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PubMed2005

Paraoxonase, total antioxidant response, and peroxide levels in children with steroid-sensitive nephrotic syndrome.

Reactive oxygen species (ROS) are reported to play a role in inducing the proteinuria of nephrotic syndrome (NS). This study investigated paraoxonase (PON), total antioxidant response (TAR), and oxidant total peroxide together with serum proteins and lipoproteins in children with steroid-sensitive NS. The study included 40 children with steroid-sensitive NS (21 with acute-period NS in group I, 19 nonproteinuric while receiving steroids in group II) and 22 sex- and age-matched formerly nephrotic children in remission weaned from steroids (group III). The following parameters were determined: total peroxide, oxidative stress index (OSI), PON and TAR. Serum proteins and lipoproteins were also determined. Patients in the active phase of NS had significantly lower PON and TAR levels and higher OSI and total peroxide values than those in full remission; no differences were found in PON, TAR, or OSI values of groups I and II. Significant correlations were found between PON, TAR, and total peroxide. Serum total protein had a significantly positive correlation with PON and negative correlation with total peroxide in acute-period NS patients. Our results demonstrate greater oxidative stress and decreased antioxidants in the active phase of steroid-sensitive NS and while patients receive steroids than during full remission. Low-dose alternate-day steroids do not seem to decrease oxidative stress even while proteinuria ceases. Despite some conflicting data increased oxidation and/or decreased antioxidant response may be related to the pathogenesis of steroid-sensitive NS.

Adrenal Cortex Hormones↗
PubMed1984

Periglomerular cell action on mitral cells in olfactory bulb shown by current source density analysis.

The sign of action of periglomerular (PG) cells on the apical dendrites of mitral cells in olfactory bulb glomeruli was investigated by constructing current source density (CSD) profiles from potentials evoked by primary olfactory nerve (PON) and lateral olfactory tract (LOT) stimulation. Evoked potentials were recorded and averaged from anesthetized rabbit simultaneously with a 1 X 16 array of electrodes positioned perpendicular to the bulbar surface. A one-dimensional CSD analysis with depth was made in the center of PON- and LOT-evoked potential activity. CSD was plotted vs depth for specific times during the average evoked potential (AEP): at the surface peaks of the first surface-negative wave (N1), the first surface-positive wave (P1), and the second surface-negative wave (N2). N1, P1 and N2 corresponded to excitation, dis-excitation (equivalent to inhibition), and dis-inhibition (re-excitation) of the granule cell population through mitral cell basal dendrites. The granule cells generated both PON and LOT oscillatory AEPs. When N1 and P1 profiles or P1 and N2 profiles were combined, the source and sink due to granule cell activity were minimized and another source-sink pair was revealed on PON but not LOT stimulation. PON-evoked N1 + P1 or P1 + N2 profiles showed a secondary souce-sink pair not present with LOT stimulation. The sink was located in the glomerular layer (GL) and outer plexiform layer (EPL) and the source in the inner EPL. It was concluded that long-lasting excitation of the mitral cells was taking place at the GL and GL/EPL border. This excitation was ascribed to concomitant PG cell activity, possibly in combination with prolonged monosynaptic PON excitation of the apical dendrites. The results support the occurrence of direct excitatory action of PG cells onto mitral cells.

Animals↗
PubMed1987

Co-distribution of neuropeptide Y and its C-terminal flanking peptide in the brain and pituitary of the frog Rana ridibunda.

By means of the peroxidase-anti-peroxidase technique, the distribution of neuropeptide tyrosine (NPY) and its C-terminal flanking peptide (C-PON) has been studied on serial sections of the brain and pituitary of the frog Rana ridibunda. Throughout the brain, NPY and C-PON-immunoreactive perikarya exhibited a remarkable co-distribution. These two peptides were found to be co-located within the same cell bodies in various brain regions including the dorsal and ventral pallium, the dorsal and ventral infundibular nuclei and the preoptic nucleus. The distribution of NPY- and C-PON-containing fibers in the brain and pituitary was similar. Sequential double immunohistochemical staining using the indirect immunofluorescence method, showed that NPY and C-PON were actually located within the same nerve processes throughout the frog brain and in the intermediate lobe of the pituitary. These studies indicate that the deduced C-PON sequence is present within the frog precursor to NPY and is formed in vivo in the frog brain. Like NPY, C-PON is transported distally in nerve terminals and is likely released with NPY in various regions of the brain and in the intermediate lobe of the pituitary.

