least be present for antioxidant and antiatherogenic effects to occur.27,70 Some authors have confirmed the PAF hydrolytic activity of serum PON-1 by using specific inhibitors of PAF-AH activity.71 In addition, in the knockout mouse model for the PON1 gene, PAF-AH activity is similar to that of the wild type.27,72 The HDL lipoprotein isolated from PON1 knockout mice is proinflammatory, that is, in absence of PON-1, PAF-AH activity is unable to maintain the antioxidant properties of the HDL particles.27,72 In transgenic animals that express human PON1, a certain degree of protection has been found against the development of atherosclerosis.27,70 Such protection has also been found in murine models that overexpress PAF-AH.67,73,74 Alternatively, coordinated action of both enzymes has been suggested in vivo, as their affinity for oxidized phospholipids varies according to the length of the esterified fatty acid chain at the sn-2 position.25,64,71,75,76 These excellent studies complete those done by Aviram et al77,78 and Rozenberg et al,36,79 who observed differential hydrolysis of oxidized lipids both in vitro and in atherosclerotic lesions using Q and R recombinant isoforms. Thus, the Q isoform lowered Cu2+--induced oxidation of the LDL particles by 33% compared to 20% for the R isoform. These latter studies focussed on developing methods to provide increasingly pure paraoxonase proteins, and so managed to show that the protein by itself seems unable to prevent oxidation of LDL particles.80-82 Recently, studies have been published of other molecular mechanisms that involve the interaction between HDL and paraoxonase and so may mediate vascular protection.83,84

Thiolactone Hydrolase Activity

Homocysteine (Hcy) measured as total plasma homocystine (tHcy) is considered as an independent and graded risk factor for cardiovascular disease.85-87 The determinants of changes in tHcy plasma concentration are by-and-large known and include both environmental and genetic factors.88-90 The molecular hypotheses that link elevated Hcy concentrations with the disease include direct toxicity towards endothelial cells, oxidation of Hcy, smooth muscle cell growth, and activation of genes important in the development of atherosclerosis.91-94 Elevated Hcy in plasma is associated with other processes related to proteins. Between 80% and 90% of plasma Hcy is bound to proteins, approximately half this protein bindings occurs through disulfide bridges and the other half through more stable amide bonds.95,96 Edition of Hcy by certain aminoacyl-t-RNA synthases inside the cell leads to the formation of the thioester homocysteine thiolactone.97 In vitro studies have shown that the formation of this lactone is directly proportional to the concentration of Hcy and inversely proportional to the concentration of methionine, and that this formation is inhibited by administration of folic acid.97,98 If most Hcy is bound into proteins and there is also mechanism that can edit Hcy, the next question would be whether the incorporation of Hcy to proteins happens during or after translation. Evidence from in vitro studies done with certain cell types shows that this incorporation occurs after translation.99,100 This is particularly important because in vitro studies have shown that N-homocysteinylation of proteins may be mediated by metabolic conversion of Hcy into its corresponding lactone in certain physiological situations. Detoxification of homocysteine thiolactone therefore constitutes a crucial mechanism. Different studies have shown hydrolysis of these lactones is one of the functions of the paraoxonase enzyme.99 The molecular identity has also been revealed. Is this hydrolytic activity against homocysteine thiolactone the main role of PON-1?

Thiolactone Hydrolase Activity and Paraoxonase Isoforms

Jakubowski et al101 showed that the hydrolysis activity of homocysteine thiolactone differs according to PON1 genotype. High thiolactonase activity was found in carriers of the R192 and L55 alleles, whereas activity was lower in carriers of the Q192 and M55 alleles. The authors suggest that low lactonase activity could be an important cardiovascular risk factor in subjects with high plasma concentrations of Hcy, an explanation supported by some studies. According to Billecke et al,102 the Q and R isoforms show variable specificity towards different lactones and also towards different carboxylic acid esters. This would certainly explain previous clinical observations on the differential pharmacological effects of lipid-lowering drugs on serum paraoxonase activity103-108 (Figure 4).

