Paraoxonase 1 and Chronic Obstructive Pulmonary Disease: A Meta-Analysis

Oxidative stress is a driving factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). While paraoxonase 1 (PON1) is an antioxidant enzyme and a potential biomarker of this disease, data regarding the status of PON-1 in COPD are inconclusive. In this regard, to shed light on this issue, we performed a meta-analysis of data on PON1 activity in COPD. Electronic databases (MEDLINE, Embase and CENTRAL) were searched for available studies on PON1 activity in patients with stable COPD published before October 2021. A meta-analysis was performed using random-effects models. Twelve studies (12 studies on paraoxonase and three on arylesterase) were identified. Patients with COPD had lower levels of paraoxonase activity (standard mean difference [SMD] −0.77, 95% confidence interval [CI] −1.35 to −0.18) and arylesterase activity (SMD −1.15, 95% CI −1.95 to −0.36) in comparison to healthy controls. In subgroup analyses, paraoxonase activity was lower in patients of studies as consisted of mainly non-severe COPD (SMD −1.42, 95% CI −2.04 to −0.79) and, by contrast, slightly higher in patients of studies including severe COPD (SMD 0.33, 95% CI 0.02 to 0.64) in comparison to healthy controls. Arylesterase activity showed a similar trend. Overall, PON1 activity was lower in patients with COPD, suggesting that PON1-related antioxidant defense is impaired in COPD. Future studies are warranted.

Paraoxonase in women with hypertension of different reproductive age. Relationship with cardio-metabolic risk factors

Annotation. Paraoxonase is a high-density lipoprotein-associated pleiotropic enzyme able to detoxify proatherogenic compounds such as oxi-low-density-lipoproteins and homocysteine-thiolactone. Low paraoxonase activity is likely to be involved in the development of cardiovascular diseases. The aim of the study – to investigate the relationship between paraoxonase activity, structural and functional markers of the heart and blood vessels, cardio-metabolic risk factors in women with hypertension of different reproductive age. The study included 193 women aged 32-70 years (55.4±0.68 years) with essential stage II hypertension. The control group consisted of 46 healthy women. The arylesterase activity of paraoxonase (EC 3.1.1.2) in blood serum was determined by spectrophotometric method. Statistical processing of the obtained results was performed in the application package SPSS22 (© SPSS Inc.). The mean and standard error of the mean (M ± m) were calculated. Student's t-test was used. Pearson correlation analysis was performed at p <0.05. It was found that in women with hypertension there was a significant decrease (16%) in serum paraoxonase activity, compared with healthy women. Low paraoxonase activity was registered in 33.3% of premenopausal patients and 56.7% of postmenopausal patients (p˂0.05) and was associated with serum estradiol levels (r=0.33, 0.41, p<0.05). Low paraoxonase activity was associated with aberrant levels of lipids, homocysteine, obesity, metabolic syndrome, increased left ventricular mass index and carotid intima-media thickness, decreased brachial artery endothelium-dependent vasodilation. Thus, the decrease in serum paraoxonase activity in women with hypertension is related with the reproductive age of patients and the development of unfavorable metabolic, structural and functional changes in the heart and blood vessels.

POS0442 RELATIONSHIP BETWEEN PARAOXONASE-1 GENOTYPE, ACTIVITY AND MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING TOFACITINIB

