Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells

Mackness, Bharti; Hine, David; Liu, Yifen; Mastorikou, Maria; Mackness, Mike

doi:10.1016/j.bbrc.2004.04.056

Cited by 154 publications

(112 citation statements)

References 25 publications

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“…Moreover, we speculated that AHR deficiency could constitute such a defect. Both paraoxonase-1, an HDL-associated enzyme with a well established role in preventing LDL oxidation and cardiovascular disease, and NQO1, a shear-inducible gene that maintains the endogenous lipid-soluble antioxidants ␣-tocopherolhydroquinone and ubiquinol in their reduced and active forms, are directly regulated by AHR activation (12,(32)(33)(34). In addition, exogenous activation of the AHR is sufficient for the induction of the macrophage ''foam cell'' phenotype (35), a lipid-laden form generated by uptake of modified LDL from the sera (36).…”

Section: Discussionmentioning

confidence: 99%

The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

McMillan

Bradfield²

2007

Proc. Natl. Acad. Sci. U.S.A.

116

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Endogenous activation of the aryl hydrocarbon receptor (AHR) is required for normal vascular development. This biology led us to investigate the interplay between the AHR and vascular physiology by using an in vitro model of fluid shear stress. Using this system, we show that fluid flow induces a robust AHR-mediated increase in CYP1 expression. Furthermore, we demonstrate that incubation with sheared bovine or human sera is sufficient for AHR activation, indicating that direct cellular exposure to shear stress is not required for this response. Fractionation of sera by size and density revealed the AHR-activating factor to be low-density lipoprotein (LDL). Purified LDL (0.1 mg/ml) from sheared sera induces a 6-fold increase in AHR-mediated signaling as compared with LDL purified from static sera. Similar results were obtained by exposing a purified fraction of LDL to fluid flow, suggesting that shear stress is capable of directly modifying LDL structure and/or function. In addition, we show that LDL can be converted to an AHR-activating species by conventional methods of lipoprotein modification, such as NaOCl oxidation. Finally, we demonstrate that an increased level of AHR-activating LDL is present in the sera of AHR null mice as compared with heterozygous littermates, suggesting a role for the Ahr locus in the physiological response to modified LDL in vivo. Overall, these data demonstrate a previously undescribed relationship between LDL modification and AHR biology and provide a potential explanation for the vascular abnormalities observed in AHR null mice.AHR ͉ cyp1a1 ͉ cyp1b1 ͉ shear stress T he aryl hydrocarbon receptor (AHR) is a ligand activated basic-helix-loop-helix (bHLH) transcription factor that belongs to the PAS (Per-Arnt-Sim) family of nuclear sensors (1). The AHR binds to numerous environmental contaminants including tetrachlorodibenzo-p-dioxin (TCDD), benzo[a]pyrene, and coplanar polychlorinated biphenyls (2). Upon binding these xenobiotic ligands, the AHR translocates to the nucleus and dimerizes with a second bHLH-PAS protein known as the Ah receptor nuclear translocator (ARNT). The AHR-ARNT complex can then bind to dioxin response elements (DREs) found upstream of target genes, leading to their transcriptional up-regulation. The CYP1 family of cytochrome P450s, CYP1A1, CYP1A2 and CYP1B1, as well as the phase II enzymes GST-A1 and NQO1 are among the genes that are regulated by the AHR (2, 3). The enzymes encoded by these genes display metabolic activity toward many AHR ligands, prompting the idea that this pathway represents an adaptive response to xenobiotic exposure (2, 3).In addition to its role in the metabolic response to xenobiotics, the AHR also has an important role in vascular development. Mice that harbor a null allele at the Ahr locus display a number of vascular phenotypes. These include a patent ductus venosus (DV), persistent hyaloid arteries in the eye, decreased hepatic perfusion, a confused vascularization in the corneal limbus, and cardiac hypertrophy (4-6). Experiments usi...

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Section: Discussionmentioning

confidence: 99%

The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

McMillan

Bradfield²

2007

Proc. Natl. Acad. Sci. U.S.A.

116

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“…Several experiments have shown PON1 to have a protective function in atherosclerosis (Mackness et al 2004, Camps et al 2012. In this process modifications of lipoproteins, such as oxidation, might lead to foam cell formation crucial for lipid plaque development (Fig.…”

Section: Pon1 Changes In Different Diseasesmentioning

confidence: 99%

“…Purified PON1 or HDL containing PON1 inhibit the ox-LDL stimulated MCP-1 production. In contrast, avian HDL (which lacks PON1) do not supress this process (Mackness et al 2004). It has been shown that paraoxonase, due to its activity, prevents LDL-derived oxidized phospholipid formation (ie.…”

Section: Pon1 Changes In Different Diseasesmentioning

confidence: 99%

A review of paraoxonase 1 properties and diagnostic applications

Kulka¹

2016

Polish Journal of Veterinary Sciences

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Paraoxonase 1 (PON1) is an arylesterase associated with serum high density lipoprotein particles. Its name is derived from hydrolyzing one of several organophosphate compounds, namely paraoxon. Recent studies have shown that PON1 plays a protective role in diseases associated with oxidative stress such as atherosclerosis and diabetes mellitus. Studies have demonstrated reduction-oxidative state changes involving PON1 in humans and laboratory animal models. Although there is less information about the role of this enzyme in veterinary medicine, new data suggest that PON1 might be a new oxidative stress marker in animal patients, similarly to humans.

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“…The cholesterol-loaded macrophages together with T lymphocytes produce a wide array of proinflammatory cytokines and accelerate plague progression (Hansson 2005). In vitro, HDL has been shown to inhibit the expression of monocyte chemoattractant protein (MCP)-1, an important proinflammatory chemokine in endothelial cells (Mackness et al 2004;Navab et al 1991). Furthermore, the potential anti-inflammatory effects of HDL have been demonstrated by several in vivo studies.…”

Section: Mechanisms Under Physiological Conditionsmentioning

confidence: 99%

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

Riwanto

Rohrer

Eckardstein

et al. 2014

Handbook of Experimental Pharmacology

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Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipidmodifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.

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Paraoxonase-1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells

Cited by 154 publications

References 25 publications

The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

A review of paraoxonase 1 properties and diagnostic applications

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

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