Figure 4. A: Mean concentration of total plasma homocysteine (tHcy) according to the PON1 genotypes Gln192 Arg RR (Arg/Arg); QR (Gln/Arg); QQ (Gln/Gln) in a control group of 243 healthy men not receiving pharmacological treatment.107 ,108 B: Mean concentration of total plasma homocysteine according to the PON1 genotype Gln192 Arg in a group of 20 patients treated with statins.107,108

The SR-B1 (CLA1) Gene

The metabolism of the HDL particles involves a selective cell uptake process such that HDL components enter the cholesterol ester but not the protein fraction.109 This selective uptake process is mediated in mouse by the scavenger receptor class B type 1 or SR-B1.110,111 This is the first HDL receptor that has been well characterized at the molecular level.110

In 1993, Calvo and Vega112 identified a new sequence related to the CD36 receptor and to the lysosomal integral membrane protein II (LIMPII). The new gene was denominated CLA1 (CD36 and LIMPII analogue 1). Murao et al113 confirmed that the SR-B1 sequence was 81% identical with the CLA1 sequence. Alternative splicing of the CLA1 gene produces 2 forms, giving rise to 2 messengers from which 2 proteins of 409 and 509 amino acids have been deduced. The form identified by Murao et al,113 similar to SR-B1, corresponds to the 509-amino-acid protein.

Acton et al110 have identified several polymorphisms of the sequence of the human CLA1 gene in a healthy control population. The authors characterized intron variants (introns 3 and 5) and exon variants (exons 1, 8 and 11) by single-chain conformational analysis and sequencing. Two findings are, in our opinion, particularly interesting. The Gly→Ser substitution located in the second coded amino acid in the cDNA molecule (G/A substitution in the first triplet base) has already been associated with higher plasma concentrations of HDL and lower concentrations of LDL in men. On the other hand, the C→T substitution, located in the third base of codon 350 of the cDNA molecule, is associated with lower concentrations of LDL in women.

CLA1 (SR-B1) and Antioxidant Properties of HDL

There are several mechanisms responsible for the antiatherogenic effects of HDL particles. The most important is reverse cholesterol transport, a mechanism by which HDL particles take up excess cholesterol from extrahepatic tissues. Cholesterol is esterified through LCAT action then selectively transported to the liver, where CLA-1 mediated entry into the cholesterol ester occurs110-112,114 (Figure 1). Uptake of cholesterol ester by the liver is coupled with the synthesis and secretion of bile acids.115,116 The importance of the antiatherogenic effects of CLA-1 lies in the metabolism of HDL, as shown by experiments with SR-B1 and LCAT knockout murine models and models, also in mouse, with transient overexpression of SR-B1.114,117-119

The CLA1/SR-B1 gene mediates the 2-way transport of cholesterol and nonesterified phospholipids between the HDL particles and different cell types. The physiological role of this 2-way mechanism has not been satisfactorily clarified.120

The antiatherogenic importance of HDL particles is also derived from their direct or indirect antioxidant activity, as they are able to sequester CEOOH from LDL and subsequently eliminate it through reverse transport as cholesteryl ester hydroxides (CEOH).121 Some authors have shown that most of the CEOOH in humans are associated with HDL,21 whereas others have found them to be associated with LDL particles.22 For the purposes of this review, it is important to highlight that the selective uptake of CEOOH by parenchymal hepatic cells, mediated by CLA-1, is approximately 3 times greater than for native cholesterol ester.121

The role of SR-B1 in the metabolism of HDL particles poses a fundamental question. It is necessary to determine whether hepatic expression of SR-B1 favors atherogenesis when HDL concentrations are reduced, or whether antiatherogenic actions occurs on elimination of cholesterol ester. The findings presented earlier reveal a fundamental antiatherogenic role. This is because expression occurs mainly in the liver, where its activity as a scavenger receptor would be important. Furthermore, regulation appears different, at least in macrophages and in Kupffer cells. Some regulation mechanisms are subtle. Thus, HDL particles themselves regulate the expression of SR-B1 in macrophages. Particles of HDL induce activation of PPAR-gamma (messenger and protein) and its translocation to the nucleus, but they also induce phosphorylation of PPAR-gamma mediated by MAP-kinases, so preventing expression of the response genes (SR-B1 and CD36 among others) and thereby suggesting a mechanism iny which HDL particles inhibit lipid accumulation.122

CLA-1 (SR-B1), PON-1, and Lipid Oxidation: Hypothesis

Navab et al14,15 presented experimental evidence to support the LDL seeding mechanism. Their work and other experiments also showed that the action of normal HDL particles on LDL particles effectively deactivates the atherogenic load of the LDL particles. It has also been shown that reverse transport processes participate in the elimination of this atherogenic load. Moreover, reverse transport of lipid hydroperoxides, in particular, CEOOH is, as mentioned earlier, much more effective than that of native phospholipids and cholesterol esters.121 It would therefore follow that the PON-1 enzymatic activity for elimination of lipid hydroperoxides and CEOOH and their elimination by reverse cholesterol transport would contribute synergisti decrease in cardiovascular risk.

