Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome

Abstract

Background-The metabolic syndrome is typified by obesity, dyslipidemia, diabetes, hypertension, increased oxidative stress, and accelerated atherosclerosis. Paraoxonase1 (PON1), a high-density lipoprotein (HDL)-associated antioxidant enzyme that prevents the oxidation of low-density lipoprotein (LDL), is low in the metabolic syndrome. Methods and Results-We used adenovirus-mediated PON1 gene transfer (AdPON1) to overexpress human PON1 in mice with combined leptin and LDL receptor deficiency, a model of metabolic syndrome. PON1 activity, plasma lipids, the titer of autoantibodies against malondialdehyde (MDA)-modified LDL, and atherosclerosis in AdPON1 mice were compared with these in mice that received a control recombinant adenovirus (AdRR5). PON1 activity was increased 4.4-fold (PϽ0.001) in AdPON1 mice (Nϭ12), whereas in AdRR5 mice (Nϭ11) activity did not change. Expressing human PON1 significantly reduced the total plaque volume, the volume of plaque macrophages, and of plaqueassociated oxidized LDL. It increased the percentage of smooth muscle cells in the plaques. Expressing human PON1 lowered the titer of autoantibodies against MDA-modified LDL, a proxy for oxidized LDL in mice. It had no overall effect on plasma total cholesterol and triglycerides, as evidenced by the similar area under the curves, and on the HDL distribution profile. Conclusion-Our data suggest that in this mouse model of metabolic syndrome, expressing human PON1 inhibited the development of atherosclerosis, probably by reducing the amount of oxidized LDL in plasma and in the plaque, thereby preventing its proatherogenic effects. Adenovirus-mediated gene transfer of human PON1 may be a potential and useful tool to prevent/retard atherosclerosis in humans. Key Words: atherosclerosis Ⅲ metabolic syndrome Ⅲ oxidized LDL Ⅲ paraoxonase-1 I nsulin resistance is now receiving increasing attention not only as a precursor to type 2 diabetes but also as a predictor of increased risk of cardiovascular disease. 1 Fat distributed in the abdominal region is a risk factor for type 2 diabetes and cardiovascular disease and is associated closely with insulin resistance. 2 In the metabolic syndrome, increased oxidative stress associated with insulin resistance appears to be a major cause of accelerated atherosclerosis. 3,4 Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that, among many other functions, metabolizes pro-inflammatory lipids formed during the oxidation of low-density lipoprotein (LDL) and is therefore potentially anti-atherogenic. 5 PON1 destroys LDL lipid peroxides on LDL and in arteries in vitro and ex vivo. [5][6][7] In PON1 knockout mice, an atherogenic diet causes significantly greater atherosclerosis than in wild-type littermates, whereas overexpressing human PON1 in mouse models of atherosclerosis reduces macrophage oxidative stress and inhibits the development of atherosclerosis. 8,9 The extent to which macrophages infiltrate the artery wall also appears to be dependent on the activity of PON1. 10 PON1 inhi...

Stevioside inhibits atherosclerosis by improving insulin signaling and antioxidant defense in obese insulin-resistant mice

“…Therefore, we measured the titer of autoantibodies against malondialdehyde (MDA)-modified LDL as a proxy for ox-LDL in mice, as described before. 13,17,18 Real-time reverse transcription-PCR analysis The levels of RNA expression in extracts of white visceral (IP) adipose tissue and aorta were measured by quantitative realtime reverse transcription-PCR. Total RNA was extracted with Trizol reagent (Invitrogen, Merelbeke, Belgium) and purified on RNeasy Mini kit columns (Qiagen, Venlo, The Netherlands).…”

Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein E knockout mice

“…Moreover, the decrease in serum oxidative stress and circulating ox-LDL was parallel to a decrease of ox-LDL contents in the plaque. 25 However, no human or mouse PON3 were detected in the HDL isolated from hPON3 transgenic mice that exhibited a significant decrease in atherosclerotic lesion formation.…”

Nuclear Factor-Kappa B and Other Oxidative Stress Biomarkers in Serum of Autistic Children

“…The paraoxonase family of enzymes has recently received attention for their postulated role in several neurological disorders [26]. The paraoxonase 1 (PON1) enzyme is synthesized in the liver and released into circulation where it binds with high density lipoproteins and protects low density lipoproteins and cellular membranes from oxidative damage [33] [59] [60]. It possesses organophosphatase, arylesterase and lactonase activities [60] and exerts peroxidase activities that may be important in neurodegenerative disorders associated with oxidative stress [26].…”

“…The paraoxonase 1 (PON1) enzyme is synthesized in the liver and released into circulation where it binds with high density lipoproteins and protects low density lipoproteins and cellular membranes from oxidative damage [33] [59] [60]. It possesses organophosphatase, arylesterase and lactonase activities [60] and exerts peroxidase activities that may be important in neurodegenerative disorders associated with oxidative stress [26]. Plasma levels of this enzyme decreases in neurological diseases such as multiple sclerosis during relapse [61], major depression [62], patients with Alzheimer's disease or other dementias [63] [64].…”