Animals↗
PubMed1993

The preoptic nucleus: the probable location of the circadian pacemaker of the hagfish, Eptatretus burgeri.

By recording the locomotor activity rhythm of hagfish, Eptatretus burgeri, in which surgical lesions of the preoptic nucleus (PON) were made, we searched for the location of the circadian pacemaker in the hypothalamus. The characteristic rhythms were lost in animals lacking the anterior part of the hypothalamus, which includes the PON. Cuts in front of the PON did not affect the rhythm, but cuts behind the PON caused the animals to loose their rhythms. Destruction of the PON with a high-frequency lesion generator also caused loss of rhythms. These findings indicate that the pacemaker may be located in the PON, which has retinofugal connections.

Animals↗
PubMed2005

Quantitative analysis of protein dynamics during asymmetric cell division.

In dividing Drosophila sensory organ precursor (SOP) cells, the fate determinant Numb and its associated adaptor protein Pon localize asymmetrically and segregate into the anterior daughter cell, where Numb influences cell fate by repressing Notch signaling. Asymmetric localization of both proteins requires the protein kinase aPKC and its substrate Lethal (2) giant larvae (Lgl). Because both Numb and Pon localization require actin and myosin, lateral transport along the cell cortex has been proposed as a possible mechanism for their asymmetric distribution. Here, we use quantitative live analysis of GFP-Pon and Numb-GFP fluorescence and fluorescence recovery after photobleaching (FRAP) to characterize the dynamics of Numb and Pon localization during SOP division. We demonstrate that Numb and Pon rapidly exchange between a cytoplasmic pool and the cell cortex and that preferential recruitment from the cytoplasm is responsible for their asymmetric distribution during mitosis. Expression of a constitutively active form of aPKC impairs membrane recruitment of GFP-Pon. This defect can be rescued by coexpression of nonphosphorylatable Lgl, indicating that Lgl is the main target of aPKC. We propose that a high-affinity binding site is asymmetrically distributed by aPKC and Lgl and is responsible for asymmetric localization of cell-fate determinants during mitosis.

Animals↗
PubMed2006

Association analysis of the paraoxonase-1 gene with Alzheimer's disease.

Genetic variants in the paraoxonase (PON) gene cluster, particularly a single C/T promoter polymorphism (rs 705381) in the PON-1 gene, have recently been associated with Alzheimer's disease (AD). The T allele, in particular, presents an increased risk for the development of AD. Here, we investigate the potential role of this polymorphism in an Italian case-control population consisting of 306 sporadic AD patients and 275 controls, and also evaluate a possible interaction with the ApoE genotype. No association between the PON-1 polymorphism and AD was observed. The T allele frequency was slightly over-represented in AD patients compared to the controls, but this was far from being statistically significant. Our sample was evaluated to have 97.3% power to detect an OR of 2.0 (64.3% power with OR=1.5) at an alpha level of 0.05. No evidence of an interaction between the T risk-allele and the ApoE epsilon4 allele status and no effect of the PON-1 polymorphism on age at onset was detected. Our results do not support other studies indicating that the PON-1 promoter polymorphism plays a major role in AD, suggesting that other large studies are necessary to further elucidate the effect of PON on the development of the disease in the general population.

Aged↗
PubMed2001

A multiplex PCR-based DNA assay for the detection of paraoxonase gene cluster polymorphisms.

