Abstract
Background and Aims: Patients on maintenance hemodialysis (HD) face an increased risk of atherosclerosis, a crucial problem and the leading cause of cardiovascular morbidity and mortality. This study was designed to evaluate the effects of zinc supplementation on paraoxonase (PON) enzyme activity in patients on HD. Methods: This double-blind randomized controlled trial was conducted from June 2005 to June 2007. Sixty HD patients were enrolled and divided into two groups: treatment (case) and control. The treatment and control groups were treated with 100 mg/day zinc or placebo, respectively, for 2 months. Serum zinc concentration was measured by atomic absorption spectrophotometry. PON activity was evaluated by spectrophotometric method. Lipid profile was determined using commercial kits, and apolipoprotein AI (Apo-AI) and B (Apo-B) levels were measured by commercial immunoturbidimetric kits. Results: In the case group, there was no significant change in the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and Apo-B levels, while the serum levels of high-density lipoprotein (HDL), Apo-AI, and PON activity were significantly increased (p = 0.02). In the control group, although significant increases were observed in the serum levels of TC, TG, and Apo-B (p = 0.009, 0.019, and 0.001, respectively), the serum PON activity was significantly decreased (p = 0.025) and the serum levels of HDL, LDL, and Apo-AI were not changed. At the end of intervention period, the serum level of Apo-AI and PON activity were significantly higher in the case group. Conclusions: Zinc supplementation increased both the activity of PON and the serum level of Apo-AI in the HD patients.
INTRODUCTION
Patients on maintenance hemodialysis (HD) face an increased risk of atherosclerosis, a crucial problem and the leading cause of cardiovascular morbidity and mortality.Citation1 Nutritional parameters are important factors affecting cardiovascular diseases (CVD), especially in HD patients.Citation2,3 It has been shown that vitamin and mineral deficiencies play considerable roles in the development and progression of CVD in patients with chronic renal failure (CRF) or on chronic HD.Citation4–6 Zinc is a trace element associated with antioxidant enzymes activity,Citation7,8 and several studies have demonstrated zinc deficiency as a common problem in patients with CRF or on HDCitation9,10 and that these patients are at a higher risk of CVD due to oxidative stress and inflammation.Citation11,12 In fact, zinc metabolism is affected by impaired renal function, alteration of metabolic balance and dialysis treatment, and increased fecal excretion in patients with CRF or on HD.Citation10
Dyslipidemia, common in patients undergoing HD, is another independent risk factor for CVD.Citation13,14 The main pattern of dyslipidemia in these patients is characterized by elevated concentration of very low-density lipoprotein (VLDL) and intermediate density lipoprotein (IDL).Citation15 Another important factor exposing HD patients to develop premature atherogenesis is activation of reactive oxygen species (ROS) and impairment of antioxidant defense mechanisms.Citation16,17 The association between the low level of antioxidant agents and atherogenesis and CVD mortality has been reported before.Citation18
Contrary to the effect of dyslipidemia and oxidative stress, there is a high-density lipoprotein (HDL)-associated phosphodiesterase, which has been shown to be inversely correlated with the risk of atherosclerosis.Citation19,20 This enzyme, serum paraoxonase (PON), is synthesized mainly by the liver.Citation21 PON has been shown to be associated with triglyceride (TG)-rich lipoproteins [chylomicrons and VLDL-cholesterol (VLDL-C)] as well as with apolipoprotein AI (Apo-AI) and clustering in HDL,Citation22 but not with LDL.Citation23,24 PON has the capacity of hydrolyzing specific oxidized lipids,Citation25–27 thus preventing the induction of inflammatory responses in arterial wall cellsCitation28 and reducing oxidative stress in atherosclerotic lesions.Citation29 PON also protects HDL from oxidation and increases its ability to induce macrophage cholesterol efflux.Citation29,30 In humans, epidemiologic studies have shown that PON has an independent risk factor for coronary disease.Citation31,32
With only limited information available on the effects of zinc on PON activity and on its relation with apolipoproteins and HDL, this study was carried out to determine the effects of zinc supplementation on apolipoproteins AI and B levels, and PON activity in patients on maintenance HD.
SUBJECTS AND METHODS
This clinical trial was carried out in Tabriz University of Medical Sciences (TUMS) from June 2005 to June 2007. Sixty patients, 22 women and 38 men, with mean age of 52.77 ± 12.71 years were enrolled in the study from the Imam Khomeini Hospital.
The protocol of study complied with the Declaration of Helsinki, and was approved by the ethics committee of TUMS. All participants gave informed consent.
All the patients were on maintenance HD for at least 6 months and in stable clinical conditions. The dialysis schedule was not modified during the study period. The exclusion criteria were users of HMG Co-A antagonists, Fibrates, Aspirin, β-blockers, vitamins (except folic acid), Pentoxifylline, fish oil, or other antioxidant drugs in the recent 3 months, active smoking, malnutrition, chronic inflammation (such as diabetic foot, active hepatitis, and HIV infection), symptomatic benign prostate hypertrophy, active coronary artery disease (by symptoms and ECG) in the recent 3 months, candidate for transplantation, and poorly controlled diabetes mellitus (Hb-A1c > 7.5).
