Chlorogenic acid protects paraoxonase 1 activity in high density lipoprotein from inactivation caused by physiological concentrations of hypochlorite

We hypothesized that chlorogenic acids, the main phenolics in coffee, many fruits and Ilex paraguariensis extracts, protect paraoxonase 1 activity in HDL from inactivation by chlorination at concentrations of HOCl (50 mu M) and chlorogenic acid (2-10 mu M) compatible with those found in humans. When human HDL was incubated in the presence of HOCl/OCl-, a concentration dependent loss of activity was apparent. Of interest, 5 caffeoylquinic acid at 5 mu mol/L affords more than 60% protection of the activity reaching 100% at 25 mu mol/L. This compound and the plant sources that are rich in them may be protectors of paraoxonase 1 activity. (C) 2009 Elsevier B.V. All rights reserved.

Methylmercury-induced inhibition of paraoxonase-1 (PON1)-implications for cardiovascular risk

Methylmercury (MeHg) has been associated with increased risk for cardiovascular disease in some but not all epidemiology studies. These inconsistent results may stem from the fact that exposure typically occurs in the context of fish consumption, which is also associated with cardioprotective factors such as omega-3 fatty acids. Mechanistic information may help to understand whether MeHg represents a risk to cardiovascular health. MeHg is a pro-oxidant that inactivates protein sulfhydryls. These biochemical effects may diminish critical antioxidant defense mechanism(s) involved in protecting against atherosclerosis. One such defense mechanism is paraoxonase-1 (PON1), an enzyme present on high-density lipoproteins and that prevents the oxidation of blood lipids and their deposition in vascular endothelium. PON1 is potentially useful as a clinical biomarker of cardiovascular risk, as well as a critical enzyme in the detoxification of certain organophosphate oxons. MeHg and other metals are known to inhibit PON1 activity in vitro. MeHg is associated with lowered serum PON1 activity in a fish-eating population. The implications of lowering PON1 are evaluated by predicting the shift in PON1 population distribution induced by various doses of MeHg. An MeHg dose of 0.3 μg/kg/d is estimated to decrease the population average PON1 level by 6.1% and to increase population risk of acute cardiovascular events by 9.7%. This evaluation provides a plausible mechanism for MeHg-induced cardiovascular risk and suggests means to quantify the risk. This case study exemplifies the use of upstream disease biomarkers to evaluate the additive effect of chemical toxicity with background disease processes in assessing human risk.

Concentrações de paraoxonase 1 (PON1) no soro de ovelhas crioulas lanadas avaliados durante o ciclo reprodutivo.

2015

Exogenous paraoxonase-1 during oocyte maturation improves bovine embryo development in vitro.

The aims of this study were (i) to measure the direct effects of exogenous human recombinant PON1 (rPON1) on bovine oocyte maturation at the molecular level (gene expression) and (ii) to measure the carry-over effects of PON1 on pre-implantation embryo development in vitro.

Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome, but not overweight or obesity

Background The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence. Aims and methods This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerström Nicotine Dependence Scale. Results PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder. Discussion PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS.

A randomised controlled trial of increasing fruit and vegetable intake and how this influences the carotenoid concentration and activities of PON-1 and LCAT in HDL from subjects with type 2 diabetes

Background

High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D.

Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL₂ and HDL₃ by rapid ultracentrifugation. Carotenoids were measured in serum, HDL₂ and HDL₃ by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL₂ and HDL₃ by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL₂ and HDL₃ by a fluorometric assay.

In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL₂ and particularly HDL₃, (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL₃ (p = 0.006 and 0.044, respectively).

To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein.

Determinants of Coronary and Carotid Atherosclerosis in Finnish Patients with Clinically Suspected Coronary Artery Disease. A Quantitative Angiography and Ultrasound Study