Paraoxonase (PON) is a high-density lipoprotein (HDL) associated protein which is supposed to protect low-density lipoprotein (LDL) against oxidation and to play a role in the development of atherosclerosis. Interindividual variability in serum PON activity is attributable to common variants in components of the PON gene cluster on chromosome 7. We describe experimental conditions that permit the simultaneous determination of three common PON polymorphisms (PON1-192, PON1-55 and PON2-311) that are tightly associated with an increased risk of atherosclerosis. We used a multiplex PCR-based DNA assay using mismatch primers that introduce a unique recognition site for the endonuclease HinfI in the PCR products in case of presence of the R allele of PON 1-192, of the L allele of PON1-55 and of the S allele of PON2-311. The restriction analysis with HinfI allows to identify an electrophoretic band pattern which is specific for the combination of the three polymorphisms. This technique could be applied in the association studies aimed at assessing the role of PON and their polymorphisms in many clinical settings. In a preliminary study on a small population sample from south Italy about 10% of chromosomes exhibited the presumed risk-related haplotype R(192)/L(55)/S(311).

Alleles↗
PubMed1998

Effect of N-methyl-D-aspartate receptor blockade on the control of cerebral O2 supply/consumption balance during hypoxia in newborn pigs.

Using dizocilpine (MK-801), we tested the hypothesis that N-methyl-D-aspartate (NMDA) receptors are important controllers of cerebral O2 supply/consumption balance in newborn piglets both during normoxia and hypoxia. Twenty-five 2 to 7-day-old piglets were anesthetized and divided into four groups: (1) Normoxia (n = 6), (2) Normoxia + MK-801 (n = 6), (3) Hypoxia (n = 6), and (4) Hypoxia + MK-801 (n = 7). Regional cerebral blood flow (rCBF) in ml/min/100 g was measured using 14C-iodoantipyrine, and we determined arterial and venous O2 saturations by microspectrophotometry, calculating cerebral O2 consumption (VO2) in ml O2/min/100 g in the cortex, hypothalamus and pons. MK-801 did not significantly affect regional VO2 or rCBF in normoxic piglets. Hypoxia resulted in an increase in local rCBF compared to controls: from 41 +/- 6 to 103 +/- 18 in the cortex; 34 +/- 7 to 101 +/- 20 in the hypothalamus; and 45 +/- 10 to 95 +/- 11 in the pons. Pretreatment with MK-801 abolished this hypoxic flow effect in the cortex (51 +/- 2) and hypothalamus (49 +/- 5), but not in the pons (91 +/- 17). Similar results were observed for VO2 with control values of 1.9 +/- 0.3, 1.6 +/- 0.2 and 2.1 +/- 0.3 for the cortex, hypothalamus and pons respectively. Hypoxia resulted in an increase in the VO2 to 3.9 +/- 0.4 (cortex), 3.8 +/- 0.6 (hypothalamus) and 3.9 +/- 0.8 (pons). Pretreatment with MK-801 prior to hypoxia abolished these effects in the cortex (2.1 +/- 0.2) and hypothalamus (2.1 +/- 0.2), but not in the pons (2.9 +/- 0.2). These findings suggest that NMDA receptors may play a role in the control of cerebral metabolism during hypoxia in this immature porcine model.

Animals↗
PubMed2007

Serum paraoxonase/arylesterase activities in phenylketonuric patients on diet.

AIM: To compare serum paraoxonase/arylesterase (PON-aryl) activities in phenylketonuric (PKU) patients with high and low phenylalanine (Phe) blood concentration. PATIENTS AND METHODS: Seventeen poorly controlled PKU children (off diet) underwent clinical and laboratory examinations before and after 30 days adhering to their special diet (on diet), whereas controls (N=24) were examined once. Lipid, lipoprotein levels and paraoxonase (PON 1) activities were measured with the Bayer Advia 1650 Clinical Chemistry System. Apolipoprotein AI (Apo AI) levels were determined by the Dade Behring BN ProSpec nephelometer, whereas total antioxidant capacity (TAC), PON-aryl and Phe levels were measured spectrophotometrically. RESULTS: Phe significantly differed among the groups. Lipids and lipoproteins, except high-density-lipoprotein-cholesterol (HDL-C) and Apo AI, were higher when off diet than those on diet. HDL-C and Apo AI were similar in patients and controls. TAC (0.99+/-0.19 mmol/l) was significantly lower when the patients were off diet than when they adhered to diet and controls (1.71+/-0.20 and 1.81+/-0.20 mmol/l P<0.001 respectively). PON 1 and PON-aryl activities (68+/-2 U/min/ml, 88+/-26 KU (min/ml) in children with high Phe were reduced as compared with those with low blood Phe levels (152+/-41 U/min/ml, 107+/-23 KU/min/ml P<0.001) and controls (146+/-43 U/min/ml, 109+/-41 KU/min/ml P<0.001). The enzyme activities positively correlated with HDL-C and Apo AI when PKU patients were on diet and controls as well as with TAC in all the groups, whereas negatively correlated with Phe levels. CONCLUSIONS: PON-aryl activities are strongly related to the dietary control of PKU patients.

