Insights into the role of paraoxonase 2 in human pathophysiology.

Paraoxonase 2 (PON2) is a ubiquitously expressed intracellular enzyme that is known to have a protective role from oxidative stress. Clinical studies have also demonstrated the significance of PON2 in the manifestation of cardiovascular and several other diseases, and hence, it is considered an important biomarker. Recent findings of its expression in brain tissue suggest its potential protective effect on oxidative stress and neuroinflammation. Polymorphisms of PON2 in humans are a risk factor in many pathological conditions, suggesting a possible mechanism of its anti-oxidative property probably through lactonase activity. However, exogenous factors may also modulate the expression and activity of PON2. Hence, this review aims to report the mechanism by which PON2 expression is regulated and its role in oxidative stress disorders such as neurodegeneration and tumor formation. The role of PON2 owing to its lactonase activity in bacterial infectious diseases and association of PON2 polymorphism with pathological conditions are also highlighted.

The Effects of Acute and Chronic Exercise on Paraoxonase-1 (PON1): A Systematic Review With Meta-Analysis.

Purpose: To determine the acute and chronic effects of exercise on Paraoxonase-1 (PON1) concentration and activity. Methods: A literature search was performed using 16 electronic databases. Effect sizes (ES) were computed and two-tailed α values < .05 and non-overlapping 95% confidence intervals (95%CI) were considered statistically significant. Heterogeneity, inconsistency (I2), and small-study effects using the LFK index were examined. Results: Eighteen studies (n = 377 participants) met the criteria for inclusion. The acute effects of exercise on PON1 concentration were trivial and non-significant (ES = -.03, 95%CI = -.39 to .34, p > .05), heterogeneous (p = .05), moderately inconsistent (I2 = 48%), with minor asymmetry (LFK index = 1.34). The chronic effects of exercise on PON1 concentration were also trivial and non-significant (ES = -.04, 95%CI = -.53 to.45, p > .05), homogenous (p = .65), displayed low inconsistency (I2 = 0%), and minor asymmetry (LFK index = -1.14). The acute effects of exercise on PON1 activity were trivial and non-significant (ES = .11, 95%CI = -.02 to.24, p > .05), homogenous (p = .85), showed low inconsistency (I2 = 0%), and no asymmetry (LFK index = .82). The chronic effects of exercise on PON1 activity were trivial and non-significant (ES = .31, 95%CI = -.03 to.65, p > .05), homogenous (p = .17), moderately inconsistent (I2 = 36%), with no asymmetry (LFK index = .60). Conclusion: Acute and chronic exercise training, overall, exerted a trivial effect on PON1 concentration and activity.

Paraoxonase 2 protects against the CML mediated mitochondrial dysfunction through modulating JNK pathway in human retinal cells.

BACKGROUND: Paraoxonase 2 (PON2) a known anti-apoptotic protein, has not been explored against Nε-(carboxymethyl)lysine (CML), induced mitochondrial dysfunction and apoptosis in human retinal cells. Hence this present study aims to investigate the potential role of PON2 in mitigating CML-induced mitochondrial dysfunction in these cells. METHODS: PON2 protein was quantified in HRECs (Human retinal endothelial cells), ARPE-19 (Retinal pigment epithelial cells) cells upon CML treatment and also in cadaveric diabetic retina vs respective controls. ROS production, mitochondrial membrane potential (MMP), mitochondrial permeability transition pore (mPTP) opening, the release of Cyt-c, Bax, Caspase-3, Fis1, Mfn1, Mfn2, mitochondrial morphology, and the signaling pathway was assessed using DCFDA, JC-1, CoCl2, immunofluorescence or western blotting analysis in both loss-of-function or gain-of-function experiments. RESULTS: PON2 protein was downregulated in HREC and ARPE-19 cells upon CML treatment as well as in the diabetic retina (p = 0.035). Decrease in PON2 augments Fis1 expression resulting in fragmentation of mitochondria and enhances the ROS production, decreases MMP, facilitates mPTP opening, and induces the release of Cyt-c, which activates the pro-apoptotic pathway. Whereas PON2 overexpression similar to SP600125 (a specific JNK inhibitor) was able to decrease Fis1 (p = 0.036) and reverse the Bcl-2 and Bax ratio, and inhibit the JNK1/2 signaling pathway. CONCLUSION: Our results confirm that PON2 has an anti-apoptotic role against the CML mediated mitochondrial dysfunction and inhibits apoptosis through the JNK-Fis1 axis. GENERAL SIGNIFICANCE: We hypothesis that enhancing PON2 may provide a better therapeutic potential against diabetic vascular disease.

