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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 1  |  Page : 82-88

Paraoxonase-1 enzyme activity in rheumatoid arthritis patients: association with carotid intima-media thickness?


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia Governorate, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia Governorate, Egypt

Date of Submission18-Jan-2016
Date of Decision01-Mar-2016
Date of Acceptance07-Mar-2016
Date of Web Publication25-Mar-2020

Correspondence Address:
Aly M El-Kholy
Sahel Algawaber Village, Alshohadaa City, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_5_16

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  Abstract 


Objectives
The aim was to find the relationship of biochemical determinants of paraoxonase-1 (PON1) enzyme activity with carotid intima-media thickness (IMT) as a surrogate marker of atherosclerotic cardiovascular (CV) disease risk in patients with rheumatoid arthritis (RA).
Background
There is strong correlation between patients with RA and CV morbidity and mortality that cannot be explained by traditional risk factors alone. And this could be due to abnormal function of high-density lipoproteins (HDL). HDL promotes cholesterol efflux, as well as protects low-density lipoprotein (LDL) against oxidation, and this ability has been referred to as an 'anti-inflammatory' function because the lipid oxidation products derived from LDL are highly proinflammatory. PON1 is an HDL-associated enzyme that promotes antioxidant and anti-inflammatory properties of HDL by preventing the formation of oxidized LDL and inactivating oxidized phospholipids.
Patients and methods
The authors conducted a case–control study, including 30 RA patients and 20 controls, enrolled in Menoufia, Egypt. B-mode Doppler ultrasound imaging to measure carotid IMT, C-reactive protein (CRP), erythrocyte sedimentation rate, lipid profile, and PON1 activity were measured.
Results
RA patients tended to be more dyslipidemic as evidenced by decreased HDL and increased total cholesterol, tryglycerides (TGD), and LDL, which showed increased carotid IMT and decreased PON1 activity than the control group. Patients with carotid plaque tended to be more dyslipidemic and plasma PON1 activity tended to be lower than in patients without carotid plaque. A significant correlation between plasma PON1 activity and systemic inflammation as measured by the erythrocyte sedimentation rate and hsCRP level was noted.
Conclusion
Our data suggest that the lower the activity of PON1, the higher the atherosclerotic CV disease risk in RA patients, as assessed by the presence of carotid plaque. There is a significant correlation between plasma PON1 activity and systemic inflammation in RA patients. Higher hsCRP levels were associated with lower PON1 activity.

Keywords: atherosclerotic cardiovascular disease, carotid intima-media thickness, carotid plaque, paraoxonase-1 enzyme, rheumatoid arthritis


How to cite this article:
Shoeib SA, Tawfeek AR, Fathy WM, Nouh MZ, El-Kholy AM. Paraoxonase-1 enzyme activity in rheumatoid arthritis patients: association with carotid intima-media thickness?. Menoufia Med J 2020;33:82-8

How to cite this URL:
Shoeib SA, Tawfeek AR, Fathy WM, Nouh MZ, El-Kholy AM. Paraoxonase-1 enzyme activity in rheumatoid arthritis patients: association with carotid intima-media thickness?. Menoufia Med J [serial online] 2020 [cited 2020 Aug 14];33:82-8. Available from: http://www.mmj.eg.net/text.asp?2020/33/1/82/281309


  Introduction Top


There is strong correlation between patients with rheumatoid arthritis (RA) and cardiovascular (CV) morbidity and mortality that cannot be explained by traditional risk factors alone[1]. And this could be due to the abnormal function of high-density lipoproteins (HDL)[2]. HDL promotes cholesterol efflux, as well as protects low-density lipoprotein (LDL) against oxidation[3], and this ability has been referred to as an 'anti-inflammatory' function because the lipid oxidation products derived from LDL are highly proinflammatory[4]. Paraoxonase 1 (PON1) is an HDL-associated enzyme that promotes antioxidant and anti-inflammatory properties of HDL by preventing the formation of oxidized LDL and inactivating oxidized phospholipids[5]. Lower PON1 enzyme activity that depends on genetic polymorphisms has been associated with CV risk in the general population[6].


  Patients and Methods Top


This study was carried at the Internal Medicine Department, Menoufia University Hospital; it follows the ethical standards of our institution. Informed consents from all patients and controls were obtained in accordance with the local ethics committee from May 2015 till December 2015. The studied groups are divided into two groups. Group I included 30 RA patients and group II included 20 healthy individuals of matched sex and age who served as controls. All RA patients met the American College of Rheumatology 2010 revised classification criteria.