We attempted to address this question through analysis of polymorphic alleles described for the CLA1 gene (exons 1 and 8 and intron 5) by assigning them a measurable phenotype and determining an associated cardiovascular risk. Then, in a second phase, we assessed whether any association had occurred with some of the allelic variants described for the PON1 gene. We were able to confirm the presence of this genetic synergy. We also found that some of the allelic variants of CLA-1 modulated the plasma content of CEOOH. However, we did not obtain similar phenotypic evidence associated with PON1 polymorphisms.123


An atheroprotective role linked to reverse transport should be considered in addition to the antioxidative effect of different enzymes associated with HDL particles. The identification of multiple substrates for the paraoxonase-1 enzyme has extended the perspective of vascular protection mediated by HDL particles, although the exact molecular mechanisms by which this occurs have yet to be identified. The characterization of the CLA-1 receptor, its function, and its possible role as a determinant of the variation of plasma concentrations of oxidized lipids contributes to the knowledge of HDL metabolism and suggests the need for more comprehensive approaches in human studies, as well as the possibility of new therapeutic targets.


The authors thank the work done by the technician Ms Lidia Estupiñán-Quintana.

This study was partially funded with a research grant from the Instituto de Salud Carlos III (FIS 01/0190) and FUNCIS 6/2002 (and extension).