On the Role of Paraoxonase-1 and Chemokine Ligand 2 (C-C motif) in Metabolic Alterations Linked to Inflammation and Disease. A 2021 Update.

Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins, and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, both produce metabolic alterations that influence the pathogenesis of the disease. In this review, we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, inducing migration and infiltration of immune cells in target tissues and disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets.

Dysfunctional High-density Lipoprotein: The Role of Myeloperoxidase and Paraoxonase-1.

Low circulating high-density lipoproteins (HDL) are not only defining criteria for metabolic syndrome, but are more generally associated with atherosclerotic cardiovascular disease (ASCVD) and other chronic diseases. Oxidative stress, a hallmark of cardio-metabolic disease, further influences HDL activity by suppressing their function. Especially the leukocyte- derived enzyme myeloperoxidase (MPO) has recently attracted great interest as it catalyzes the formation of oxidizing reactive species that modify the structure and function of HDL, ultimately increasing cardiovascular risk. Contrariwise, paraoxonase-1 (PON1) is an HDL-associated enzyme that protects HDL from lipid oxidation and then acts as a protective factor against ASCVD. It is noteworthy that recent studies have demonstrated how MPO, PON1 and HDL form a functional complex in which PON1 partially inhibits the MPO activity, while MPO in turn partially inactivates PON1.In line with that, a high MPO/PON1 ratio characterizes patients with ASCVD and metabolic syndrome and has been suggested as a potential marker of dysfunctional HDL as well as a predictor of ASCVD. In this review, we summarize the evidence on the interactions between MPO and PON1 with regard to their structure, function and interaction with HDL activity. We also provide an overview of in vitro and experimental animal models, finally focusing on clinical evidence from a cohort of patients with ASCVD and metabolic syndrome.

Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM Directed to Malondialdehyde and Paraoxonase 1 Activity.

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in a cross-sectional study that enrolled schizophrenia patients with (n = 40) and without (n = 40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial least squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), which lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA, and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Albuminuria, the High-Density Lipoprotein Proteome, and Coronary Artery Calcification in Type 1 Diabetes Mellitus.

Objective- Albuminuria is an important risk factor for cardiovascular disease in diabetes mellitus. We determined whether albuminuria associates with alterations in the proteome of HDL (high-density lipoprotein) of subjects with type 1 diabetes mellitus and whether those alterations associated with coronary artery calcification. Approach and Results- In a cross-sectional study of 191 subjects enrolled in the DCCT (Diabetes Control and Complications Trial)/EDIC study (Epidemiology of Diabetes Interventions and Complications), we used isotope dilution tandem mass spectrometry to quantify 46 proteins in HDL. Stringent statistical analysis demonstrated that 8 proteins associated with albuminuria. Two of those proteins, AMBP (α1-microglobulin/bikunin precursor) and PTGDS (prostaglandin-H2 D-isomerase), strongly and positively associated with the albumin excretion rate ( P<10-6). Furthermore, PON (paraoxonase) 1 and PON3 levels in HDL strongly and negatively associated with the presence of coronary artery calcium, with odds ratios per 1-SD difference of 0.63 (95% CI, 0.43-0.92; P=0.018) for PON1 and 0.59 (95% CI, 0.40-0.87; P=0.0079) for PON3. Only 1 protein, PON1, associated with both albumin excretion rate and coronary artery calcification. Conclusions- Our observations indicate that the HDL proteome is remodeled in type 1 diabetes mellitus subjects with albuminuria. Moreover, low concentrations of the antiatherosclerotic protein PON1 in HDL associated with both albuminuria and coronary artery calcification, raising the possibility that alterations in HDL protein cargo mediate, in part, the known association of albuminuria with cardiovascular risk in type 1 diabetes mellitus. Visual Overview- An online visual overview is available for this article.