The etiology of end-stage renal disease (ESRD) were diabetic nephropathy (n = 14), chronic glomerulonephritis (n = 13), polycystic kidney disease (n = 4), urologic problems (n = 7), chronic interstitial nephropathy (n = 2), and unknown causes (n = 20).
Patients were randomly divided into two groups: treatment and control. The treatment group received 100 mg zinc sulfate plus starch daily, whereas the patients in the control group were given only starch. The period of treatment was 2 months (60 days) for both groups.
Sampling was done before (D0) and 2 months after zinc supplementation (D61). Prior to HD sessions, 5 mL fasting venous blood samples were obtained and collected into empty tubes. Blood samples were immediately stored in ice at 4°C. The serum was then separated from the cells by centrifugation at 3000 rpm for 10 min and the serum divided into two parts. One part was stored in serum form and the another was stored in EDTA containing micro tubes at –79°C until analysis.
Total cholesterol (TC), TG, and HDL levels were determined using commercial reagents (Pars Azmoon, Tehran, Iran) with an automated chemical analyzer (Abbott analyzer, Abbott laboratories, Abbott Park, North Chicago, IL, USA). LDL was calculated using the Friedewald equation.Citation33 The serum Apo-AI and Apo-B levels were assayed by commercially available immunoturbidimetric kits (Pars Azmoon).
PON activity measurements were performed in the absence (basal activity) and presence of NaCl (salt-stimulated activity).Citation34 Briefly, the rate of PON (O,O-diethyl-O-P-nitrophenylphosphate) hydrolysis was measured by the increase of absorbance at 412 nm at 25°C. The amount of generated nitrophenol was calculated from the molar absorptivity coefficient at pH 8, which was 17,100 M−1 cm−1. PON activity was expressed as IU/L serum.
Statistical analyses were performed using SPSS version 13.0 for windows software package (SPSS Inc., Chicago, IL, USA). Results are presented as mean values ± a standard deviation (SD). After determining the distribution of continuous variables by Kolmogorov–Smirnov test, Paired student’s t-test was used to assess the significance of intra-group changes during the intervention period and Independent sample t-test was applied to compare the results of the two groups. Correlation was evaluated by Pearson’s test. The results were considered statistically significant when the p-value was less than 0.05.
RESULTS
Dietary zinc intake, BMI and age were not significantly different between the two groups at the beginning (p = 0.27, p = 0.55, and p = 0.34, respectively) and end of the study (p = 0.36, p = 0.63, and p = 0.34, respectively).
shows the mean values of serum TC, TG, HDL, LDL-C, Apo-AI, Apo-B, and PON activity in the treatment group on days D0 and D61 of the study. There was no significant change in the serum levels of TC, TG, and Apo-B, while the serum levels of HDL, Apo-AI, and PON activity was significantly increased.
Table 1. Lipid profile, Apo-AI, Apo-B levels, and PON activity in the treatment group.
demonstrates the mean values of serum TC, TG, HDL, LDL-C, Apo-AI, Apo-B, and PON activity in the control group on days D0 and D61 of the study. Although significant increases were observed in the serum levels of TC, TG, and Apo-B, the serum PON activity was significantly decreased. The serum levels of HDL, LDL-C, and Apo-AI did not change.
Table 2. Lipid profile, Apo-AI, Apo-B levels, and PON activity in the control group.
Table 3. Comparison of the lipid profile, Apo-AI, Apo-B levels, and PON activity between the treatment and control groups.
The mean values of serum TC, TG, HDL, LDL-C, Apo-AI, Apo-B levels, and PON activity were not different between the treatment and control groups at the beginning of the study. presents the comparison of the TC, TG, HDL, LDL-C, Apo-AI, Apo-B serum levels and the PON activity between the treatment and control groups after the intervention period. Only the serum level of Apo-AI and PON activity were significantly higher in the treatment group, and other evaluated parameters including the serum TC, TG, HDL, LDL, and Apo-B levels were not significantly different between these two groups.
DISCUSSION
Zinc supplementation increased both the activity of PON and the serum level of Apo-AI in the HD patients. In people with CRF, especially patients under chronic HD, vulnerability to oxidative damage may be partly attributed to lower antioxidant micronutrient status and lower trace element levels.Citation10 Impaired zinc status has been reported previously as an aggravating factor in the progression of oxidative damage in many situations. In addition, it has been shown that correcting zinc deficiency leads to decreased lipid peroxidation in several studies,Citation35,36 but this effect of zinc has not been well documented in HD patients. Also, our knowledge of the effects of zinc on PON activity and its relation to apolipoproteins and HDL is scarce.