Analysis of Variance↗
PubMed2005

Antiphospholipid antibodies are associated with enhanced oxidative stress, decreased plasma nitric oxide and paraoxonase activity in an experimental mouse model.

OBJECTIVE: Oxidative stress contributes to atherosclerosis, and evidence of enhanced oxidative stress exists in antiphospholipid syndrome (APS). In a non-lupus murine model, we evaluated whether anticardiolipin (aCL) antibodies could affect the oxidant/antioxidant balance as an early biochemical step of APS. METHODS: Hybridomas producing human and murine aCL and anti-beta(2)-glycoprotein I (abeta2-GPI) monoclonal antibodies were injected into three groups of five female BALB/c severe combined immunodeficiency (SCID) mice. Corresponding hybridomas secreting non-antiphospholipid antibodies of the same isotype were employed as controls. Sera and organs were collected after 30 days. Paraoxonase (PON) activity, peroxynitrite, superoxide, nitric oxide (NO) and nitrotyrosine were measured in plasma. Expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) was assessed by western blot and immunohistochemistry. RESULTS: PON activity and NO (sum of nitrate and nitrite) levels were reduced in the human aCL IgG group (P<0.002 and P<0.04, respectively), whilst peroxynitrite and superoxide and expression of total antioxidant capacity of plasma were increased (P<0.01). PON and NO were decreased in the murine abeta2-GPI IgG and IgM aCL groups (P<0.03 and P<0.05, respectively). Nitrotyrosine was elevated in the human aCL IgG group (P<0.03). Western blotting showed reduced iNOS expression in the hearts of the IgG aCL group, confirmed by immunostaining. PON inversely correlated with IgG aCL titres (P<0.001), superoxide (P<0.008) and peroxynitrite levels (P<0.0009). Peroxynitrite and total IgG aCL were independent predictors of PON (P<0.0009 and P<0.02, respectively). Superoxide was the only independent predictor of NO (P<0.008) and of nitrotyrosine (P<0.002). CONCLUSION: aCL antibodies are associated with the decreased PON activity and reduced NO that may occur in the preclinical phase of APS.

Animals↗
PubMed2006

Role of peroxynitrite in secondary oxidative damage after spinal cord injury.

Peroxynitrite (PON, ONOO(-)), formed by nitric oxide synthase-generated nitric oxide radical ( NO) and superoxide radical (O(2) (-)), is a crucial player in post-traumatic oxidative damage. In the present study, we determined the spatial and temporal characteristics of PON-derived oxidative damage after a moderate contusion injury in rats. Our results showed that 3-nitrotyrosine (3-NT), a specific marker for PON, rapidly accumulated at early time points (1 and 3 h) and a significant increase compared with sham rats was sustained to 1 week after injury. Additionally, there was a coincident and maintained increase in the levels of protein oxidation-related protein carbonyl and lipid peroxidation-derived 4-hydroxynonenal (4-HNE). The peak increases of 3-NT and 4-HNE were observed at 24 h post-injury. In our immunohistochemical results, the co-localization of 3-NT and 4-HNE results indicates that PON is involved in lipid peroxidative as well as protein nitrative damage. One of the consequences of oxidative damage is an exacerbation of intracellular calcium overload, which activates the cysteine protease calpain leading to the degradation of several cellular targets including cytoskeletal protein (alpha-spectrin). Western blot analysis of alpha-spectrin breakdown products showed that the 145-kDa fragments of alpha-spectrin, which are specifically generated by calpain, were significantly increased as soon as 1 h following injury although the peak increase did not occur until 72 h post-injury. The later activation of calpain is most likely linked to PON-mediated secondary oxidative impairment of calcium homeostasis. Scavengers of PON, or its derived free radical species, may provide an improved antioxidant neuroprotective approach for the treatment of post-traumatic oxidative damage in the injured spinal cord.