Paraoxonase-1 activities in individuals with different HDL circulating levels: Implication in reverse cholesterol transport and early vascular damage.

BACKGROUND AND AIMS: Epidemiological data showing that high-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular disease have led to the idea that cholesterol contained in this lipoprotein may be protective. Against, recent evidence suggests that the athero-protection from HDLs may result from other functions, unrelated to the carried cholesterol. HDL accessory proteins, such as paraoxonase 1 (PON1), have been suggested to endows HDL with antioxidant and anti-inflammatory properties and to contribute to the athero-protective function of the lipoprotein. We aimed to evaluate whether extreme fluctuation in HDL-C levels correlates with PON1 activity. METHODS: Levels of PON1-related arylesterase and lactonase were assessed in subjects with primary hyperalphalipoproteinemia (HAL, HDL-C>90th percentile), hypoalphalipoproteinemia (HA, HDL-C<10th percentile) and controls. Cholesterol efflux capacity (CEC) through several pathways and other metabolic parameters and markers of vascular disease were also determined. RESULTS: Despite the marked change in HDL-C and Apoliprotein A1 (APO A1) (p < 0.001 for all comparisons), arylesterase and lactonase were only slightly increased in HAL compared with HA subjects (p < 0.05), but not vs. controls. This change in PON1 activities was no longer significant after adjustment for either HDL-C or APO A1. Both enzymatic activities were positively associated only with aqueous diffusion CEC (r = 0.318, p < 0.05 and r = 0.355, p < 0.05, respectively) and negatively with the presence of plaques (p < 0.05). CONCLUSIONS: We showed that extreme high/low HDL-C levels are not associated with equal increase/decrease in PON1 activities. This enzyme appears to contribute to the HDL role in reverse cholesterol transport and anti-atherosclerosis processes. Further investigation is required to corroborate our findings.

Serum paraoxonase (a high-density lipoprotein-associated lipophilic antioxidant) activity in clinical follow-up of patients with acute pancreatitis, with particular emphasis on oxidative stress parameters and lipid profile: a prospective pilot trial.

The purpose of this study was to investigate the possible role of PON-1, an antioxidant lipophilic enzyme linked to HDL-C (high-density lipoprotein cholesterol), on the pathophysiology and clinical follow-up of acute pancreatitis. Biochemical tests, PON-1 and oxidative stress parameters (malonyl dialdehyde, MDA; superoxide dismutase, SOD; total antioxidant capacity, TAC) were evaluated in the sera of patients with acute pancreatitis at admission (day 0), day 3 and day 10 of follow-up, between June and September 2017. SPSS 13.0 statistical software package programme was used for statistical analyses.Mean age was 51.4 of the total 25 patients. Ranson scores were 0-1 points (60%), 3-4 points (24%) and 5-6 points (16%). CTSI (computed tomography severity index) scores were calculated, and most of the patients were seen to have mild or average pancreatitis (96%). While total cholesterol, triacylglycerol and LDL-C (low-density lipoprotein) levels stayed in their normal limits, there was a significant decrement tendency. HDL-C level was seen to rise significantly above its upper limit at day 10 (p < 0.001). Mean PON-1 levels were measured as 69.23, 76.72 vs. 113.15 U/mL at days 0, 3 and 10, respectively; and it was positively correlated with HDL-C (p < 0.001). Serum SOD increased also in parallel with PON-1 (20.49 vs. 39.46 U/mL) while MDA level decreased significantly (3.9 vs. 2.28 µM, p < 0.001). TAC was seen to rise significantly after treatment (0.52 vs. 1.22 mM). In conclusion, decreased PON-1 and HDL-C together with antioxidants SOD and TAC at the early period of acute pancreatitis were seen to rise after treatment, while the previously higher MDA level decreased in parallel. This reveals the importance of the balance between oxidative stress and antioxidant defense mechanisms in clinical progression of the disease, and the potential of PON-1 as a promising clinical marker.

Paraoxonase 1 in endothelial cells impairs vasodilation induced by arachidonic acid lactone metabolite.