All participants underwent full history taking and clinical examination. Disease activity in RA patients was determined by a count of tender and swollen joints (28 joints assessed), and patient's pain, fatigue, and stiffness assessments. Also they underwent laboratory investigations including first, markers of inflammation, including high--sensitive C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR); second, lipid profile: total cholesterol (TC), triglycerides, LDL, HDL; and third, carotid ultrasound imaging. A standard protocol including B (brightness)–mode grayscale, color, and spectral Doppler techniques was used to study the carotid arteries of all participants. Bilateral common carotid arteries (CCAs), internal carotid arteries, external carotid arteries, and carotid bulbs were examined. The presence of atherosclerotic plaque was defined as increased arterial medial wall thickness exceeding that of the surrounding wall by at least 50% [Figure 1]. Intima-medial thickness (IMT) of the far wall of the distal CCA was measured 1 cm proximal to the flow divider (the area where the column of blood in the CCA splits into the internal carotid artery and external carotid artery). Measurements were obtained at end diastole, and the mean of three measurements was used for the CCA-IMT value. Fourth, determination of PON1 activity: PON1 activity was quantified using paraoxon as the substrate and measuring the increase in absorbance at 405 nm due to the formation of 4-p-nitrophenol over a period of 12 min (at 20-s intervals).
Figure 1: Ultrasound duplex image of the carotid plaque.

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For the control group we had assessed the lipid profile, PON1 activity, and carotid ultrasound imaging.

Specimen collection and preparation for analysis

Isolate the test samples soon after collecting, then analyze immediately (within 2 h) or in aliquots and store at −20°C for long time. Avoid multiple freeze–thaw cycles. Serum: coagulate at room temperature for 10–20 min, then centrifuge at a speed of 2000–3000 rpm. for 20 min to collect the supernatant. If precipitation appeared, centrifuge again.

Plasma: Collect plasma using EDTA or citrate as an anticoagulant, and mix for 10–20 min, then centrifuge at a speed of 2000–3000 rpm for 20 min of collection. If precipitation occurs, centrifuge again.

Limitation of the procedure

  1. Coagulate blood samples completely, then centrifuge, and avoid hemolysis and particle
  2. NaN3 cannot be used as a test sample preservative, since it is the inhibitor for horseradish peroxidase (HRP)
  3. After collecting samples, analyze immediately or in aliquots and store frozen at −20°C. Avoid repeated freeze–thaw cycles.


Expected values

It is recommended that each laboratory establishes its own expected ranges, which may be unique to the population it serves, depending on its demographics.

Statistical evaluations

We used the Statistical Package of the Social Sciences (SPSS, IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.) to perform the analysis. Categorical data were presented as numbers and percentages and continuous variables as means ± SD. χ2-test was used for categorical variables and whenever one cell of the expected was equal to or less than 5; Fisher's exact test was done. Student's t-test or Mann–Whitney test was used as appropriate for comparison between two quantitative variables. For quantitative data:

  1. One-way analysis of variance test is used for comparison between more than two groups having quantitative variables
  2. Kruskal–Wallis test (nonparametric test) is a test of significance used for comparison between more than two non-normally distributed groups having quantitative variables
  3. Spearman's correlation coefficient test (r-test) is a test of significance used to study the correlation between non-normally distributed quantitative variables. Correlation coefficient test (r-test) results may be positive (+) correlation or negative (−) correlation. It is used to quantify the strength of the linear relationship between two variables:


  1. P greater than 0.05 was considered statistically nonsignificant
  2. P less than 0.05 was considered statistically significant
  3. P less than or equal to 0.001 was considered statistically highly significant.



