A biphasic U-shape effect of cellular oxidative stress on the macrophage anti-oxidant paraoxonase 2 (PON2) enzymatic activity

Shiner, Maayan; Fuhrman, Bianca; Aviram, Michael

doi:10.1016/j.bbrc.2006.08.150

Cited by 32 publications

(17 citation statements)

References 42 publications

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“…A compensatory effect of increased PON2 expression after oxidative stress has also been reported in a macrophage cell line. 28 However, subsequently, Rosenblat and colleagues 29 reported decreased PON2 expression in macrophages from hypercholesterolemic subjects treated with acetylated-LDL and oxidized-LDL. Very recently, Levy et al 30 demonstrated that PON2 expression in intestinal specimens is downregulated after induction of oxidative stress by iron/ ascorbate.…”

Section: Discussionmentioning

confidence: 99%

Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis

Fortunato

Taranto

Bracale

et al. 2008

ATVB

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Objective-Many gene products involved in oxidation and inflammation are implicated in the pathogenesis of atherosclerosis. We investigated paraoxonase 2 (PON2), 5-lipoxygenase (5-LO), and 5-LO activating protein (FLAP) expression and malondialdehyde (MDA) levels in carotid lesions to assess their involvement in plaque formation. Methods and Results-We measured gene expression and MDA levels in atherosclerotic plaques from 59 patients undergoing carotid endarterectomy, and in plaque-adjacent tissue from 41/59 patients. Twenty-three fetal carotids and 6 mammary arteries were also investigated. Real-time polymerase chain reaction and immunohistochemistry revealed decreased PON2 expression in plaques versus adjacent regions (PϽ0.005, PϽ0.001, respectively), mammary arteries (PϽ0.031, PϽ0.001, respectively), and fetal carotids (both PϽ0.001). mRNA levels of 5-LO and FLAP were higher (PϽ0.038, PϽ0.005, respectively) in lesions versus fetal carotids. MDA was higher in plaques versus plaque-adjacent tissue and fetal carotids. PON2 mRNA was downregulated by oxidative stress in 5 ex vivo experiments, thereby indicating its possible atheroprotection role. Conclusions-We demonstrate that PON2 mRNA and protein are decreased in plaques versus plaque-adjacent tissue, mammary arteries, and fetal carotids. Our data indicate that the protective effect of PON2 could fail during atherosclerosis exacerbation; this was confirmed by the increase of MDA levels. Key Words: atherosclerosis Ⅲ paraoxonase 2 (PON2) Ⅲ carotid plaque Ⅲ oxidative stress Ⅲ fetal carotid and mammary artery C arotid atherosclerotic plaques are important risk factors for stroke, which is in turn a major cause of morbidity and mortality. 1 Lipid oxidation plays a key role in the pathogenesis of atherosclerosis. 2,3 The production of oxidized molecules is related to an imbalance between oxidant and antioxidant factors. 3,4 Accumulation of oxidized low-density lipoprotein (ox-LDL) in artery walls is an initiating event of fatty streak development. 5,6 Moreover, oxidized products give rise to inflammatory events which, in turn, lead to the progression of plaques. 7,8 Increasing evidence suggests that genes such as paraoxonases (PONs) and lipoxygenases (LOs), which are involved in oxidative stress and inflammation, play key roles in the onset and progression of atherosclerotic plaques. 9,10 The PON family consists of 3 genes (PON1, PON2, and PON3) that have similar antioxidant properties but different expression profiles: PON1 and PON3 are expressed in the liver and circulate in close association with apolipoprotein A-1 in high-density lipoprotein (HDL), 11,12 whereas PON2 is expressed in many different types of tissues and cells including cells of the artery wall. 13 PON polymorphisms are associated with atherosclerosis, diabetes, prostate cancer, Alzheimer dementia, Parkinson disease, and acquired hearing loss. 14 -20 Interestingly, a study of PON2-deficient mice showed that PON2 protected against atherogenesis in vivo by modulating lipoprotein properties, thereby ...