Background. Cardiovascular disease (CVD) remains the most serious threat to life and health in industrialized countries. Atherosclerosis is the main underlying pathology associated with CVD, in particular coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease. Risk factors play an important role in initiating and accelerating the complex process of atherosclerosis. Most studies of risk factors have focused on the presence or absence of clinically defined CVD. Less is known about the determinants of the severity and extent of atherosclerosis in symptomatic patients. Aims. To clarify the association between coronary and carotid artery atherosclerosis, and to study the determinants associated with these abnormalities with special regard to novel cardiovascular risk factors. Subjects and methods. Quantitative coronary angiography (QCA) and B-mode ultrasound were used to assess coronary and carotid artery atherosclerosis in 108 patients with clinically suspected CAD referred for elective coronary angiography. To evaluate anatomic severity and extent of CAD, several QCA parameters were incorporated into indexes. These measurements reflected CAD severity, extent, and overall atheroma burden and were calculated for the entire coronary tree and separately for different coronary segments (i.e., left main, proximal, mid, and distal segments). Maximum and mean intima-media thickness (IMT) values of carotid arteries were measured and expressed as mean aggregate values. Furthermore, the study design included extensive fasting blood samples, oral glucose tolerance test, and an oral fat-load test to be performed in each participant. Results. Maximum and mean IMT values were significantly correlated with CAD severity, extent, and atheroma burden. There was heterogeneity in associations between IMT and CAD indexes according to anatomical location of CAD. Maximum and mean IMT values, respectively, were correlated with QCA indexes for mid and distal segments but not with the proximal segments of coronary vessels. The values of paraoxonase-1 (PON1) activity and concentration, respectively, were lower in subjects with significant CAD and there was a significant relationship between PON1 activity and concentration and coronary atherosclerosis assessed by QCA. PON1 activity was a significant determinant of severity of CAD independently of HDL cholesterol. Neither PON1 activity nor concentration was associated with carotid IMT. The concentration of triglycerides (TGs), triglyceride-rich lipoproteins (TRLs), oxidized LDL (oxLDL), and the cholesterol content of remnant lipoprotein particle (RLP-C) were significantly increased at 6 hours after intake of an oral fatty meal as compared with fasting values. The mean peak size of LDL remained unchanged 6 hours after the test meal. The correlations between total TGs, TRLs, and RLP-C in fasting and postprandial state were highly significant. RLP-C correlated with oxLDL both in fasting and in fed state and inversely with LDL size. In multivariate analysis oxLDL was a determinant of severity and extent of CAD. Neither total TGs, TRLs, oxLDL, nor LDL size were linked to carotid atherosclerosis. Insulin resistance (IR) was associated with an increased severity and extent of coronary atherosclerosis and seemed to be a stronger predictor of coronary atherosclerosis in the distal parts of the coronary tree than in the proximal and mid parts. In the multivariate analysis IR was a significant predictor of the severity of CAD. IR did not correlate with carotid IMT. Maximum and mean carotid IMT were higher in patients with the apoE4 phenotype compared with subjects with the apoE3 phenotype. Likewise, patients with the apoE4 phenotype had a more severe and extensive CAD than individuals with the apoE3 phenotype. Conclusions. 1) There is an association between carotid IMT and the severity and extent of CAD. Carotid IMT seems to be a weaker predictor of coronary atherosclerosis in the proximal parts of the coronary tree than in the mid and distal parts. 2) PON1 activity has an important role in the pathogenesis of coronary atherosclerosis. More importantly, the study illustrates how the protective role of HDL could be modulated by its components such that equivalent serum concentrations of HDL cholesterol may not equate with an equivalent, potential protective capacity. 3) RLP-C in the fasting state is a good marker of postprandial TRLs. Circulating oxLDL increases in CAD patients postprandially. The highly significant positive correlation between postprandial TRLs and postprandial oxLDL suggests that the postprandial state creates oxidative stress. Our findings emphasize the fundamental role of LDL oxidation in the development of atherosclerosis even after inclusion of conventional CAD risk factors. 4) Disturbances in glucose metabolism are crucial in the pathogenesis of coronary atherosclerosis. In fact, subjects with IR are comparable with diabetic subjects in terms of severity and extent of CAD. 5) ApoE polymorphism is involved in the susceptibility to both carotid and coronary atherosclerosis.

No or only population-specific effect of PON1 on human longevity: A comprehensive meta-analysis

Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet).