  Results Top


Demographic and clinical characteristics and laboratory findings

[Table 1] shows that there were no differences between the studied groups regarding age, sex, BMI, hypertension, or smoking, while there was high prevalence of diabetes mellitus (DM), carotid plaque, and family history of atherosclerotic cardiovascular disease (ASCVD) among the patient group. Mean ± SD of serum TC (210.6 ± 50.3), TGD (186 ± 49.4), and LDL-c (132.1 ± 36.2) were higher and HDL-C (44.1 ± 8.6) was lower in the patient group than the control. Also, rheumatoid patients showed increased carotid IMT (0.65 ± 0.1) and decreased PON-1activity (17.5 ± 4.2) than the control group.
Table 1: Demographic characteristics and laboratory data of the studied groups

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Clinical characteristics of patients with carotid plaque and of those without are presented in [Table 2].
Table 2: Demographic characteristics and laboratory data of patients with rheumatoid arthritis as regards the presence or absence of carotid plaque

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Patients with plaque were older (53.6 ± 5.8), had positive family history of ASCVD (P = 0.019), and had a greater prevalence of hypertension (P = 0.019) and DM (P = 0.003). Trends toward higher TC (262 ± 35.1), triglycerides (236.5 ± 32.4) and LDL-c levels (168.5 ± 15.9) and lower HDL levels (36.5 ± 4.6) in patients with plaque compared with those without plaque were noted, and these results were statistically significant.

Systemic inflammation measured by mean values of ESR (85.1 ± 25.3) and hsCRP (53 ± 22.1) was significantly higher in patients with carotid plaque compared with those without.

Association of paraoxonase-1 activity with carotid plaque in rheumatoid arthritis patients

To further examine the potential relationship of PON1 to ASCVD risk in RA patients, the paraoxonase assay was used to assess the activity of the PON1 enzyme in the plasma from RA patients. In bivariate analysis [Table 2], mean ± SD plasma PON1 activity tended to be lower in patients with carotid plaque (14.1 ± 2.03 nmoles/ml/min) than in patients without carotid plaque (18.7 ± 4.1 nm/ml/min) and this means that lower plasma PON1 activity was associated with an increased risk of carotid plaque, while higher plasma PON1 activity was associated with a decreased risk of carotid plaque (P < 0.006).

Association of paraoxonase-1 activity with systemic inflammation in rheumatoid arthritis patients

A significant correlation between plasma PON1 activity and systemic inflammation as measured by the ESR (r=−0.47, P = 0.008) and hsCRP (r=−0.473, P = 0.009) levels was noted in this RA cohort [Figure 2]. Higher levels of hsCRP and ESR were associated with decreased PON1 activity [Table 3].
Table 3: Correlation coefficient (r) between paraoxonase-1 and patients parameters

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Figure 2: a) Correlation coefficient of PON1 activity and ESR; (b) correlation coefficient of PON1 activity and CRP; (c) correlation coefficient of PON1 activity and TC; (d) correlation coefficient of PON1 activity and TGD; (e) correlation coefficient of PON1 activity and common carotid IMT; (f) correlation coefficient of PON1 activity and LDL; and (g) correlation coefficient of PON1 activity and HDL. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; PON1, paraoxonase-1; TC, total cholesterol.

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Also, lower levels of TC (r=−0.54, P = 0.002), TGD (r=−0.59, P = 0.001), and LDL-c (r=−0.669, P < 0.001) and higher levels of HDL-C (r=−0.71, P < 0.001) were associated with higher paroxonase-1 activity. Significant negative correlation between common carotid IMT and PON-1 activity was noted (r=−0.45, P = 0.014) [Table 3].


  Discussion Top


RA is a systemic, chronic inflammatory disease that primarily affects joints and leads to pain, deformity, joint destruction, and disability[7]. Patients with RA have a known increased atherosclerotic risk including increased risk of sudden death, which is not fully explained by traditional coronary risk factors[8],[9]. Accelerated atherosclerosis in RA patients could be due to increased inflammatory markers, dyslipidemia, oxidative stress, hyperhomocysteinemia, inactivity, drugs' side effects, and increase in thrombotic factors[10].

Human PON1 is a calcium-dependent esterase closely related with HDL-C-containing Apo-AI that has been shown to confer antioxidant properties to HDL-C by decreasing the accumulation of lipid peroxidation products[11],[12].

HDL-C protects against atherosclerosis by returning excess cholesterol from peripheral tissues back to the liver for reuse or excretion into the bile[11]. Reports suggest an antioxidative function for HDL-C, which may contribute to its antiatherogenic activity[11]. A significant correlation between PON1 activity and HDL has been observed in a study by Calabresi et al.[13].

In this study, we found that RA patients showed a high prevalence of DM, carotid plaque, and positive family history of ASCVD. Wasko et al.[14] have found that the link between type 2 DM and RA could be due to inflammation and controlling inflammation may improve insulin sensitivity and subsequently reduce the risk of developing type 2 DM in RA patients. This may also reduce the risk of CVD in this high-risk group. According to Charles-Schoeman et al.[15], there were no differences in the prevalence of DM among the studied groups.