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Section: Discussionmentioning

confidence: 99%

Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis

Fortunato

Taranto

Bracale

et al. 2008

ATVB

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“…PON2 expression is regulated by cellular cholesterol content (285, 311) and cellular oxidative stress (309), and PPAR-c, AP-1 activation (310), and NADPH oxidase activation (101,308) all play important roles in stimulating PON2 mRNA expression. Fuhrman et al identified the signal transduction pathway initiated by uPA that promotes PON2 transcription in macrophages (100).…”

Section: Biological Macromolecules Modulate Pons Expressionmentioning

confidence: 99%

The Human Paraoxonase Gene Cluster As a Target in the Treatment of Atherosclerosis

She

Chen

Yan

et al. 2012

Antioxidants & Redox Signaling

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The paraoxonase (PON) gene cluster contains three adjacent gene members, PON1, PON2, and PON3. Originating from the same fungus lactonase precursor, all of the three PON genes share high sequence identity and a similar b propeller protein structure. PON1 and PON3 are primarily expressed in the liver and secreted into the serum upon expression, whereas PON2 is ubiquitously expressed and remains inside the cell. Each PON member has high catalytic activity toward corresponding artificial organophosphate, and all exhibit activities to lactones. Therefore, all three members of the family are regarded as lactonases. Under physiological conditions, they act to degrade metabolites of polyunsaturated fatty acids and homocysteine (Hcy) thiolactone, among other compounds. By detoxifying both oxidized low-density lipoprotein and Hcy thiolactone, PONs protect against atherosclerosis and coronary artery diseases, as has been illustrated by many types of in vitro and in vivo experimental evidence. Clinical observations focusing on gene polymorphisms also indicate that PON1, PON2, and PON3 are protective against coronary artery disease. Many other conditions, such as diabetes, metabolic syndrome, and aging, have been shown to relate to PONs. The abundance and/or activity of PONs can be regulated by lipoproteins and their metabolites, biological macromolecules, pharmacological treatments, dietary factors, and lifestyle. In conclusion, both previous results and ongoing studies provide evidence, making the PON cluster a prospective target for the treatment of atherosclerosis. Antioxid. Redox Signal. 16, 597-632.

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“…PON2, like PON1, was shown to protect against atherosclerosis development (17,18), and this could be related to PON2 ability to inhibit cell-mediated LDL oxidation, oxidized LDL (OxLDL)-induced monocytes chemotaxis, and formation of reactive oxygen species (ROS) (13,14,19). Macrophage oxidative stress was shown to affect PON2 expression and activities in a biphasic U-shape pattern (14,20). Upregulation of macrophage PON2 was shown to occur via several mechanisms, including NADPH-oxidase activation (21), pomegranate juice polyphenolic antioxidants (22), unesterified cholesterol accumulation (23), and urokinase plasminogen activator (24).…”

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confidence: 99%

Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

Rosenblat

Coleman

Reddy

et al. 2009

Journal of Lipid Research

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This study questioned the role of paraoxonase 2 (PON2) in attenuation of macrophage lipids accumulation. Mouse peritoneal macrophages (MPMs) harvested from PON2-deficient mice versus control C57BL/6 mice, look like foam cells and were larger in size and filled with lipid droplets. Macrophage triglyceride (but not cholesterol) content, biosynthesis rate, and microsomal acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) activity (not mRNA and protein) in PON2-deficient versus control MPM were all significantly increased by 4.6-, 3.6-, and 4.4-fold, respectively. Similarly, microsomal DGAT1 activity and cellular triglyceride content were significantly decreased in human PON2-transfected cells as well as upon incubation of PON2-deficient MPM with recombinant PON2. In all the above experimental systems, PON2 also decreased macrophage oxidative state. Incubation of PON2-deficient MPM with the free radicals generator 2,2′-amidinopropane hydrochloride increased cellular oxidative stress and DGAT1 activity by 2.2-and 3.4-fold, respectively, whereas incubation of microsomes from PON2-deficient MPM with superoxide dismutase decreased DGAT1 activity by 40%. We thus conclude that PON2 attenuates macrophage triglyceride accumulation and foam cell formation via inhibition of microsomal DGAT1 activity, which appears to be sensitive to oxidative state.-Rosenblat, M., R. Coleman, S. T. Reddy, and M. Aviram. Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1. J. Lipid Res. 2009. 50: 870-879.

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A biphasic U-shape effect of cellular oxidative stress on the macrophage anti-oxidant paraoxonase 2 (PON2) enzymatic activity

Cited by 32 publications

References 42 publications

Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis

Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis

The Human Paraoxonase Gene Cluster As a Target in the Treatment of Atherosclerosis

Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

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