Patients with CRF are introduced to increased oxidative stress because of the imbalance between pro- and antioxidant systems.Citation37 During HD sessions, a direct increase in blood levels of ROS has been demonstrated using whole blood chemiluminescence.Citation38 ROS has been incriminated in the lipid peroxidation, atherogenesis, and increased risk of CVD in patients with uremia and considered to act by increasing the activity of monocytes and oxidation of LDL.Citation39,40 The latter modification is considered to play a pivotal role in the initiation and progression of atherosclerosis because the oxidized LDL stimulates foam cell formation.Citation40 Deficiencies of antioxidant agents are suggested to exert deleterious effects on the vascular system and are associated with atherosclerosis by leaving the endothelium defenseless against ROS.Citation41 Antioxidants may retard the atherosclerosis and growth of vascular plaques by opposing lipid peroxidation of LDL.Citation42
HDL protects against atherosclerosis by returning excess cholesterol from peripheral tissues back to the liver for reuse or excretion into the bile. Reports also suggest an antioxidant activity for HDL.Citation43 However, HD patients often show lipoprotein abnormalities characterized by reduced HDL and moderate hypertriglyceridemia.Citation44 In such a lipid profile, higher numbers of LDL are exposed to pro-oxidants and therefore, oxidized LDL level increases.Citation45 At the same time, a decreased HDL level plays a weak role in reversing cholesterol transport and has a lower ability to protect LDL against oxidation.Citation45 The underlying mechanism by which HDL inhibits LDL oxidation is partly enzymatic, and there is increasing evidence that PON could be involved in this process.
Human PON is a calcium-dependent esterase closely associated with apolipoprotein A-I and J-containing HDL particles, and hydrolyzes organophosphates and Arylesters.Citation46,47 It has antioxidant properties and decreases the accumulation of lipid peroxidation products.Citation48 Previous studies have indicated that PON can prevent LDL oxidation by hydrolyzing lipid peroxides in the lipoprotein; therefore, it may protect against the development of atherosclerosis.Citation49,50 Various studies show that patients on HD have decreased PON activity, which might indicate a greater risk of premature atherosclerosis and increased vascular disease.Citation51,52
Several studies have consistently shown that PON activity in HD patients is lower than normal people, even when the concentration was adjusted for HDL-cholesterol or apolipoprotein A-I. Also there were no significant associations between serum PON1 concentrations and the PON1 genetic polymorphisms in this group of patients.Citation51,53,54 Dysmetabolism phenomenon linked to uremia results in increased oxidative stress and inflammation, which propose their bidirectional and synergistic relationship as a vicious circle of unwanted events in HD patients.Citation55 In addition, it has been shown that malnutrition along with increased inflammation (higher hsCRP and IL-6) and oxidative stress (lower anti-oxidative) have negative influences on PON1 activity and are associated with higher mortality in patients on long-term HD.Citation56
Lower levels/deficiency of zinc was reported in HD patients.Citation57 Szpanowska et al. have shown a statistically significant lower intake of zinc in the patients under HD.Citation58 Another study has shown that concentration of zinc in erythrocytes is significantly lower in children with CRF even in the pre-dialysis state.Citation59 According to the mentioned literature and also many other investigations, patients under chronic HD are in a state of zinc deficiency.
Zinc is an essential trace element required for the function of more than 300 enzymes and many other biological factors.Citation60,61 The antioxidant properties of zinc have been clearly demonstrated and, for the most part, appear to be independent of the activity of zinc metalloenzymes.Citation62,63 Its antioxidative mechanism can be generally divided into acute and chronic effects. The acute effect involves two mechanisms: protection of protein sulfhydryl or reduction of OH formation from H2O2 through the antagonism of redox-active and transition metals including iron and copper.Citation63 The chronic effect involves exposure of an organism to zinc on a long-term basis, resulting in induction of some other substances that are ultimate antioxidants, such as the metallothionein.Citation63 So, zinc deficiency in patients with uremia and on HD may result in increased oxidative stress which is implicated in accelerated atherogenesis in the presence of CRF.Citation11,12
Our study showed that compensating this deficiency improves patient’s antioxidative defense. Zinc supplementation was associated with the improvement of antioxidant capacity measured by PON activity in the present study. Our findings are in agreement with previous data on the antioxidative effects of zinc supplementation and show that at least a part of this effect is due to increased PON activity. In the present study, we provided the first evidence, to the best of our knowledge, that zinc supplementation in HD patients is one of the effective methods to increase the PON activity.
In conclusion we suggest that zinc supplementation has potential beneficial effects on oxidative stress and exerts an anti-atherosclerotic effect in HD patients, which is effected by increasing PON activity. These results are particularly important in the light of deleterious consequences of oxidative stress in patients under chronic HD.
ACKNOWLEDGMENTS
The Present study was supported by the Drug Applied Research Center of Tabriz University of Medical Sciences.
Declaration of interest: The authors have no proprietary interest in any aspect of this study. The authors had full control of the design of the study, methods used, outcome parameters and results, analysis of data, and production of the written report.
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