Dietary Antioxidants and Paraoxonases Against LDL Oxidation and Atherosclerosis Development

Aviram, Michael; Kaplan, Marielle; Rosenblat, Mira; Fuhrman, Bianca

doi:10.1007/3-540-27661-0_9

Cited by 109 publications

(77 citation statements)

References 204 publications

(157 reference statements)

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“…35 PON1 is hypothesized to be an important determinant of the antiatherogenic functions of HDL, which are associated with the enzyme's capability to protect low-density lipoprotein, 36 as well as HDL, 37 from oxidation, to decrease macrophage oxidative status, 38 to stimulate cholesterol efflux from macrophages, 39 to decrease oxidative status in atherosclerotic lesions, 4 and to confer cytoprotection against apoptosis by upregulating macrophage scavenger receptor B-I. 40 Thus, decreased PON1 release from the liver in response to uPA would appear to be deleterious and promoting atherogenesis.…”

Section: Discussionmentioning

confidence: 99%

Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

Khateeb

Kiyan²,

Aviram³

et al. 2012

ATVB

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Objective-The atherosclerotic lesion is characterized by lipid peroxide accumulation. Paraoxonase 1 (PON1) reduces atherosclerotic lesion oxidative stress, whereas urokinase-type plasminogen activator (uPA) increases oxidative stress in atherosclerotic lesions and contributes to the progression and complications of atherosclerosis. We hypothesized that uPA may promote oxidative stress in the arterial wall via modulation of PON1 activity. Because the liver is the main site for PON1 production, in the present study, we tested whether uPA influences PON1 expression in hepatocytes. Methods and Results-HuH7 hepatocytes were incubated in culture with increasing concentrations of uPA. uPA decreased PON1 gene expression and activity in a dose-dependent manner and accordingly suppressed PON1 secretion from hepatocytes. This effect required uPA/uPA receptor interaction. uPA downregulated PON1 gene expression via inactivation of peroxisome proliferator-activated receptor-␥ (PPAR␥) activity, and this effect was dependent on uPA-mediated mitogen-activated protein kinase kinase activation. Mechanistic studies showed that uPA enhanced mitogen-activated protein kinase kinase-PPAR␥ interaction, resulting in PPAR␥ nuclear export to the cytosol. Conclusion-This study provides the first evidence that uPA interferes with PPAR␥ transcriptional activity in hepatocytes, resulting in downregulation of PON1 expression and its secretion to the medium. This may explain, at least in part, the prooxidative effect of uPA in the vascular wall. Key Words: Hepatocytes Ⅲ PPAR␥ Ⅲ paraoxonase 1 (PON1) Ⅲ urokinase T he atherosclerotic lesion is dominated by accumulation of lipid peroxides, along with the progression of early plaque development. 1 Paraoxonase 1 (PON1) is a calciumdependent, high-density lipoprotein (HDL)-bound lipolactonase with antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions 2 and to attenuate atherosclerosis development. Immunohistochemical analysis has revealed accumulation of PON1 in the human atherosclerotic lesion as it progresses from fatty streak to advanced lesion. 3 Recently, it was demonstrated that PON1 acts to reduce the oxidizing potency of lipids in atherosclerotic lesions, thus providing protection against oxidation. 4 Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease 5 and is an independent risk factor for coronary artery disease. 6 A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. 7 Urokinase-type plasminogen activator (uPA) is a serine protease enzyme of the fibrinolytic system, and uPA binding to its receptor (uPAR) is implicated in plasmin generation. The uPA/uPAR system has also a nonproteolytic role that extends beyond its role in fibrinolysis. 8 uPA is expressed in human atherosclerotic vessel wall, mainly in association with macrophages, 9 a...

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Section: Discussionmentioning

confidence: 99%

Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

Khateeb

Kiyan²,

Aviram³

et al. 2012

ATVB

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“…The combination of various types of polyphenols makes the pomegranate antioxidants unique and different. from other antioxidants by having a much wider spectrum of action against several and not just one type of free radicals (Aviram et al, 2005). The antioxidants activity of propolis represented by increase of antioxidant enzymes activities and/ or decrease ROS as documented by many researchers (Newairy et Immuno-histochemically (IMHC) cardiac markers are important for AMI (Ortmann et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Possible Cardioprotective Action of Pomegranate Juice Punica Granatum and Propolis Against Myocardial Infarction Induced in Rats.

Aloutaibi¹,

Gashlan²,

Moselhy³

et al. 2017

Afr J Tradit Complement Altern Med

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Background: The present study was conducted to evaluate the protective role of pomegranate juice alone or in combination with propolis extract against isoproterenol (ISO) induced myocardial infarction in rats. Material and Methods: Male Wister albino rats (n=60) weighing 220-280g were divided into six groups each group contain ten rats; group I: negative control fed standard diet. Group (II-VI): Rats were injected subcutaneously with isoproterenol (150 mg/kg) for 3 days. Group III: Rats were given pomegranate juice 1ml /rat / day. Group IV: Rats were given propolis extract (50 mg/kg BW). Group V: Rats were given pomegranate juice + propolis extract. Group VI: Rats were given glyceronitrate (2.6mg/kg.bw/day). Results: The ISO-induced myocardial infarction in untreated rats has indicated by significant (p < 0.001) elevation of cardiac marker enzymes such as aspartate aminotransferase (AST), Lactate dehydrogenase (LDH), creatine kinase (CK), and cardiac troponin I (CnI ) when compared with control group. Rats treated with pomegranate juice and propolis extracts showed highly significant (p<0.001) improvement in cardiac marker enzymes activities when compared with untreated myocardial infarction group. Histological investigation showed features of damaged muscles (atrophy, necrosis) which while it was ameliorated in treated groups with superior effect with pomegranate juice. Conclusion: It was concluded that, pomegranate juice in combination with propolis have a potential to alleviate the oxidative stress that induce myocardial infarction and therefore reduce the incidence of cardiovascular diseases.

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“…48 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. 49,50 Various studies show that patients on HD have decreased PON activity, which might indicate a greater risk of premature atherosclerosis and increased vascular disease. 51,52 Several studies have consistently shown that PON activity in HD patients is lower than normal people, even when the concentration was adjusted for HDLcholesterol or apolipoprotein A-I.…”

Section: Discussionmentioning

confidence: 99%

Paraoxonase Enzyme Activity Is Enhanced by Zinc Supplementation in Hemodialysis Patients

et al. 2012

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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 ¼ 0.02). In the control group, although significant increases were observed in the serum levels of TC, TG, and Apo-B (p ¼ 0.009, 0.019, and 0.001, respectively), the serum PON activity was significantly decreased (p ¼ 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.

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Dietary Antioxidants and Paraoxonases Against LDL Oxidation and Atherosclerosis Development

Cited by 109 publications

References 204 publications

Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

Urokinase-Type Plasminogen Activator Downregulates Paraoxonase 1 Expression in Hepatocytes by Stimulating Peroxisome Proliferator–Activated Receptor-γ Nuclear Export

Possible Cardioprotective Action of Pomegranate Juice Punica Granatum and Propolis Against Myocardial Infarction Induced in Rats.

Paraoxonase Enzyme Activity Is Enhanced by Zinc Supplementation in Hemodialysis Patients

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