RA patients, in our study, tended to be more dyslipidemic as evidenced by decreased HDL and increased TC, TGD, and LDL. Our study showed accelerated atherosclerosis process in the form of increased carotid IMT among patients with RA. However, a contradictory study reported that RA does not result in CIM thickening[16]. The mechanisms of RA-related CIM thickening included increased levels of Ox-LDL[17],[18], vWF activity[19], serum mannose binding lectin[20], and PWV[21] as well as increased levels of inflammation markers[19],[22] such as IL17[23], and CRP[24] and lower levels of carotene[18], vitamin D, CD34+ cells[17],[21], and NO[18].

In this study, plaque formation and thickened CIMT are more among diabetic RA patients than nondiabetic rheumatoid patients and this correlation was significant; this was in agreement with the study of Kisiel et al.[25].

Compared with the controls, in this study, RA patients showed a significant decrease of PON1 activity. Such results are in basic agreement to the previous reports of Charles-Schoeman et al.[15], Altinadg et al., Baskol et al., Isik et al., and Tanimoto et al. [10,26–28]. The low PON1 activities in RA patients may result from the damage of PON1 proteins by the action of high amounts of reactive oxygen species produced in RA patients rather than reduced synthesis[29].

Rheumatic patients with plaque are more hypertensive, diabetic, and dyslipidemic with increased inflammatory markers than patients without plaque. Charles-Schoeman et al.[15] have found that patients with plaque were older, more likely to be male, and had a greater prevalence of hypertension. They noted higher levels of TC and triglycerides in patients with plaque compared with those without plaque, although these results were not statistically significant and HDL and LDL cholesterol levels were notably similar between the groups. There were no differences in the prevalence of DM among the groups in their study.

Inflammatory markers among patients with plaque are higher than those without, and these patients showed decreased PON1 activity and these results are in agreement with the study of Charles-Schoeman et al.[15]

According to our study, decreased PON1 activity correlates significantly with plaque formation and increased carotid IMT in the patient group and these results in basic agreement with Charles-Schoeman et al.[15]

Baskol et al.[27] reported that increased ROS levels in RA might result in a pro-oxidation environment, which in turn could result in decreased antioxidant PON1 activity and increased malondialdehyde levels. It has been previously shown that PON1 activity was decreased in some diseases due to ROS pathogenesis under oxidative stress and inflammation conditions such as ulcerative colitis and Behcet's disease[30],[31]. Increased plasma Ox-LDL concentrations have been reported in patients with hypercholesterolemia, end-stage renal disease, diabetes, coronary artery disease, and the metabolic syndrome [29,32–34]. Aviram et al.[33],[34] clearly demonstrated that PON1 inactivation by Ox-LDL resulted in both the reduction of paraoxonase and arylesterase activities and serum paraoxonase activity and HDL susceptibility to oxidation to be inversely correlated. Navab et al.[35] have suggested that paraoxonase activity also protects the antiatherogenic activity of HDL.

The limitation of our study is the relatively small sample size that could limit our ability to generalize the results to RA patients in general. The decrease in the activities of PON 1, which has antioxidant and antiatherogenic properties, might influence both progression of the disease and the development of atherosclerosis in RA. These findings might provide evidence for the fact that early treatment of inflammatory process may reduce the risk of atherosclerosis and atherosclerotic CV events in RA.


  Conclusion Top


The findings of the study suggest that the lower the activity of PON1, the higher the ASCVD risk in RA patients, as assessed by the presence or absence of carotid plaque. This study shows a significant correlation between plasma PON1 activity and systemic inflammation as measured by the hsCRP level in RA patients. Higher hsCRP levels were associated with lower PON1 activity. Further CV outcome studies using a large number of patients are needed to validate the utility of PON1 as a biomarker of ASCVD risk in patients with RA. Our data support previous work implicating abnormal HDL function as a potential mechanism and biomarker of ASCVD risk in RA patients. Further large-scale studies, including studies of both biochemical and genetic determinants of PON1, are warranted to confirm these findings. Identification of alternative pathways that account for the increased CV risk in RA patients remains important so that appropriate primary prevention strategies and targeted CV therapeutics can be developed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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