Correspondence: Prof. J.C. Rodríguez Pérez.
Unidad de Investigación-Nefrología. Hospital Universitario de Gran Canaria Doctor Negrín.
Barranco de la Ballena, s/n. 35010 Las Palmas de Gran Canaria. España.
Navab M, Ananthramaiah GM, Reddy ST, van Lenten BJ, Ansell BJ, Fonarow GC, et al..
The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL..
J Lipid Res, 45 (2004), pp. 993-1007
Witztum JL, Steinberg D..
The oxidative modification hypothesis of atherosclerosis:does it hold for humans? Trends Cardiovasc Med, 11 (2001), pp. 93-102
Cathcart MK, McNally AK, Chisolm GM..
Lipoxygenase-mediated transformation of human low density lipoprotein to an oxidized and cytotoxic complex..
J Lipid Res, 32 (1991), pp. 63-70
Sparrow CP, Parthasarathy S, Steinberg D..
Enzymatic modification of low density lipoprotein by purified lipoxygenase plus phospholipase A2 mimics cell-mediated oxidative modification..
J Lipid Res, 29 (1988), pp. 745-53
Yla-Herttuala S, Rosenfeld ME, Parthasarathy S, Sigal E, Sarkioja T, Witztum JL, et al..
Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts..
J Clin Invest, 87 (1991), pp. 1146-52
Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H, et al..
Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice..
Arterioscler Thromb Vasc Biol, 20 (2000), pp. 2100-5
Hatley ME, Srinivasan S, Reilly KB, Bolick DT, Hedrick CC..
Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice..
J Biol Chem, 278 (2003), pp. 25369-75
Reilly KB, Srinivasan S, Hatley ME, Patricia MK, Lannigan J, Bolick DT, et al..
12/15-Lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo..
J Biol Chem, 279 (2004), pp. 9440-50
Zhao L, Cuff CA, Moss E, Wille U, Cyrus T, Klein EA, et al..
Selective interleukin-12 synthesis defect in 12/15-lipoxygenase-deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia..
J Biol Chem, 277 (2002), pp. 35350-6
Sun D, Funk CD..
Disruption of 12/15-lipoxygenase expression in peritoneal macrophages. Enhanced utilization of the 5-lipoxygenase pathway and diminished oxidation of low density lipoprotein..
J Biol Chem, 271 (1996), pp. 24055-62
Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, et al..
Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice..
J Clin Invest, 103 (1999), pp. 1597-604
Cyrus T, Pratico D, Zhao L, Witztum JL, Rader DJ, Rokach J, et al..
Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice..
Circulation, 103 (2001), pp. 2277-82
Belkner J, Chaitidis P, Stender H, Gerth C, Kuban RJ, Yoshimoto T, et al..
Expression of 12/15-lipoxygenase attenuates intracellular lipid deposition during in vitro foam cell formation..
Arterioscler Thromb Vasc Biol, 25 (2005), pp. 797-802
Navab M, Hama SY, Cooke CJ, Anantharamaiah GM, Chaddha M, Jin L, et al..
Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: step 1..
J Lipid Res, 41 (2000), pp. 1481-94
Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson AD, et al..
Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3..
J Lipid Res, 41 (2000), pp. 1495-508
Serdyuk AP, Morton RE..
Lipid transfer inhibitor protein defines the participation of lipoproteins in lipid transfer reactions: CETP has no preference for cholesteryl esters in HDL versus LDL..
Arterioscler Thromb Vasc Biol, 19 (1999), pp. 718-26
Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, et al..
Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol..
N Engl J Med, 350 (2004), pp. 1505-15
Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, et al..
Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib..
Arterioscler Thromb Vasc Biol, 24 (2004), pp. 490-7
Oliveira HC, Quintao EC..
In vitro cholesteryl ester bidirectional flow between high-density lipoproteins and triglyceride-rich emulsions: effects of particle concentration and composition, cholesteryl ester transfer activity and oleic acid..
J Biochem Biophys Methods, 32 (1996), pp. 45-57
Berti JA, Salerno AG, Bighetti EJ, Casquero AC, Boschero AC, Oliveira HC..
Effects of diabetes and CETP expression on diet-induced atherosclerosis in LDL receptor-deficient mice..
Bowry VW, Stanley KK, Stocker R..
High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors..
Proc Natl Acad Sci USA, 89 (1992), pp. 10316-20
Nourooz-Zadeh J, Tajaddini-Sarmadi J, Ling KL, Wolff SP..
Low-density lipoprotein is the major carrier of lipid hydroperoxides in plasma. Relevance to determination of total plasma lipid hydroperoxide concentrations..
Biochem J, 313 (1996), pp. 781-6
Heinecke JW, Lusis AJ..
Paraoxonase-gene polymorphisms associated with coronary heart disease:support for the oxidative damage hypothesis? Am J Hum Genet, 62 (1998), pp. 20-4