Aldehydes↗
PubMed2004

Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism.

Human paraoxonase 1 (PON-1) is a serum high-density lipoprotein-associated enzyme mainly secreted by the liver. It has endogenous and exogenous substrates and displays protective properties with respect to cardiovascular disease and organophosphate intoxication. In the HuH7 human hepatoma cell line, PON-1 activity and mRNA levels were increased by dietary polyphenolic compounds such as quercetin but also by toxic ligands of the aryl hydrocarbon receptor (AhR) such as 3-methylcholanthrene (3-MC). However, the 2,3,7,8-tetrachlorobenzo(p)dioxin (TCDD) was a poor inducer. Transient and stable transfection assays indicated that these compounds increased the PON-1 gene promoter activity in an AhR-dependent manner, since their effect was inhibited by 7-keto-cholesterol and AhR-directed short interfering RNA. Deletions and mutations studies showed that a xenobiotic responsive element (XRE)-like sequence within the PON-1 promoter mediated the effect of 3-MC and quercetin. In contrast with consensus XREs from the cytochrome P450 1A1 gene, the PON-1 XRE-like element mediated preferentially the effect of quercetin compared to the results seen with TCDD. Furthermore, AhR binding to this element was preferentially activated by quercetin. These observations provide a molecular mechanism for the regulation of the cardioprotective enzyme PON-1 by polyphenols. They suggest also that AhR ligands may differentially regulate gene expression depending on the DNA target sequence.

Aryldialkylphosphatase↗
PubMed2002

Neurotransmitter levels in brains of chronically Jiawey Siwu-treated rats.

Levels of monoamines and metabolites, excitatory amino acids, and gamma-aminobutyric acid (GABA) were investigated in discrete brain areas of chronic Jiawey Siwu (JS)-treated rats. Male Sprague-Dawley rats were dosed orally for 3 months with normal saline or JS at 0.21, 1.05 or 4.2 g/kg/day. Body weights of these four groups were similar over 3 months. Most effects of JS revealed a dose dependency with levels of neurotransmitters. Levels of norepinephrine (NE) and epinephrine (EPI) in cerebral cortex; EPI, vanillylmandelic acid (VMA), dopamine (DA) and 5-hydroxytryptamine (5-HT) in medulla oblongata; DA in midbrain; NE and 5-HT in amygdala; and 5-HT in hypothalamus had decreased in JS-treated rats. 3-Methoxytyramine (3-MT) in cerebral cortex; 5-hydroxyindole-3-acetic acid (5-HIAA) in medulla oblongata; NE, 3-MT and homovanillic acid (HVA) in pons; EPI and 3-MT in midbrain; 3-MT and HVA in amygdala; 3-MT, 3,4-dihydroxyphenylacetic acid (DOPAC), HVA and 5-HIAA in cerebellum; HVA in hypothalamus; and DOPAC and HVA in hippocampus had all increased in JS-treated rats. In pons, 5-HT increased with low and decreased with high JS doses. Ratios of DA/3-MT in pons and midbrain; DA/HVA in pons and cerebellum; and 5-HT/5-HIAA in medulla oblongata, cerebellum and hypothalamus had decreased. Furthermore, aspartate (ASP) and glutamate (GLU) levels had decreased in cerebral cortex, midbrain, hypothalamus and hippocampus or amygdala, and increased in pons. GABA levels were reduced in cerebral cortex, and higher in medulla oblongata, pons, amygdala, cerebellum, hippocampus and striatum of JS-treated rats. These results indicate that the synthesis and (or) metabolism of NE, DA, EPI and 5-HT, and the levels of ASP, GLU and GABA in rat brains were differentially regionally altered by JS, which may contribute to the central manifestations of JS treatment.

Animals↗
PubMed2003

Primate pupillary light reflex: receptive field characteristics of pretectal luminance neurons.

