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Sant Andreu Salou, Spain

MacKness B.,Pontech Art | Marsillach J.,University of Washington | Elkeles R.S.,Imperial College London | Godsland I.F.,Imperial College London | And 6 more authors.
Disease Markers | Year: 2012

Objectives: To determine any association between serum paraoxonase-1 (PON1) activity, protein and coding region genetic polymorphisms and coronary artery calcification (CACS) and to determine factors which modulate serum PON1 in type 2 diabetes (T2DM). Methods and results: 589 patients (419 Caucasian, 120 South Asian, 50 other) from the PREDICT Study were investigated. All patients were asymptomatic for coronary disease and had established T2DM. CACS, lipids, lipoproteins, inflammatory markers, insulin resistance and PON1 activity, concentration and Q192R and L55M genotypes were measured. Independent associations were: 1) PON1 activity negatively with insulin resistance, triglycerides and PON1-55 genotype and positively with PON1-192 genotype; 2) PON1 concentration negatively with Caucasian ethnicity, duration of diabetes and statin use and positively with plasma creatinine and PON1-192 genotype. There was no association between CACS and any of the PON1 activity, concentration or genotype and this finding was not different in the various ethnic groups within the PREDICT study. Conclusion: PON1 is modulated by a number of factors, some of which are reported here for the first time, including ethnicity and insulin resistance in subjects with T2DM. No association between CACS and PON1 was found. © 2012 - IOS Press and the authors. All rights reserved.

Hine D.,University of Manchester | MacKness B.,Pontech Art | MacKness M.,Pontech Art
IUBMB Life | Year: 2012

The inhibition of low-density lipoprotein (LDL) oxidation by high-density lipoprotein (HDL) is a major antiatherogenic property of this lipoprotein. This activity is due, in part, to HDL associated proteins. However, whether these proteins interact in the antioxidant activity of HDL is unknown. LDL was incubated with apolipoprotein A1 (apo A1), lecithin:cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON1) alone or in combination, in the presence or absence of HDL under oxidizing conditions. LDL lipid peroxide concentrations were determined. Apo A1, LCAT, and PON1 all inhibit LDL oxidation in the absence of HDL and enhance the ability of HDL to inhibit LDL oxidation. Their effect was additive rather than synergistic; the combination of these proteins significantly enhanced the length of time LDL was protected from oxidation. This seemed to be due to the ability of PON1 to prevent the oxidative inactivation of LCAT. Apo A1, LCAT, and PON1 can all contribute to the antioxidant activity of HDL in vitro. The combination of apo A1, LCAT, and PON1 prolongs the time that HDL can prevent LDL oxidation, due, at least in part, to the prevention LCAT inactivation. Copyright © 2011 Wiley Periodicals, Inc.

Hine D.,University of Manchester | MacKness B.,Pontech Art | MacKness M.,Pontech Art
IUBMB Life | Year: 2011

Therapeutic strategies to increase high-density lipoprotein (HDL) to treat or prevent vascular disease include the use of cholesteryl-ester transfer protein (CETP) inhibitors. Here, we show, to the best of our knowledge for the first time, that addition of CETP to HDL enhances the ability of HDL to inhibit low-density lipoprotein oxidation by ∼ 30% for total HDL and HDL 2 (both P < 0.05) and 75% for HDL 3 (P < 0.01). Therefore, CETP inhibition may be detrimental to the antiatherosclerotic properties of HDL, and these findings may partly explain the failure of the CETP inhibitor, torcetrapib, treatment to retard vascular disease despite large increases in HDL, in addition to its "off target" toxicity, a property which appears not to be shared by other members of this class of CETP inhibitor currently under clinical trial. Further, detailed studies are urgently required. © 2011 International Union of Biochemistry and Molecular Biology, Inc.

Mackness M.,Pontech Art | Mackness B.,Pontech Art
Clinical Biochemistry | Year: 2011

Objectives: To investigate the effects of dilution on high-density lipoprotein (HDL) associated paraoxonase-1 (PON1) activity. Design and methods: HDL was prepared by ultracentrifugation, diluted with TRIS buffer pH 8.2 (0-128 fold) and assayed spectrophotometrically for PON1 activity using paraoxon and phenyl acetate. Results: HDL-PON1 activity increased progressively with dilution to over 200% of the undiluted activity by 128 fold dilution (P< 0.001). Conversely HDL size decreased. Conclusion: These results indicate the urgent need to standardise conditions for measuring PON1 activity. © 2011 Elsevier Inc.

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