Elsevier

Clinical Biochemistry

Volume 41, Issue 13, September 2008, Pages 1067-1073
Clinical Biochemistry

PON1 status is influenced by oxidative stress and inflammation in coronary heart disease patients

https://doi.org/10.1016/j.clinbiochem.2008.06.009Get rights and content

Abstract

Objectives

High-density lipoprotein (HDL) associated paraoxonase 1 (PON1) is an essential component of HDLs' capability to protect low-density lipoproteins (LDL) from oxidative modification and thus to limit the atherosclerotic process. The aim of the current study was to investigate the association between oxidative stress status, indices of inflammation and PON1 status parameters.

Design and methods

We determined the relationship between the oxidative stress status, inflammatory markers and PON1 status parameters in 261 middle-aged subjects: 156 coronary heart disease (CHD) patients and 105 CHD-free subjects (as the control group). The PON1 status involved PON1 activity measurements towards two substrates: paraoxon (POase activity) and diazoxon (DZOase activity) and subsequent PON1Q192R activity phenotype determination.

Results

A statistically significant greater malondialdehyde (MDA) concentration in the RR phenotype subjects compared to QQ subjects within the CHD group was apparent (P < 0.05). Multiple linear regression analysis revealed an independent influence of plasmatic SOD activity (P < 0.05) on POase values and MDA (P < 0.01) and O2radical dot (P < 0.05) on DZOase values. Involvement of inflammatory markers (fibrinogen and hsCRP) in the regression model did not hinder the influence of SOD and MDA on POase and DZOase activities, respectively.

Conclusions

Our CHD patients were in a state of oxidative stress, which was most evident in the RR phenotype group. The QQ phenotype group is associated with the lowest oxidative stress status level and also with a better capacity for anti-oxidative protection. Oxidative stress in CHD patients is maintained by systemic low-grade inflammation, which results in PON1 enzymatic activity exhaustion. Therefore, deeper investigation of an effective anti-oxidative and anti-inflammatory therapy should be necessary in order to increase anti-oxidative potency and improve PON1 status of CHD patients.

Introduction

Throughout recent years PON1 has been demonstrated to protect LDLs against oxidation, to reverse the biological effects of oxidised LDLs and preserve the function of HDLs by inhibiting their oxidation [1], [2], [3]. Deakin and James [4] postulated the theory that factors influencing serum levels of PON1, either genetically or environmentally, would in turn affect the capacity of HDLs to protect LDLs from oxidation and consequently could be linked to the development of atherosclerosis. The latter is the underlying cause of 50% of mortality in the Western world. Therefore, PON1 has been identified and studied as a potential therapeutic agent against atherosclerosis development [5]. Inflammation is an important factor for the initiation and development of the atherosclerotic process. The acute-phase response is linked to atherosclerosis and causes changes to HDL particles. Under inflammatory conditions HDLs loose their ability to participate in reverse cholesterol transport and to protect LDLs from oxidation. These pro-inflammatory changes in HDLs are often caused by down-regulation of hepatic PON1 mRNA [6]. Mackness et al. [7] have demonstrated that the total quantity of lipid peroxides formed when LDLs and HDLs were incubated together under oxidising conditions was less than the total quantity of lipid peroxides formed when LDLs were incubated alone under similar conditions. Studies that have investigated the PON1Q192R polymorphism relationship with cardiovascular diseases are controversial; some of them found positive connection between PON1192RR genotype and coronary disease [8], [9] and some did not find any relationship [10], [11]. PON1 activity has been reported to be decreased in CHD and that its activity is more important than its genotype in CHD prediction [12], [13]. In vitro and in vivo studies suggest that PON1 is the primary enzyme responsible for the anti-oxidant activity of HDLs [14], [15]. Purified human PON1 decreases the generation and accumulation of lipoperoxides in LDLs [7]. In addition, PON1, by destroying oxidised phospholipids, reduces the ability of oxidised LDLs to induce monocyte binding and transmigration and thus inflammation in the vessel wall [1]. There are substrate-dependent differences among PON1Q192R isoforms; the Q variant has a higher diazoxonase activity (DZOase), whereas paraoxonase activity (POase) predominates in the R variant [16]. By measuring the DZOase/POase activity ratios, it is possible to discriminate between the PON1Q192, PON1QR192 and PON1R192 phenotypes.

Since oxidative stress [17] and inflammation [18] are also implicated in CHD development, we decided to determine the possible relationship between PON1 activity and 192 phenotype (QQ, QR and RR), oxidative stress status parameters and inflammatory markers in an attempt to unveil which of the two factors were responsible for lowered PON1 activities in CHD patients.

Section snippets

Study population

We recruited 165 CHD patients and 105 subjects deemed free of CHD. We had to exclude 9 CHD patients due to diabetes (5 patients), renal illness (3 patients) and hepatic illness (1 patient) from our study thereby reducing the total number of patients to 156. The CHD group was recruited from patients that had been referred to the Institute for Cardiology, Clinical Centre of Serbia (Belgrade) for clarification of a provisional diagnosis of ischemic heart disease via coronary angiography. None of

Characteristics of the two study groups

The basic characteristics of the two study groups are shown in Table 1. As we expected CHD patients had a higher percentage of smokers, hypertensive and obese subjects. A significantly higher concentration of both serum TG and lipoprotein (a) [Lp(a)] was evident in the patient group. In contrast, their HDL-C and apoA-I concentrations were lower compared to the control population. There was no significant difference between the patients and the controls when t-C, LDL-C and apoB were compared.

PON1 activities, oxidative stress status and inflammatory markers

Discussion

We have previously reported significantly higher POase and significantly lower DZOase activities in the group of RR phenotype carriers compared with both QR and QQ phenotype groups in both control and CHD populations [13]. We also found significantly lower PON1 activities among all three phenotypes in CHD patients compared to the same phenotype in the control group [13]. CHD patients in our current study were in a state of oxidative stress and diminished anti-oxidative protection (Table 2),

Acknowledgments

We are grateful to Verica Milanovic and Marina Baranin for their excellent support with the laboratory analyses. We also want to thank our colleague Dr. David R. Jones for his help in editing the manuscript. We thank Nikola Spasic for help in Figure preparation. This work was financially supported by a grant from the Ministry of Science and Environmental Protection, Republic of Serbia (Project number 145036B).

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