This study examined the response properties of luminance neurons found within the pretectal olivary nucleus (PON), which is the pretectal nucleus that mediates the primate pupillary light reflex. We recorded the activity of 121 single units in alert, behaving rhesus monkeys trained to fixate a back-projected laser spot while a luminance stimulus was presented. The change in the firing rate of luminance neurons was measured as a function of changes in the size, retinal illuminance, and position of the stimulus. We found that these neurons possessed large receptive fields, which were sufficiently distinct that they could be placed into three classes. Approximately 40% of the PON luminance neurons responded well to stimuli presented in either the contralateral or ipsilateral hemifield. These neurons were classified as "bilateral" neurons. In the primate, retinal projections to the pretectum and other retinorecipient nuclei are organized such that direct retinal input can only account for the contralateral hemifield responses of these neurons. Thus the representation of the ipsilateral hemifield in "bilateral" PON cells must result from input from a nonretinal source. Approximately 30% of PON neurons responded only to stimuli presented in the contralateral hemifield. These neurons were classified as "contralateral" neurons. Finally, approximately 30% of PON neurons responded to stimuli presented at or near the animal's fixation point. These neurons were classified as "macular" neurons. The mean firing rates of all classes of neurons increased with increases in stimulus size and luminance within their receptive fields. The thresholds and magnitude of these responses closely matched those that would be appropriate for mediating the pupillary light reflex. In summary, these results suggest that all three classes of PON neurons contribute to the behaviorally observed pupillomotor field characteristics in which stimuli at the macular produce substantially larger pupillary responses than more peripheral stimuli. The contributions of "bilateral" and "contralateral" cells account for pupillary responses evoked by peripheral changes in luminance, whereas the contributions of all three cell classes account for the larger pupillary responses evoked by stimuli in the central visual field.

Action Potentials↗
PubMed2004

Induction of the paraoxonase-1 gene expression by resveratrol.

OBJECTIVE: The human paraoxonase-1 (PON-1) is a high-density lipoprotein-associated enzyme, mainly secreted by the liver, that displays protective properties toward cardiovascular disease and organophosphate intoxication. Resveratrol is a polyphenolic phytoalexin found in grapes and wine and is thought to display cardioprotective effects. It is able to interact with transcriptional modulators such as the estrogen receptor alpha (ERalpha). We investigated the effect of resveratrol on the PON-1 gene expression. METHODS AND RESULTS: PON-1 activity assays, Northern blot, and transfection experiments showed that resveratrol increased the PON-1 gene expression in human hepatocyte primary cultures and in the HuH7 hepatoma cell line involving a transcriptional mechanism. The resveratrol effect was not ERalpha-dependent and was surprisingly mediated by the aryl hydrocarbon receptor (AhR) and an unconventional AhR responsive element in the PON-1 gene promoter. This agonist effect of resveratrol was specific for this DNA motif and was not observed on classical AhR responsive elements. CONCLUSIONS: These observations suggest that the PON-1 gene induction may be involved in the cardioprotective properties of resveratrol. They also highlight a ligand-dependent differential modulation of AhR-sensitive genes.

Aryldialkylphosphatase↗
PubMed2006

Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes.

OBJECTIVE: During inflammation, the serum amyloid A (SAA) content of HDL increases, whereas apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON-1) decrease. It remains unclear whether SAA physically displaces apoA-I or if these changes derive from coordinated but inverse transcriptional regulation of the HDL apolipoprotein genes. Because cytokines stimulate the hepatic expression of inflammatory markers, we investigated their role in regulating SAA, apoA-I, and PON-1 expression. METHODS AND RESULTS: A cytokine mixture (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, and IL-6) simultaneously induced SAA and repressed apoA-I and PON-1 expression levels. These effects were partially inhibited in cells pretreated with either nuclear factor kappaB (NF-kappaB) inhibitors (pyrrolidine dithiocarbamate, SN50, and overexpression of super-repressor inhibitor kappaB) or after exposure to the peroxisome proliferator-activated receptor-alpha (PPARalpha) ligands (WY-14643 and fenofibrate). Consistent with these findings, the basal level of SAA was increased, whereas apoA-I and PON-1 decreased in primary hepatocytes from PPARalpha-deficient mice as compared with wild-type mice. Moreover, neither WY-14643 nor fenofibrate had any effect on SAA, apoA-I, or PON-1 expression in the absence of PPARalpha. CONCLUSIONS: These results suggest that cytokines increase the expression of SAA through NF-kappaB transactivation, while simultaneously decreasing the expression of apoA-I and PON-1 by inhibiting PPARalpha activation. Inflammation may convert HDL de novo into a more proatherogenic form by coordinate but inverse transcriptional regulation in the liver, rather than by physical displacement of apoA-I by SAA.

