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

Marsillach, Judit; Becker, Jessica O.; Vaisar, Tomáš; Hahn, Bevra H.; Brunzell, John D.; Furlong, Clement E.; Boer, Ian H. de; McMahon, Maureen; Hoofnagle, Andrew N.; Dcct,

doi:10.1021/pr5011586

Cited by 52 publications

(48 citation statements)

References 52 publications

(121 reference statements)

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“…Although low levels of PON1 activity were associated with a modest inverse risk of CHD in a population-based study, this relationship was abolished after adjustment for HDL-C and apoA-I, suggesting that low PON1 activity is not a causal factor in atherogenesis 71 . In a cross-sectional analysis of patients with autoimmune disease or type 1 diabetes mellitus with subclinical atherosclerosis, PON3 was depleted in HDL particles and the antioxidant function of HDL was reduced 72 . We are unaware, however, of prospective studies that have established a role for PON3 in human atherosclerosis.…”

Section: Hdl Functionality and Atherosclerosismentioning

confidence: 99%

Dysfunctional HDL and atherosclerotic cardiovascular disease

et al. 2015

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High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

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Section: Hdl Functionality and Atherosclerosismentioning

confidence: 99%

Dysfunctional HDL and atherosclerotic cardiovascular disease

et al. 2015

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“…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]. Of note is that the technique used to measure PON3 in these studies is different (in-house serum ELISA [135] in the first studies vs. HDL LC-MS/MS in the latter study).…”

Section: Pon3mentioning

confidence: 99%

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

Furlong

Marsillach

Jarvik

et al. 2016

Chemico-Biological Interactions

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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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“…(27) As well as varying in size, HDL particles vary in protein content, as HDL's proteome is very rich. Alterations in protein cargo have been associated with pathological states, such as inflammation (28), poor response to therapy (29), autoimmune disease (30), and diabetes (31). Further improvements in quantitative techniques (32,33) and their application to clinical studies should identify panels of protein biomarkers that may be pharmacologically modifiable to reduce risk.…”

Section: Hdl-c Hypothesismentioning

confidence: 99%

The High Density Lipoprotein Cholesterol Hypothesis Revisited

2018

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IntroductionClassical epidemiology has established the incremental contribution of the high-density lipoprotein cholesterol (HDL-C) measure in the assessment of atherosclerotic cardiovascular disease (CVD) risk, yet, genetic epidemiology does not support a causal relationship between HDL-C and the future risk of myocardial infarction. Therapeutic interventions directed toward cholesterol loading of the HDL particle have been based on epidemiological studies that have established HDL cholesterol as a biomarker of atherosclerotic CVD risk. The reference range of HDL-C is 40-50 mg/dL in men and 50-60 mg/dL in women. However, therapeutic interventions such as niacin, cholesterylester transfer protein (CETP) inhibitors increase HDL-C in patients treated with statins, but have repeatedly failed to reduce CVD events.(1) Clinical trials with pharmacological therapies that increase the cholesterol content of HDL particles have failed to establish this convenient metric as The High Density Lipoprotein Cholesterol Hypothesis Revisited R E V I E W A R T I C L E B ACKGROUND:The strong inverse association of plasma levels of high-density lipoprotein cholesterol (HDL-C) with coronary heart disease (CHD) found in human epidemiological studies led to the development of the 'HDL-C hypothesis', which posits that intervention to raise HDL-C will result in reduced risk of CHD. However, recent evidence has raised doubts about the hypotheses that elevating HDL-C is necessarily therapeutic. Genetic variations that associate with altered HDL-C do not strongly associate with altered cardiovascular disease risk.CONTeNT: HDL-mediated cholesterol efflux from macrophage foam cells or measurements of the flux of cholesterol from macrophages to the liver and feces seem to correlate better with atherosclerotic burden than with HDL-C levels. Thus, it may be time to modify the HDL-C hypothesis to the 'HDL flux hypothesis', where intervention to promote cholesterol efflux and reverse cholesterol transport will reduce CHD risk, regardless of whether it affects plasma HDL-C levels. A deeper understanding of the complex biology of HDL metabolism and its relationship to reverse cholesterol transport and atherothrombotic events is urgently needed. This might lead to biomarkers of HDL flux and functionality that are more informative than simple measurements of HDL-C levels. SUmmARy:It is now clear from recent clinical trial and genetic studies that some approaches to raising HDL-C levels may have no effect on CHD. This suggests the need to evaluate HDL-C-raising therapies in different clinical populations, as well as therapies targeted toward HDL flux and function rather than simply HDL-C elevation. Perhaps moving from a focus on the HDL-C hypothesis to a focus on the HDL flux hypothesis will permit a biologically based reassessment of the optimal therapeutic approach to targeting HDL for reduction in cardiovascular risk.KeywORDS: reverse cholesterol transport, cholesterol efflux capacity, HDL dysfunction, HDL particle size, HDL lipidomics, HD...

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

Cited by 52 publications

References 52 publications

Dysfunctional HDL and atherosclerotic cardiovascular disease

Dysfunctional HDL and atherosclerotic cardiovascular disease

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

The High Density Lipoprotein Cholesterol Hypothesis Revisited

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