α-Tocopherol induces proatherogenic changes to HDL2 & HDL3: An in vitro and ex vivo investigation

Introduction: High density lipoproteins (HDL) have considerable potential for improving cardiovascular health. Additionally, epidemiological studies have identified an inverse relationship between a-tocopherol intake and cardiovascular disease, which has not been translated in randomised controlled trials. Objectives: This study assessed if increased α-tocopherol within HDL2 and HDL3 (HDL2&3) influenced their antiatherogenic potential. In the first of two in vitro investigations, the oxidation potential of HDL2&3 was assessed when α-tocopherol was added following their isolation. In the second, their oxidation potential was assessed when HDL2&3 were isolated from serum pre-incubated with α-tocopherol. Additionally, a 6-week placebo-controlled intervention with α-tocopherol assessed if α-tocopherol influenced the oxidation potential and activities of HDL2&3-associated enzymes, paraoxonase-1 (PON-1) and lecithin cholesteryl acyltransferase (LCAT). Results: Conflicting results arose from the in vitro investigations, whereby increasing concentrations of α-tocopherol protected HDL2&3 against oxidation in the post-incubated HDL2&3, and promoted HDL2&3-oxidation when they were isolated from serum pre-incubated with α-tocopherol. Following the 6-week placebo-controlled investigation, α-tocopherol increased in HDL2&3, while HDL2&3 became more susceptible to oxidation, additionally the activities of HDL2&3-PON-1 and HDL2-LCAT decreased. Conclusion: These results have shown for the first time that α-tocopherol induces changes to HDL2&3, which could contribute to the pathophysiology of cardiovascular disease.

Suco de laranja reduz o colesterol em indivíduos normolipidêmicos

Objetivos Neste estudo foi investigado o efeito do consumo habitual de suco de laranja no perfil dos lípides e lipoproteínas em homens e mulheres normolipidêmicos. Métodos Todos os voluntários (n=29) consumiram 750mL/dia de suco de laranja durante 60 dias. Variáveis bioquímicas como perfil lipídico, apolipoproteínas, glicose, paraoxonase1 e o tamanho de HDL foram medidas antes e após o período de suplementação com suco de laranja. Também foram realizadas medidas antropométricas e inquéritos dietéticos. Resultados O consumo crônico de suco de laranja reduziu significativamente o colesterol total nos homens (11%, p<0,05) e nas mulheres (10%, p<0,05) e o LDL-C nos homens e mulheres (15%, p<0,05). O HDL-C e a apoA-I também diminuíram, refletindo a redução do colesterol total. Os triacilgliceróis, apo B, PON1, tamanho da HDL, IMC, gordura corporal e circunferência abdominal não foram modificados com o tratamento com suco de laranja. Conclusão Neste estudo, mostrou-se que o suco de laranja apresenta propriedade redutora sobre o colesterol, e foi sugerido que a associação dos flavonóides cítricos com a vitamina C previne o estresse oxidativo e o desenvolvimento da aterosclerose.

Suco de laranja reduz colesterol e insulina no sangue de indivíduos saudáveis

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Proteção cardiovascular e papel antioxidante do suco de laranja em indivíduos com execesso de peso

Pós-graduação em Alimentos e Nutrição - FCFAR

Association between diet and polymorphisms in individuals with statin-controlled dyslipidaemia grouped according to oxidative stress biomarkers

The objective of this study was to investigate whether differences in diet and in single-nucleotide polymorphisms (SNPs) found in paraoxonase-1 (PON-1), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), cholesterol ester transfer protein (CETP) and apolipoprotein E (APOE) genes, are associated with oxidative stress biomarkers and consequently with susceptibility of low-density cholesterol (LDL) to oxidation. A multivariate approach was applied to a group of 55 patients according to three biomarkers: plasma antioxidant activity, malondialdehyde and oxidized LDL (oxLDL) concentrations. Individuals classified in Cluster III showed the worst prognoses in terms of antioxidant activity and oxidative status. Individuals classified in Cluster I presented the lowest oxidative status, while individuals grouped in Cluster II presented the highest levels of antioxidant activity. No difference in nutrient intake was observed among the clusters. Significantly higher gamma- and delta-tocopherol concentrations were observed in those individuals with the highest levels of antioxidant activity. No single linear regression was statistically significant, suggesting that mutant alleles of the SNPs selected did not contribute to the differences observed in oxidative stress response. Although not statistically significant, the p value of the APO E coefficient for oxLDL response was 0.096, indicating that patients who carry the TT allele of the APO E gene tend to present lower plasma oxLDL concentrations. Therefore, the differences in oxidative stress levels observed in this study could not be attributed to diet or to the variant alleles of PON-1, CETP, HMGCR or APO E. This data supports the influence of gamma-tocopherol and delta-tocopherol on antioxidant activity, and highlights the need for further studies investigating APO E alleles and LDL oxidation.

Air Pollution and High Density Lipoprotein Structure and Function

Thesis (Ph.D.)--University of Washington, 2016-06