Mackness MI, Arrol S, Durrington PN..
Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein..
FEBS Lett, 286 (1991), pp. 152-4
Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, la Du BN..
Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase..
J Clin Invest, 101 (1998), pp. 1581-90
Shih DM, Gu L, Hama S, Xia YR, Navab M, Fogelman AM, et al..
Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model..
J Clin Invest, 97 (1996), pp. 1630-9
Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, et al..
Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis..
Nature, 394 (1998), pp. 284-7
Oda MN, Bielicki JK, Ho TT, Berger T, Rubin EM, Forte TM..
Paraoxonase 1 overexpression in mice and its effect on high-density lipoproteins..
Biochem Biophys Res Commun, 290 (2002), pp. 921-7
McElveen J, Mackness MI, Colley CM, Peard T, Warner S, Walker CH..
Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction..
Clin Chem, 32 (1986), pp. 671-3
Mackness MI, Harty D, Bhatnagar D, Winocour PH, Arrol S, Ishola M, et al..
Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus..
Atherosclerosis, 86 (1991), pp. 193-9
Abbott CA, Mackness MI, Kumar S, Boulton AJ, Durrington PN..
Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins..
Arterioscler Thromb Vasc Biol, 15 (1995), pp. 1812-8
Hasselwander O, McMaster D, Fogarty DG, Maxwell AP, Nicholls DP, Young IS..
Serum paraoxonase and platelet-activating factor acetylhydrolase in chronic renal failure..
Clin Chem, 44 (1998), pp. 179-81
Schiavon R, de Fanti E, Giavarina D, Biasioli S, Cavalcanti G, Guidi G..
Serum paraoxonase activity is decreased in uremic patients..
Clin Chim Acta, 247 (1996), pp. 71-80
Tomas M, Latorre G, Senti M, Marrugat J..
The antioxidant function of high density lipoproteins: a new paradigm in atherosclerosis..
Rev Esp Cardiol, 57 (2004), pp. 557-69
Rosenblat M, Draganov D, Watson CE, Bisgaier CL, la Du BN, Aviram M..
Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress..
Arterioscler Thromb Vasc Biol, 23 (2003), pp. 468-74
Rozenberg O, Rosenblat M, Coleman R, Shih DM, Aviram M..
Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice..
Free Radic Biol Med, 34 (2003), pp. 774-84
Bielicki JK, Forte TM, McCall MR..
Minimally oxidized LDL is a potent inhibitor of lecithin:cholesterol acyltransferase activity..
J Lipid Res, 37 (1996), pp. 1012-21
Bielicki JK, Forte TM..
Evidence that lipid hydroperoxides inhibit plasma lecithin:cholesterol acyltransferase activity..
J Lipid Res, 40 (1999), pp. 948-54
Bergmeier C, Siekmeier R, Gross W..
Distribution spectrum of paraoxonase activity in HDL fractions..
Clin Chem, 50 (2004), pp. 2309-15
Getz GS, Reardon CA..
Paraoxonase, a cardioprotective enzyme: continuing issues..
Curr Opin Lipidol, 15 (2004), pp. 261-7
Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE..
The molecular basis of the human serum paraoxonase activity polymorphism..
Nat Genet, 3 (1993), pp. 73-6
Adkins S, Gan KN, Mody M, la Du BN..
Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes..
Am J Hum Genet, 52 (1993), pp. 598-608
Garin MC, James RW, Dussoix P, Blanche H, Passa P, Froguel P, et al..
Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes..
J Clin Invest, 99 (1997), pp. 62-6
Odawara M, Tachi Y, Yamashita K..
Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus..
J Clin Endocrinol Metab, 82 (1997), pp. 2257-60
Ruiz J, Blanche H, James RW, Garin MC, Vaisse C, Charpentier G, et al..
Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes..
Lancet, 346 (1995), pp. 869-72
Serrato M, Marian AJ..
A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease..
J Clin Invest, 96 (1995), pp. 3005-8
Suehiro T, Nakauchi Y, Yamamoto M, Arii K, Itoh H, Hamashige N, et al..
Paraoxonase gene polymorphism in Japanese subjects with coronary heart disease..
Int J Cardiol, 57 (1996), pp. 69-73
Antikainen M, Murtomaki S, Syvanne M, Pahlman R, Tahvanainen E, Jauhiainen M, et al..
The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns..
J Clin Invest, 98 (1996), pp. 883-5
Herrmann SM, Blanc H, Poirier O, Arveiler D, Luc G, Evans A, et al..
The Gln/Arg polymorphism of human paraoxonase (PON 192) is not related to myocardial infarction in the ECTIM Study..
Atherosclerosis, 126 (1996), pp. 299-303
Ombres D, Pannitteri G, Montali A, Candeloro A, Seccareccia F, Campagna F, et al..
The gln-Arg192 polymorphism of human paraoxonase gene is not associated with coronary artery disease in italian patients..
Arterioscler Thromb Vasc Biol, 18 (1998), pp. 1611-6
Lawlor DA, Day IN, Gaunt TR, Hinks LJ, Briggs PJ, Kiessling M, et al..