Background:Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme with paraoxonase, lactonase and arylesterase activities.1 PON1 contributes to the antioxidant properties of HDL, and is being investigated for its atheroprotective properties.1 Patients (pts) with rheumatoid arthritis (RA) who are homozygous for the RR genotype of the Q192R gene polymorphism on PON1 (rs662) have increased paraoxonase activity, and lower risk of carotid plaques, vs those with QQ or QR genotypes.2 Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA.Objectives:To investigate the relationship between PON1 genotype/activity and risk of major adverse cardiovascular events (MACE) in the tofacitinib RA clinical programme.Methods:In this post hoc analysis, data were pooled from pts enrolled in nine Phase 2/3 studies of tofacitinib in RA. Enzyme activities in pt plasma samples were measured at individual study baseline (BL) and at follow-up visits using three substrates: paraoxon (paraoxonase activity), dihydrocoumarin (lactonase activity) and phenylacetate (arylesterase activity). The effect of the PON1 Q192R genotype (QQ, QR or RR) on BL paraoxonase/lactonase/arylesterase activity was assessed using linear regression for each study, with age and sex as covariates, and then fixed-effect meta-analysis assessed effects across studies. The risk of MACE by enzyme activity was determined using Cox proportional hazards regression stratified by clinical studies. Univariate regression against BL enzyme activity and other risk factors, as well as both minimally and fully adjusted multivariable regressions against time-varying enzyme activity, are presented.Results:The analysis included 1969 pts with RA who received ≥1 dose of tofacitinib and had PON1 activity measures available at BL; 39 pts had ≥1 MACE event. Compared with the QQ genotype, the RR genotype had a highly significant positive association with BL paraoxonase activity, and a highly significant negative association with BL lactonase and arylesterase activity (Table 1). A univariate analysis identified several BL covariates significantly associated with risk of MACE (Figure 1a). Time-varying models found a highly significant association of increased paraoxonase activity over time with lower risk of future MACE, even after controlling for low-density lipoprotein or HDL cholesterol levels, and other traditional cardiovascular (CV) risk factors identified in univariate analysis (Figure 1b), with similar findings for lactonase and arylesterase (data not shown).Table 1.Effect of PON1 genotype (RR vs QQ) on BL enzyme activitynEstimate95% CIp valueCochran’s Q testParaoxonase12291.0350.93, 1.141<0.00010.209Lactonase1188-0.375-0.505, -0.246<0.00010.025Arylesterase1231-1.016-1.382, -0.649<0.00010.251Fixed-effects model; estimate >0 favours RR genotype and <0 favours QQ genotypeBL, baseline; CI, confidence intervalConclusion:Higher activity of the HDL-associated protein PON1 over time was associated with a significantly reduced risk of future MACE in pts with RA receiving tofacitinib, after controlling for traditional CV risk factors and cholesterol levels. Further investigation of PON1 as a novel functional lipid biomarker to assess CV risk in pts with RA is warranted.References:[1]Mackness & Mackness. Gene 2015; 567: 12-21.[2]Charles-Schoeman et al. Arthritis Rheum 2013; 65: 2765-2772.Acknowledgements:Study sponsored by Pfizer Inc. Medical writing support was provided by Jennifer Higginson, CMC Connect, and funded by Pfizer Inc.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer Inc, Regeneron-Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Craig Hyde Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Shunjie Guan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Neil Parikh: None declared, Jennifer Wang: None declared, Ani Shahbazian: None declared, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Andrews Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Influence of phospholipase A2 and paraoxonase activity on endothelial function changes in various forms of coronary artery disease

Funding Acknowledgements Type of funding sources: None. High phospholipase A2 activity is associated with atherosclerotic disorders of the arteries, while paraoxonase activity decreases with increasing atherogenic plasma activity. The purpose is to study the relationship between the combined effect of phospholipase A2 and paraoxonase activity on vascular endothelial dysfunction in various forms of coronary artery disease. We examined 152 men 52.5 ± 0.8 years, including 53 - STEMI, 32 - NSTEMI, 67 - chronic chronic coronary syndromes (CCS). Methods. All patients were examined for endothelial function of the brachial artery with a test for reactive hyperemia and vasodilation with exogenous NO, as well as determination of phospholipase A2 activity and plasma paraoxonase activity. All studiies conform to the principles of the Declaration of Helsinki of the World Medical Association. Results. Dynamics evaluation of endothelial function indicates a significant increase in blood flow in the brachial artery after compression in the NSTEMI group, but a decrease in the STEMI group after vasodilation of exogenous NO. Analysis of phospholipase A2 activity and paraoxonase showed an increasing the first in STEMI group compared to NSTEMI one and CCS while decreasing the second in the corresponding groups (Tab. 1). The results of the study confirm the association of increased activity of phospholipase A2 with vascular disorders severity, the correction of which should be considered a priority in prospective studies. The fact of reducing the activity of paraoxonase should be considered in the correction treatment of vascular disorders. Tab. 1 CCS NSTEMI STEMI LSD criteria D% 7,48 ± 0,39 6,65 ± 0,54 6,77 ± 0,62 {1-2} V% 54,71 ± 1,01 51,13 ± 1,92 42,16 ± 3,29 p1 &lt; 0,0001 p2 = 0,010 {3} / {1, 2} D% (NO) 10,35 ± 0,47 8,24 ± 0,96 10,28 ± 0,98 {1, 2} V% (NO) 55,60 ± 1,12 37,71 ± 3,72 p1 &lt; 0,0001 28,12 ± 3,94 p1 &lt; 0,0001 {1} / {2, 3} sPA2 1,12 ± 0,03 1,25 ± 0,04 p1 &lt; 0,0001 1,34 ± 0,04 p1 &lt; 0,0001 {1} / {2, 3} PAO 0,54 ± 0,01 0,50 ± 0,01 0,44 ± 0,01 p1 &lt; 0,0001 p2 &lt; 0,0001 {1} / {2,3} D% - diameter of brachial artery after compression. V% - blood flow velocity after compression. sPA2 -phospholipase A2. PAO - paraoxanase. p - reliability on Sheffe"s criteria.