INTRODUCTION: Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated lactonase, which is known for its antiatherogenic properties. Previous studies in PON1 knockout (PON1KO) mice revealed that PON1KO mice have low blood pressure, which is inversely correlated with the renal levels of the cytochrome P450 -derived arachidonic acid metabolite 5,6-epoxyeicosatrienoic acid (5,6-EET). Our previous studies revealed that 5,6-EET is unstable, transforming to the δ-lactone isomer 5,6-δ-DHTL, an endothelium-derived hyperpolarizing factor (EDHF) that mediates vasodilation, and it is a potential substrate for PON1. AIM: To elucidate the role of PON1 in the modulation of vascular resistance via the regulation of the lactone-containing metabolite 5,6-δ-DHTL. RESULTS: In mouse resistance arteries, PON1 was found to be present and active in the endothelial layer. Vascular reactivity experiments revealed that 5,6-δ-DHTL dose-dependently dilates PON1KO mouse mesenteric arteries significantly more than wild type (w.t.) resistance arteries. Pre-incubation with HDL or rePON1 reduced 5,6-δ-DHTL-dependent vasodilation. FACS analyses and confocal microscopy experiments revealed that fluorescence-tagged rePON1 penetrates into human endothelial cells' (ECs') in both dose- and time- dependent manner, accumulate in the perinuclear compartment, and retains its lactonase activity in the cells. The presence of rePON1, but not the presence of PON1 loss-of-lactonase-activity mutant, reduced the Ca2+ influx in the ECs mediated by 5,6-δ-DHTL. CONCLUSION: PON1 lactonase activity in the endothelium affects vascular dilation by regulating Ca2+ influx mediated by the lactone-containing EDHF 5,6-δ-DHTL.

High-density lipoproteins (HDL) composition and function in preeclampsia.

PURPOSE: To evaluate (a) the properties of high-density lipoproteins (HDL)/cholesterol, which include apolipoprotein A-1 (ApoA1) and paraoxonase1 (PON1), both are negative predictors of cardiovascular risk and (b) HDL function, among women with preeclampsia (PE). PE is a multi-system disorder, characterized by onset of hypertension and proteinuria or other end-organ dysfunction in the second half of pregnancy. Preeclampsia is associated with increased risk for later cardiovascular disease. The inverse association between HDL, cholesterol levels and the risk of developing atherosclerotic cardiovascular disease is well-established. METHODS: Twenty-five pregnant women [19 with PE and 6 with normal pregnancy (NP)] were recruited during admission for delivery. HDL was isolated from blood samples. PON1 activity and HDL were analyzed. An in vitro model of endothelial cells was used to evaluate the effect of HDL on the transcription response of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) mRNA expression. RESULTS: PON1 activity (units/ml serum) was lower in the PE group compared to normal pregnancy (NP) (6.51 ± 0.73 vs. 9.98 ± 0.54; P = 0.015). Increased ApoA1 was released from PE-HDL as compared to NP-HDL (3.54 ± 0.72 vs. 0.89 ± 0.35; P = 0.01). PE-HDL exhibited increased VCAM-1 mRNA expression and decreased eNOS mRNA expression on TNF-α stimulated endothelial cells as compared to NP-HDL. CONCLUSIONS: HDL from women with PE reduced PON1 activity and increased ApoA1 release from HDL particles. This process was associated with increased HDL diameter, suggesting impaired HDL anti-oxidant activity. These changes might contribute to higher long-term cardiovascular risks among women with PE.

Paraoxonase 2 prevents the development of heart failure.

