Serum paraoxonase-3 concentration in HIV-infected patients. Evidence for a protective role against oxidation

Aragonès, Gerard; García-Heredia, Anabel; Rull, Anna; Beltrán‐Debón, Raúl; Marsillach, Judit; Alonso-Villaverde, Carlos; Mackness, Bharti; Mackness, Michael I.; Pedro‐Botet, Juan; Pardo-Reche, Pedro; Joven, Jorge; Camps, Jordi

doi:10.1194/jlr.p018457

Cited by 15 publications

(12 citation statements)

References 40 publications

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“…42–45 Additionally, the finding that lower PON3 in HDL correlates with subclinical atherosclerosis contradicts previous studies reporting increased PON3 protein concentrations (as measured by ELISA) in atherosclerosis vs. healthy subjects. 44, 46, 47 One explanation for this apparent discrepancy could be the sample used to determine PON3 concentration, serum in the previous studies and isolated HDL from plasma in the current study. These results are consistent with the proposal that certain HDL particles ( e.g.…”

Section: Discussionmentioning

confidence: 76%

Paraoxonase-3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis

Marsillach¹,

Becker²,

Vaisar³

et al. 2015

J. Proteome Res.

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Patients with autoimmune diseases have a significantly increased risk of developing cardiovascular disease. In disease, high density lipoprotein (HDL) particles lose their anti-inflammatory and antioxidant properties, becoming dysfunctional. The purpose of this study was to test the hypothesis that alterations in the HDL proteomic profile are associated with subclinical atherosclerosis and HDL dysfunction in patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes. Targeted proteomics was used to quantify the relative abundance of 18 proteins in HDL from SLE patients with and without atherosclerotic plaque detectable by carotid ultrasound. Changes in the proteomic profile were compared against the in vitro ability of HDL to protect against lipid oxidation. The same proteins were quantified in HDL from patients with type 1 diabetes with or without coronary artery calcification as determined by computed tomography. In each population, paraoxonase-3 (PON3), a potent antioxidant protein, was depleted from the HDL of patients with subclinical atherosclerosis. PON3 expression in HDL was positively correlated with HDL antioxidant function. These results suggest that PON3 may be an important protein in preventing atherosclerosis and highlights the importance of antioxidant proteins in the prevention of atherosclerosis in vivo.

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Section: Discussionmentioning

confidence: 76%

Paraoxonase-3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis

Marsillach¹,

Becker²,

Vaisar³

et al. 2015

J. Proteome Res.

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“…PON1 activity measured in isolated HDL was also found to inversely correlate with age 40 , which, given that our control group was younger than HIV-infected subjects, could contribute to lower observed PON1 activity. Similar to PON1, the study by Aragonès et al reported a 3-fold increase in PON3 concentrations in HIV-infected subjects relative to control subjects, and this difference was partially reversed in patients treated with NNRTI-based ART 38 . Again, incorporation of PON3 into HDL particles may be impaired in HIV-infected subjects.…”

Section: Discussionmentioning

confidence: 85%

HIV infection induces structural and functional changes in high density lipoproteins

Siegel¹,

Borkowska²,

Dubrovsky³

et al. 2015

Atherosclerosis

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Background and Aims Coronary artery disease is a growing clinical problem in HIV-infected subjects. The increased risk of coronary events in this population has been linked to low levels of HDL, but the effects of HIV infection and anti-retroviral treatment (ART) on HDL structure and function remain unknown. Here, we aimed to determine the composition and function of HDL particles isolated from ART-naive and ART-positive HIV-infected patients. Methods and Results Proteomic profiling revealed decreased levels of paraoxonase (PON) 1 and PON 3 in HDL from HIV patients relative to HDL from uninfected controls (p<0.0001), and PON activity of HDL from control group (0.13±0.01 U/μl) was significantly higher than PON activity of HDL from HIV-infected untreated subjects (0.12±0.01U/μl, p=0.0035), subjects treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy (0.11±0.01 U/μl, p<0.0001), subjects treated with protease inhibitor (PI)-based therapy with detectable viral load (0.11±0.01 U/μl, p<0.0001), and PI-treated patients with undetectable viral load (0.12±0.01 U/μl, p=0.0164). Lipidomic profiling uncovered a negative correlation between CD4 T cell counts and particle sphingomyelin, lyso-phosphatidylcholine and ether-linked phosphatidylserine content in the ART-naive (R2=0.2611, p<0.05; R2=0.2722, p<0.05; and R2=0.3977, p<0.05, respectively) but not treated HIV-infected subjects. Functional analysis demonstrated a negative correlation between cholesterol efflux capacity of HDL and viral load in the ART-naive HIV-infected group (R2=0.26, p=0.026). Conclusions Taken together, these results indicate that HIV infection associates with a number of both protein and lipid compositional changes in HDL particles. Moreover, HIV infection affects cholesterol efflux function of HDL, thus contributing to an increased risk of atherosclerosis in this patient population.