Effect of Menopause and Hypertriglyceridemia on Lipid Transfer and Paraoxonase Activity in Diabetic Women

Introduction. The high prevalence of type 2 diabetes mellitus (DM2) and cardiovascular atherosclerotic complications are increasing in women after menopause. Studies have shown that the in vitro transfer of lipids to HDL and the determination of paraoxonase activity are robust methods to HDL functional evaluation. Objective. This study aimed at observing the difference in the paraoxonase activity and the transfer of lipids to HDL in menopause DM2-women with hypertriglyceridemia. Material and Methods. Blood samples were collected from 63 female diabetic patients with hypertriglyceridemia, matched by age group and comorbidities. The artificial nanoparticle (LDE) determined the transfer to HDL by liquid scintillation, as well the activity of paraoxonase by spectrophotometry. Results. There was a difference in paraoxonase-1 activity between the groups due to the high hypertriglyceridemia, regardless of the menopausal or non-menopausal condition. And, there was also a difference in phospholipid transfer between groups. Discussion. This study showed the presence of alterations in the activity of paraoxonase and phospholipid and cholesterol ester transfer to HDL in menopausal women groups when compared to those non-menopausal groups. Conclusion. This study showed that both diabetic hypertriglyceridemia and menopause influence the HDL metabolism, and the action of paraoxonase.

Paraoxonase 1 and Non-Alcoholic Fatty Liver Disease: A Meta-Analysis

Oxidative stress is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, reliable biomarkers of NAFLD in relation to oxidative stress are not available. While paraoxonase 1 (PON1) is an antioxidant biomarker, there appears to be mixed data on PON-1 in patients with NAFLD. The aim of this meta-analysis was to assess the current data on PON1 activity (i.e., paraoxonase and arylesterase) in patients with NAFLD. A PubMed, CENTRAL, and Embase search identified 12 eligible articles. In the meta-analysis, the paraoxonase activity was low in patients with NAFLD (mean difference (MD) −27.17 U/L; 95% confidence interval (CI) −37.31 to −17.03). No difference was noted in the arylesterase activity (MD 2.45 U/L; 95% CI −39.83 to 44.74). In a subgroup analysis, the paraoxonase activity was low in biopsy-proven nonalcoholic steatohepatitis (MD −92.11 U/L; 95% CI −115.11 to −69.11), while the activity in NAFLD as diagnosed by ultrasonography or laboratory data was similar (MD −2.91 U/L; 95% CI −11.63 to 5.80) to that of non-NAFLD. In summary, the PON1, especially paraoxonase, activity could be a useful biomarker of NAFLD. Further studies are warranted to ascertain the relevance of PON1 measurements in patients with NAFLD.

Chronic nandrolone decanoate administration effects on antioxidant parameters in Wistar rats

Chronic nandrolone decanoate exposure is associated with a modified redox status in the favor of oxidants. Paraoxonase and myeloperoxidase activities are considered sensitive biomarkers of oxidative stress and inflammation, being also predictors for coronary artery disease. The aim of our study was to investigate the impact of chronic nandrolone administration on paraoxonase and myeloperoxidase activities in Wistar rats. 16 Wistar rats were divided into two groups (n=8 for each of them): nandrolone decanoate (A) treated group and control group (C). After 12 weeks of nandrolone decanoate administration we analyzed several plasma oxidative stress parameters: TROLOX Equivalent Antioxidant Activity, paraoxonase and myeloperoxidase activities, total thiols, and advanced oxidation protein products. Our results showed a significant decreased total antioxidant activity in nandrolone treated group compared with controls, while paraoxonase activity and total thiols levels were significantly increased. Myeloperoxidase activity and advanced oxidation protein products were not significantly different between the two studied groups. In conclusion decreased plasma total antioxidant activity suggested increased oxidative stress induced by chronic high doses of nandrolone. Despite oxidative stress presence high doses of nandrolone induced also increased plasma paraoxonase activity.