The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women's Heart and Health cohort study and a meta-analysis..
Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh J..
Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies..
Mackness B, Davies GK, Turkie W, Lee E, Roberts DH, Hill E, et al..
Paraoxonase status in coronary heart disease:are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol, 21 (2001), pp. 1451-7
Hasselwander O, Savage DA, McMaster D, Loughrey CM, McNamee PT, Middleton D, et al..
Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients..
Senti M, Tomas M, Marrugat J, Elosua R..
Paraoxonase1-192 polymorphism modulates the nonfatal myocardial infarction risk associated with decreased HDLs..
Arterioscler Thromb Vasc Biol, 21 (2001), pp. 415-20
James RW, Leviev I, Righetti A..
Smoking is associated with reduced serum paraoxonase activity and concentration in patients with coronary artery disease..
Circulation, 101 (2000), pp. 2252-7
Mackness B, Mackness MI, Arrol S, Turkie W, Durrington PN..
Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification..
FEBS Lett, 423 (1998), pp. 57-60
Cao H, Girard-Globa A, Berthezene F, Moulin P..
Paraoxonase protection of LDL against peroxidation is independent of its esterase activity towards paraoxon and is unaffected by the Q*R genetic..
J Lipid Res, 40 (1999), pp. 133-9
Mochizuki H, Scherer SW, Xi T, Nickle DC, Majer M, Huizenga JJ, et al..
Human PON2 gene at 7q213: cloning, multiple mRNA forms, and missense polymorphisms in the coding sequence..
Gene, 213 (1998), pp. 149-57
Primo-Parmo SL, Sorenson RC, Teiber L, La Du BN..
The human serum paraoxonase/arylesterase gene (PON1) is one member of multigene family..
Genomics, 33 (1996), pp. 498-507
Sanghera DK, Aston CE, Saha N, Kamboh MI..
DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease..
Am J Hum Genet, 62 (1998), pp. 36-44
Draganov DI, Stetson PL, Watson CE, Billecke SS, La Du BN..
Rabbit serum paraoxonase 3 (PON3) is an HDL-associated lactonase and protects LDL against oxidation..
J Biol Chem, 275 (2000), pp. 33435-42
Stafforini DM, McIntyre TM, Zimmerman GA, Prescott SM..
Platelet-activating factor, a pleiotrophic mediator of physiological and pathological processes..
Crit Rev Clin Lab Sci, 40 (2003), pp. 643-72
Tselepis AD, John CM..
Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase..
Atheroscler Suppl, 3 (2002), pp. 57-68
Caslake MJ, Packard CJ, Suckling KE, Holmes SD, Chamberlain P, Macphee CH..
Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease..
Atherosclerosis, 150 (2000), pp. 413-9
Packard CJ, O'eilly DS, Caslake MJ, McMahon AD, Ford I, Cooney J, et al..
Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group..
N Engl J Med, 343 (2000), pp. 1148-55
Quarck R, de Geest B, Stengel D, Mertens A, Lox M, Theilmeier G, et al..
Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice..
Circulation, 103 (2001), pp. 2495-500
Chen CH..
Platelet-activating factor acetylhydrolase:is it good or bad for you? Curr Opin Lipidol, 15 (2004), pp. 337-41
Marathe GK, Zimmerman GA, McIntyre TM..
Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles..
J Biol Chem, 278 (2003), pp. 3937-47
Tward A, Xia YR, Wang XP, Shi YS, Park C, Castellani LW, et al..
Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice..
Circulation, 106 (2002), pp. 484-90
Rodrigo L, Mackness B, Durrington PN, Hernández A, Mackness MI..
Hydrolysis of platelet-activating factor by human serum paraoxonase..
Biochem J, 354 (2001), pp. 1-7
Shih DM, Xia YR, Wang XP, Miller E, Castellani LW, Subbanagounder G, et al..
Combined serum paraoxonase knockout/ apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis..
J Biol Chem, 275 (2000), pp. 17527-35
de Geest B, Stengel D, Landeloos M, Lox M, le Gat L, Collen D, et al..
Effect of overexpression of human apo A-I in C57BL/6 and C57BL/6 apo E-deficient mice on 2 lipoprotein-associated enzymes, platelet-activating factor acetylhydrolase and paraoxonase. Comparison of adenovirus-mediated human apo A-I gene transfer and human apo A-I transgenesis..
Arterioscler Thromb Vasc Biol, 20 (2000), pp. E68-E75
Theilmeier G, de Geest B, van Veldhoven PP, Stengel D, Michiels C, Lox M, et al..
HDL-associated PAF-AH reduces endothelial adhesiveness in apoE­/­ mice..
FASEB J, 14 (2000), pp. 2032-9
Subramanian VS, Goyal J, Miwa M, Sugatami J, Akiyama M, Liu M, et al..
Role of lecithin-cholesterol acyltransferase in the metabolism of oxidized phospholipids in plasma: studies with platelet-activating factor-acetyl hydrolase-deficient plasma..
Biochim Biophys Acta, 1439 (1999), pp. 95-109