BACKGROUND: Mitochondrial oxidation is a major source of reactive oxygen species (ROS) and mitochondrial dysfunction plays a central role in development of heart failure (HF). Paraoxonase 2 deficient (PON2-def) mitochondria are impaired in function. In this study, we tested whether PON2-def aggravates HF progression. METHODS AND RESULTS: Using qPCR, immunoblotting and lactonase activity assay, we demonstrate that PON2 activity was significantly decreased in failing hearts despite increased PON2 expression. To determine the cardiac-specific function of PON2, we performed heart transplantations in which PON2-def and wild type (WT) donor hearts were implanted into WT recipient mice. Beating scores of the donor hearts, assessed at 4 weeks post-transplantation, were significantly decreased in PON2-def hearts when compared to WT donor hearts. By using a transverse aortic constriction (TAC) model, we found PON2 deficiency significantly exacerbated left ventricular remodeling and cardiac fibrosis post-TAC. We further demonstrated PON2 deficiency significantly enhanced ROS generation in heart tissues post-TAC. ROS generation was measured through dihydroethidium (DHE) using high-pressure liquid chromatography (HPLC) with a fluorescent detector. By using neonatal cardiomyocytes treated with CoCl2 to mimic hypoxia, we found PON2 deficiency dramatically increased ROS generation in the cardiomyocytes upon CoCl2 treatment. In response to a short CoCl2 exposure, cell viability and succinate dehydrogenase (SDH) activity assessed by MTT assay were significantly diminished in PON2-def cardiomyocytes compared to those in WT cardiomyocytes. PON2-def cardiomyocytes also had lower baseline SDH activity. By using adult mouse cardiomyocytes and mitochondrial ToxGlo assay, we found impaired cellular ATP generation in PON2-def cells compared to that in WT cells, suggesting that PON2 is necessary for proper mitochondrial function. CONCLUSION: Our study suggests a cardioprotective role for PON2 in both experimental and human heart failure, which may be associated with the ability of PON2 to improve mitochondrial function and diminish ROS generation.

[Paraoxonase: The Universal Factor of Antioxidant Defense in Human Body].

The paraoxonase (PON) gene family includes three members: PON1, PON2, and PON3 aligned in tandem on chromosome 7 in humans. All PON proteins share considerable structural homology and have the capacity to protect cells from oxidative stress; therefore, they have been implicated in the pathogenesis of several inflammatory diseases, particularly atherosclerosis. Increased production of reactive oxygen species as a result of decreased activities of mitochondrial electron transport chain complexes plays a role in the development of many inflammatory diseases, including atherosclerosis. PON1 and PON3 proteins can be detected in plasma and reside in the high-density lipoprotein fraction and protect against oxidative stress by hydrolyzing certain oxidized lipids in lipoproteins, macrophages, and atherosclerotic lesions. Paraoxonase 2 (PON2) possesses antiatherogenic properties and is associated with lower ROS levels. PON2 is involved in the antioxidative and anti-inflammatory response in intestinal epithelial cells. In contrast to PON1 and PON3, PON2 is cell-associated and is not found in plasma. It is widely expressed in a variety of tissues, including the kidney, and protects against cellular oxidative stress. Overexpression of PON2 reduces oxidative status, prevents apoptosis in vascular endothelial cells, and inhibits cell-mediated low density lipoprotein oxidation. PON2 also inhibits the development of atherosclerosis, via mechanisms involving the reduction of oxidative stress. In this review we explore the physiological roles of PON in disease development and modulation of PONs by infective (bacterial, viral) agents.

Paraoxonase 3 inhibits cell proliferation and serves as a prognostic predictor in hepatocellular carcinoma.

Paraoxonase 3 (PON3) exerts prominent anti-inflammation and anti-oxidation properties mainly at the cellular level, and is primarily expressed in the liver. However, its role in HCC remains unexplored. Here, we investigated the expression pattern, clinical significance, and function of PON3 in HCC. PON3 mRNA and protein levels were respectively determined in two large cohorts using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) of tissue microarray. We found that PON3 was downregulated in most HCCs. Kaplan-Meier and log-rank test showed that PON3 downregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in all HCC patients, especially early-stage HCC patients. Cox regression analysis revealed that the PON3 downregulation was an independent risk factor for RFS and OS. Gain- and loss-of-function experiments revealed that PON3 suppressed cell proliferation in vivo and in vitro, which was attributed to its cell-cycle arrest effect. In addition, microarray analysis showed that some pro-proliferative genes were elevated when PON3 was knockdown, and these genes possibly involved in the underlying mechanisms. In conclusion, our studies reveal the cell proliferation inhibitory function of PON3 and offer a potential prognostic predictor and therapeutic target for HCC.

Paraoxonase 1-treated oxLDL promotes cholesterol efflux from macrophages by stimulating the PPARγ-LXRα-ABCA1 pathway.