Animals↗
PubMed1997

Increased immunolocalization of paraoxonase, clusterin, and apolipoprotein A-I in the human artery wall with the progression of atherosclerosis.

Using immunolocalization techniques, we have shown that paraoxonase (Pon), clusterin, and apolipoprotein (apo) A-I accumulate in the artery wall during the development of atherosclerosis. In normal aortas (n = 6) there were low levels of extracellular Pon, clusterin, and apoA-I, immunoreactivity. The cytoplasm of smooth muscle cells in the media showed granular positivity for both Pon and apoA-I, indicating that these proteins were undergoing lysosomal degradation. This activity was also indicated by the presence of both intact and degradation products of Pon in smooth muscle cells as shown by Western blotting. With the progression of disease from fatty streaks (n = 3) to advanced atherosclerosis (n = 8) there was an increase in Pon, apoA-I, and clusterin immunoreactivity, indicating the increasing presence of these proteins with disease progression. These proteins are the components of a specific HDL subspecies that has been implicated in the prevention of peroxidative damage to phospholipids in LDL and membranes. The increase in Pon, clusterin, and apoA-I during the development of atherosclerosis may therefore represent a protective response to the oxidative stress associated with the development of atherosclerosis.

Adult↗
PubMed2000

Short-term feeding of atherogenic diet to mice results in reduction of HDL and paraoxonase that may be mediated by an immune mechanism.

Short-term feeding (up to 7 days) of an atherogenic diet to C57BL/6 low density lipoprotein receptor-deficient mice did not result in decreased hepatic paraoxonase (PON) mRNA but caused a dramatic decrease in plasma PON activity and mass. The decreased activity and mass were temporally related to an increase in plasma and high density lipoprotein (HDL) lipid hydroperoxides and to a decrease in HDL cholesterol and native apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II). As the native apoA-I protein disappeared from the circulation, higher molecular weight forms of apoA-I appeared, some of which contained epitopes recognized by an antibody (EO6) that recognizes oxidized phospholipids. After mice consumed an atherogenic diet for 1 or 3 days, switching the mice to a low fat chow diet for 3 days resulted in a return to baseline levels of lipid hydroperoxides but only a small return toward baseline for HDL cholesterol, with no significant increase in apoA-I mass or PON activity and mass. After mice consumed an atherogenic diet for 3 days, switching to the chow diet for 3 days did not significantly alter the high molecular weight forms of apoA-I or the signal generated by EO6. In marked contrast, after mice consumed an atherogenic diet for 7 days, switching to the chow diet for 3 days resulted in a dramatic increase in native apoA-I to baseline levels, with virtual disappearance of the high molecular weight forms of apoA-I, including the form recognized by EO6. After mice consumed an atherogenic diet for 7 days, switching to the chow diet for 3 days also resulted in significant increases in HDL cholesterol and PON mass and activity, although baseline levels were not reached. IgG and IgM antibodies were found to be associated with apoA-I in control animals, were minimally decreased after the 3-day atherogenic diet, were dramatically decreased after the 7-day atherogenic diet, and returned to near or above baseline levels after a return to the chow diet for 3 days. We conclude that the atherogenic diet rapidly induces lipid hydroperoxide formation and apoA-I oxidation with the formation of high molecular weight forms of apoA-I. Concomitant with these changes in apoA-I levels, HDL cholesterol and PON activity and mass declined without changes in mRNA levels for apoA-I or PON, suggesting increased clearance of these altered HDL particles. We further conclude that between the third and seventh day of the atherogenic diet, an as-yet-unidentified mechanism for clearing the high molecular weight forms of apoA-I is induced and that this mechanism may be related to the clearance of immune complexes.

Animals↗