Ahmed Z, Ravandi A, Maguire GF, Emili A, Draganov D, la Du BN, et al..
Multiple substrates for paraoxonase-1 during oxidation of phosphatidylcholine by peroxynitrite..
Biochem Biophys Res Commun, 290 (2002), pp. 391-6
Aviram M, Billecke S, Sorenson R, Bisgaier C, Newton R, Rosenblat M, et al..
Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different from that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase allozymes Q and R..
Arterioscler Thromb Vasc Biol, 18 (1998), pp. 1617-24
Aviram M, Hardak E, Vaya J, Mahmood S, Milo S, Hoffman A, et al..
Human serum paraoxonases (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid atherosclerotic lesions: PON1 esterase and peroxidase-like activities..
Circulation, 101 (2000), pp. 2510-7
Rozenberg O, Shih DM, Aviram M..
Human serum paraoxonase 1 decreases macrophage cholesterol biosynthesis: possible role for its phospholipase-A2-like activity and lysophosphatidylcholine formation..
Arterioscler Thromb Vasc Biol, 23 (2003), pp. 461-67
Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN..
Enzymatic characterization of recombinant human paraoxonases (PON1, PON2 and PON3) - lactonases with overlapping and distinct substrate specificities..
J Lipid Res, 46 (2005), pp. 1239-47
Teiber JF, Draganov DI, la Du BN..
Purified human serum PON1 does not protect LDL against oxidation in the in vitro assays initiated with copper or AAPH..
J Lipid Res, 45 (2004), pp. 2260-8
Connelly PW, Draganov D, Maguire GF..
Paraoxonase-1 does not reduce or modify oxidation of phospholipids by peroxynitrite..
Free Radic Biol Med, 38 (2005), pp. 164-174
Rosenblat M, Vaya J, Shih D, Aviram M..
Paraoxonase 1 (PON1) enhances HDL-mediated macrophage cholesterol efflux via the ABCA1 transporter in association with increased HDL binding to the cells: a possible role for lysophosphatidylcholine..
Atherosclerosis, 179 (2005), pp. 69-77
Ribas V, Sanchez-Quesada JL, Anton R, Camacho M, Julve J, Escola-Gil JC, et al..
Human apolipoprotein A-II enrichment displaces paraoxonase from HDL and impairs its antioxidant properties: a new mechanism linking HDL protein composition and antiatherogenic potential..
Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al..
Hyperhomocysteinemia: an independent risk factor for vascular disease..
N Engl J Med, 324 (1991), pp. 1149-55
Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al..
A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians..
JAMA, 268 (1992), pp. 877-81
Anderson JL, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Madsen TE, et al..
Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined..
Circulation, 102 (2000), pp. 1227-32
Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, et al..
Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study..
JAMA, 274 (1995), pp. 1526-33
Nygard O, Vollset SE, Refsum H, Brattstrom L, Ueland PM..
Total homocysteine and cardiovascular disease..
J Intern Med, 246 (1999), pp. 425-54
Cortese C, Motti C..
MTHFR gene polymorphism, homocysteine and cardiovascular disease..
Public Health Nutr, 4 (2001), pp. 493-7
Sengupta S, Wehbe C, Majors AK, Ketterer ME, DiBello PM, Jacobsen DW..
Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine-mixed disulfide, and cystine in circulation..
J Biol Chem, 276 (2001), pp. 46896-904
Stanger O, Weger M..
Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium..
Clin Chem Lab Med, 41 (2003), pp. 1444-54
Starkebaum G, Harlan JM..
Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine..
J Clin Invest, 77 (1986), pp. 1370-6
Weiss N, Heydrick SJ, Postea O, Keller C, Keaney JF Jr, ..
, Loscalzo J. Influence of hyperhomocysteinemia on the cellular redox state: impact on homocysteine-induced endothelial dysfunction..
Clin Chem Lab Med, 41 (2003), pp. 1455-61
Liu L, Yan Y, Zeng M, Zhang J, Hanes MA, Ahearn G, et al..
Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock..
Cell, 116 (2004), pp. 617-28
Upchurch GR, Jr, Welch GN, Fabian AJ, Pigazzi A, Keaney JF, Jr, ..
, Loscalzo J. Stimulation of endothelial nitric oxide production by homocyst(e)ine..
Atherosclerosis, 132 (1997), pp. 177-85
Jakubowski H..
Molecular basis of homocysteine toxicity in humans..
Cell Mol Life Sci, 61 (2004), pp. 470-87
Jakubowski H..
Homocysteine-thiolactone and S-nitroso-homocysteine mediate incorporation of homocysteine into protein in humans..
Clin Chem Lab Med, 41 (2003), pp. 1462-6
Jakubowski H..
Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation..
J Biol Chem, 275 (2000), pp. 3957-62
Jakubowski H..
Translational accuracy of aminoacyl-tRNA synthetases: implications for atherosclerosis..
J Nutr, 131 (2001), pp. S2983-7