Here, we investigate the mechanism through which paraoxonase 1 (PON1) may regulate cholesterol efflux. Pretreatment of oxLDL with PON1 (oxLDL-PON1) contributed to the formation of LysoPC. In J774 macrophages, oxLDL-PON1 increased cholesterol efflux by more than 47% compared to oxLDL alone. oxLDL-PON1 significantly increased mRNA and protein expression of ABCA1 and ABCG1, as well as of PPARγ and LXRα compared to oxLDL alone. Intraperitoneal injection of oxLDL-PON1- or LysoPC-treated J774 macrophages significantly increased the fecal elimination of macrophage-derived cholesterol in these mice. Our results suggest that PON1 stimulates cholesterol efflux via a mechanism that involves oxidized phospholipid hydrolysis.

Paraoxonase 1 Activity Is Modulated by the rs662 Polymorphism and IgG Anti-High-Density Lipoprotein Antibodies in Patients With Rheumatoid Arthritis: Potential Implications for Cardiovascular Disease.

OBJECTIVE: Paraoxonase 1 (PON-1) is a high-density lipoprotein (HDL)-associated antioxidant enzyme that plays an important role in HDL-mediated cardioprotection. Although genetic polymorphisms are known to modulate PON-1 activity, its involvement in cardiovascular disease (CVD) in rheumatoid arthritis (RA) is controversial, suggesting that other factors may modulate its function. Since anti-HDL antibodies have been found to be related to an impaired lipid profile and occurrence of CVD in RA, this study was undertaken to examine the associations between PON-1 activity, anti-HDL antibodies, and CVD according to PON1 genetic variants in patients with RA. METHODS: Serum PON-1 activity, using paraoxon as substrate, and IgG anti-HDL antibodies were quantified in 212 RA patients and 110 healthy controls. The PON1 rs662 genotype (Q>R) was determined with TaqMan probes. An additional group of 13 biologics-naive patients with RA was prospectively followed up for 3 months. RESULTS: PON-1 activity was decreased in RA patients compared to healthy controls (P = 0.005), and an effect of the rs662 genotype was noted in both groups, with Q/Q homozygotes exhibiting the lowest PON-1 activity. The distribution of rs662 genotypes did not differ between RA patients and healthy controls (P = 0.215). In patients carrying the Q/Q genotype, anti-HDL antibodies were associated with impaired PON-1 activity (P = 0.010), and levels of anti-HDL antibodies were associated with decreased HDL levels (r = -0.680, P < 0.001) and higher prevalence of cardiovascular events, as determined in univariate and multivariate models. Furthermore, change in anti-HDL antibody levels upon tumor necrosis factor blockade was an independent predictor of improved PON-1 activity (ß = -0.369, 95% confidence interval -0.669, -0.069; P = 0.024). CONCLUSION: PON-1 activity is impaired in RA in association with the rs662 genotype and anti-HDL antibodies, the latter being recognized as a pivotal player in the link between rs662 and CVD in patients with RA.

Disfuncionalidad antioxidante de las lipoproteínas de alta densidad (HDL) en pacientes diabéticos descompensados / Antioxidant dysfunctionality of high-density lipoproteins (hdl) in decompensated diabetic patients

Introducción: las lipoproteínas de alta densidad (HDL) tienen un importante efecto protector cardiovascular mediado por su función durante el transporte reverso del colesterol, así como por otras actividades, incluyendo una significativa acción antiinflamatoria y antioxidante. La funcionalidad antiinflamatoria y antioxidante de las HDL está alterada en los pacientes diabéticos crónicos estables, aunque no existe mayor información en caso de una crisis hiperglicémica. Objetivo: determinar si durante un estado de descompensación diabética aguda las partículas de HDL exhiben un deterioro de su función antioxidante y si esta logra recuperarse una vez resuelto el cuadro agudo. Métodos: la actividad antioxidante de las HDL se midió mediante un ensayo de fluorescencia in vitro en muestras plasmáticas de pacientes diabéticos con descompensación aguda obtenidas tanto al ingreso, alcanzada la resolución intrahospitalaria del evento agudo, así como en un control ambulatorio post-hospitalización. Como comparación, se analizaron partículas de HDL de algunos sujetos sanos como condición control. Resultados: la actividad antioxidante de las HDL en pacientes con descompensación diabética aguda fue significativamente menor a la observada en el grupo control sano, y esta se fue recuperando progresivamente hasta normalizarse en el momento del control ambulatorio. La crisis hiperglicémica también demostró una baja actividad plasmática de la enzima antioxidante paraoxonasa-1, la cual aumentó significativamente en el control ambulatorio. Conclusión: las partículas de HDL presentes en pacientes con una descompensación diabética aguda presentan reducción significativa y reversible de su capacidad antioxidante, probablemente como consecuencia de una alteración en la actividad de la paraoxonasa-1 (AU)