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“…More recently, six PON3 promoter SNVs in linkage disequilibrium were significantly associated with changes in serum PON3 concentration in a healthy Mediterranean cohort [135]. The same authors studied these six SNVs in human immunodeficiency virus (HIV)-infected patients [136] and in coronary artery disease and peripheral artery disease patients [137]. However, no differences were found in these PON3 gene promoter SNVs and their haplotypes between patients and controls, suggesting that PON3 genotype neither influences serum PON3 concentration nor the course of these human diseases.…”

Section: Pon3mentioning

confidence: 99%

“…Indeed, a significant increase of PON3 concentration has been reported in chronic liver disease [138], HIV-infection [136], and coronary and peripheral artery disease [137]. However, a more recent study in patients with autoimmune disease (systemic lupus erythematosus and type 1 diabetes) has shown significant depletion of PON3 protein in HDLs of patients with autoimmune disease and subclinical atherosclerosis [139].…”

Section: Pon3mentioning

confidence: 99%

“…Lipoproteins were fractionated by FPLC. They found that in non-infected participants, PON3 was exclusively detected in HDLs, while in HIV-infected subjects a substantial amount of PON3 was measured in the smallest HDL and LDL particles [136]. The HDLs measured in patients with autoimmune disease with and without subclinical atherosclerosis were separated by ultracentrifugation, and presence of PON3 in LDLs was not studied [139].…”

Section: Pon3mentioning

confidence: 99%

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Paraoxonases-1, -2 and -3: What are their functions?

Furlong

Marsillach

Jarvik

et al. 2016

Chemico-Biological Interactions

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159

122

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Paraoxonase-1 (PON1), an esterase/lactonase primarily associated with plasma high-density lipoprotein (HDL), was the first member of this family of enzymes to be characterized. Its name was derived from its ability to hydrolyze paraoxon, the toxic metabolite of the insecticide parathion. Related enzymes PON2 and PON3 were named from their evolutionary relationship with PON1. Mice with each PON gene knocked out were generated at UCLA and have been key for elucidating their roles in organophosphorus (OP) metabolism, cardiovascular disease, innate immunity, obesity, and cancer. PON1 status, determined with two-substrate analyses, reveals an individual’s functional Q192R genotype and activity levels. The three-dimensional structure for a chimeric PON1 has been useful for understanding the structural properties of PON1 and for engineering PON1 as a catalytic scavenger of OP compounds. All three PONs hydrolyze microbial N-acyl homoserine lactone quorum sensing factors, quenching Pseudomonas aeruginosa’s pathogenesis. All three PONs modulate oxidative stress and inflammation. PON2 is localized in the mitochondria and endoplasmic reticulum. PON2 has potent antioxidant properties and is found at 3- to 4-fold higher levels in females than males, providing increased protection against oxidative stress, as observed in primary cultures of neurons and astrocytes from female mice compared with male mice. The higher levels of PON2 in females may explain the lower frequency of neurological and cardiovascular diseases in females and the ability to identify males but not females with Parkinson’s disease using a special PON1 status assay. Less is known about PON3; however, recent experiments with PON3 knockout mice show them to be susceptible to obesity, gallstone formation and atherosclerosis. Like PONs 1 and 2, PON3 also appears to modulate oxidative stress. It is localized in the endoplasmic reticulum, mitochondria and on HDL. Both PON2 and PON3 are upregulated in cancer, favoring tumor progression through mitochondrial protection against oxidative stress and apoptosis.

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Serum paraoxonase-3 concentration in HIV-infected patients. Evidence for a protective role against oxidation

Cited by 15 publications

References 40 publications

Paraoxonase-3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis

Paraoxonase-3 Is Depleted from the High-Density Lipoproteins of Autoimmune Disease Patients with Subclinical Atherosclerosis

HIV infection induces structural and functional changes in high density lipoproteins

Paraoxonases-1, -2 and -3: What are their functions?

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