Jakubowski H, Ambrosius WT, Pratt JH..
Genetic determinants of homocysteine thiolactonase activity in humans: implications for atherosclerosis..
FEBS Lett, 491 (2001), pp. 35-9
Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C, et al..
Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters..
Drug Metab Dispos, 28 (2000), pp. 1335-42
Balogh Z, Seres I, Harangi M, Kovacs P, Kakuk G, Paragh G..
Gemfibrozil increases paraoxonase activity in type 2 diabetic patients..
A new hypothesis of the beneficial action of fibrates? Diabetes Metab, 27 (2001), pp. 604-10
Davignon J, Jacob RF, Mason RP..
The antioxidant effects of statins..
Coron Artery Dis, 15 (2004), pp. 251-8
Paragh G, Asztalos L, Seres I, Balogh Z, Locsey L, Karpati I, et al..
Serum paraoxonase activity changes in uremic and kidney-transplanted patients..
Nephron, 83 (1999), pp. 126-31
Tomas M, Senti M, García-Faria F, Vila J, Torrents A, Covas M, et al..
Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients..
Arterioscler Thromb Vasc Biol, 20 (2000), pp. 2113-9
Las isoformas de la paraoxonasa-1 difieren en su capacidad de hidr??lisis frente a f??rmacos antihipertensivos e hipolipemiantes. Nefrolog??a. 2004;24 Supl 5:2.
Rodríguez FJ, Rodríguez JC, Macías A, Hernández Y, Losad.a, A, Caballero A..
Paraoxonase isoforms differ regarding to its hydrolitic activity against statin and antihypertensive drugs..
J Am Soc Nephrol, 15 (2004), pp. 645A
Glass C, Pittman RC, Civen M, Steinberg D..
Uptake of high-density lipoprotein-associated apoprotein A-I and cholesterol esters by 16 tissues of the rat in vivo and by adrenal cells and hepatocytes in vitro..
J Biol Chem, 260 (1985), pp. 744-50
Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M..
Identification of scavenger receptor SR-BI as a high density lipoprotein receptor..
Science, 271 (1996), pp. 518-20
Acton SL, Scherer PE, Lodish HF, Krieger M..
Expression cloning of SR-BI, a CD36-related class B scavenger receptor..
J Biol Chem, 269 (1994), pp. 21003-9
Calvo D, Vega MA..
Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family..
J Biol Chem, 268 (1993), pp. 18929-35
Murao K, Terpstra V, Green SR, Kondratenko N, Steinberg D, Quehenberger O..
Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes..
J Biol Chem, 272 (1997), pp. 17551-7
Varban ML, Rinninger F, Wang N, Fairchild-Huntress V, Dunmore JH, Fang Q, et al..
Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol..
Proc Natl Acad Sci USA, 95 (1998), pp. 4619-24
Ji Y, Wang N, Ramakrishnan R, Sehayek E, Huszar D, Breslow JL, et al..
Hepatic scavenger receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into bile..
J Biol Chem, 274 (1999), pp. 33398-402
Sehayek E, Ono JG, Shefer S, Nguyen LB, Wang N, Batta AK, et al..
Biliary cholesterol excretion: a novel mechanism that regulates dietary cholesterol absorption..
Proc Natl Acad Sci USA, 95 (1998), pp. 10194-99
Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M..
Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels..
Nature, 387 (1997), pp. 414-17
Ueda Y, Royer L, Gong E, Zhang J, Cooper PN, Francone O, et al..
Lower plasma levels and accelerated clearance of high density lipoprotein (HDL) and non-HDL cholesterol in scavenger receptor class B type I transgenic mice..
J Biol Chem, 274 (1999), pp. 7165-71
Wang N, Arai T, Ji Y, Rinninger F, Tall AR..
Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice..
J Biol Chem, 273 (1998), pp. 32920-6
Pussinen PJ, Karten B, Wintersperger A, Reicher H, McLean M, Malle E, et al..
The human breast carcinoma cell line HBL-100 acquires exogenous cholesterol from high-density lipoprotein via CLA-1 (CD-36 and LIMPII analogous 1)-mediated selective cholesteryl ester uptake..
Biochem J, 349 (2000), pp. 559-66
Fluiter K, Sattler W, de Beer MC, Connell PM, van der Westhuyzen DR, van Berkel TJ..
Scavenger receptor BI mediates the selective uptake of oxidized cholesterol esters by rat liver..
J Biol Chem, 274 (1999), pp. 8893-9
Han J, Hajjar DP, Zhou X, Gotto AM Jr, Nicholson AC..
Regulation of peroxisome proliferator-activated receptor-gamma-mediated gene expression. A new mechanism of action for high density lipoprotein..
J Biol Chem, 277 (2002), pp. 23582-6
Rodríguez-Esparragon F, Rodríguez-Pérez JC, Hernández-Trujillo Y, Macias-Reyes A, Medina A, Caballero A, et al..
Allelic Variants of the Human Scavenger Receptor Class B Type 1 and Paraoxonase 1 on Coronary Heart Disease. Genotype-Phenotype Correlations..
Arterioscler Thromb Vasc Biol, 25 (2005), pp. 854-60
Revista Española de Cardiología (English Edition)

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