Introduction: high density lipoproteins (HDL) have important cardiovascular protective effects mediated by their role in reverse cholesterol transport as well as other functional activities, including significant anti-inflammatory and antioxidant properties. It has been shown that HDL anti-inflammatory and antioxidant functions are defective in metabolically stable diabetic patients; however they have not been evaluated during a hyperglycemic crisis. Aim: to determine the antioxidant activity of HDL during a severe diabetic decompensation and to analyze whether this function is restored after resolution of the acute event. Methods: the antioxidant activity of HDL was measured in vitro by a fluorescent assay in plasma samples obtained from diabetic patients with acute metabolic decompensation at admission, recovery within the hospital and follow-up in ambulatory care. As a comparison, HDL particles from some healthy subjects were used as controls. Results: the HDL antioxidant function was significantly reduced in patients during an acute diabetic decompensation compared with the control group, and was gradually restored reaching normal values during the ambulatory follow-up. Hyperglycemic crisis also showed low plasma paraoxonase-1 activity, which increased significantly during at follow-up. Conclusion: HDL particles isolated from acute diabetic descompensated patients exhibit a significantly and reversibly low antioxidant capacity, which is probably due to a reduced paraoxonase-1 activity (AU)

Association Between Paraoxonase Gene Polymorphisms and Intracerebral Hemorrhage in a Korean Population.

The human paraoxonase (PON) gene family includes three members: PON1, PON2, and PON3. PON, which prevents the oxidative modification of lipoproteins, has been implicated as a potential risk factor of the cerebrovascular disease. In this study, we investigated associations between coding region single-nucleotide polymorphisms (cSNPs) of PON1, PON2, and PON3 genes and intracerebral hemorrhage (ICH) in a Korean population. Six cSNPs [rs13306698 and rs662 for PON1; rs12026 and rs7493 for PON2; rs13226149 and rs1053275 for PON3] were genotyped using direct sequencing in 145 ICH patients and 372 control subjects. Of the six cSNPs, rs12026 and rs7493, which were in complete linkage disequilibrium, were associated with ICH in log-additive (GC vs. CC vs. GG, p = 0.0008, OR = 0.53, 95 % CI = 0.36-0.78) and dominant models (GC/CC vs. GG, p = 0.0006, OR = 0.47, 95 % CI = 0.30-0.73). In addition, rs13226149 was associated with ICH in log-additive model (GA vs. AA vs. GG, p = 0.0033, OR = 0.58, 95 % CI = 0.39-0.84). In the allele frequency analysis, the C alleles of rs12026 and rs7493 and the A allele of rs13226149 were also shown to contribute to the decreased risk of ICH (p = 0.001, OR = 0.55, 95 % CI = 0.38-0.80 in rs12026 and rs7493; p = 0.003, OR = 0.58, 95 % CI = 0.40-0.83 in rs13226149). These results suggest that PON genes may be involved in the susceptibility of ICH.

Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles.

Human PON1 is a HDL-associated lipolactonase capable of preventing LDL and cell membrane oxidation and is therefore considered to be atheroprotective. PON1 contributes to the antioxidative function of HDL and reductions in HDL-PON1 activity, prevalent in a wide variety of diseases with an inflammatory component, are believed to lead to dysfunctional HDL which can promote inflammation and atherosclerosis. However, PON1 is multifunctional and may contribute to other HDL functions such as in innate immunity, preventing infection by quorum sensing gram negative bacteria by destroying acyl lactone mediators of quorum sensing, and putative new roles in cancer development and the promotion of healthy ageing. In this review we explore the physiological roles of PON1 in disease development, as well as PON1 gene and protein structure, promiscuous activities and the roles of SNPs and ethnicity in determining PON1 activity.