Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

Vladykovskaya, Elena; Ozhegov, Evgeny; Hoetker, J. David; Xie, Zhengzhi; Ahmed, Yonis; Suttles, Jill; Srivastava, Sanjay; Bhatnagar, Aruni; Barski, Oleg A.

doi:10.1194/jlr.m013854

Cited by 33 publications

(32 citation statements)

References 59 publications

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“…The precise nature of the endothelial LPC receptor is unknown, but this lipid has been reported to act as a multiactivity ligand, binding a number of proteins including: the CD36 scavenger receptor, Toll-like receptors (TLR4 and TLR2), and also the lectin-like oxLDL receptor-1 (LOX-1), after which it triggers a range of prooxidant and proinflammatory pathways (27)(28)(29). Studies also implicate G protein-coupled receptors in mediating LPC function (30).…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Canning

Kenny

Prise

et al. 2016

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

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Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA 2 , darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA 2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA 2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA 2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA 2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.diabetic retinopathy | VEGF signaling | lysophosphatidylcholine | blood-retinal barrier | lipoprotein-associated phospholipase A2

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Section: Discussionmentioning

confidence: 99%

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Canning

Kenny

Prise

et al. 2016

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

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“…117-119 Somewhat surprisingly, in cultured macrophages the metabolic product of AR (1-palmitoyl-2-(5)-hydrovaleryl- sn -glycero-3-phosphorylcholine (PHVPC)) was shown to increase the inflammatory response 10-100 fold as compared to only a 2-3 fold response to POVPC. 120 However, atherosclerosis was higher in AR null/apoE null mice than in mice null for apoE alone. 121 These authors carefully examined the relationship between levels of PAF-AH and levels of AR in regulating the macrophage response to POVPC.…”

Section: Metabolism Of Ox-plmentioning

confidence: 99%

Role of Phospholipid Oxidation Products in Atherosclerosis

Lee

Birukov

Romanoski

et al. 2012

Circulation Research

184

157

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There is increasing clinical evidence that phospholipid oxidation products (Ox-PL) play a role in atherosclerosis. This review focuses on the mechanisms by which Ox-PL interact with endothelial cells, monocyte/macrophages, platelets, smooth muscle cells and HDL to promote atherogenesis. In the last few years major progress has been made in identifying these mechanisms. It has been recognized that Ox-PL promote phenotypic changes in these cell types that have long term consequences for the vessel wall. Individual Ox-PL responsible for specific cellular effects has been identified. A model of the configuration of bioactive truncated Ox-PL within membranes has been developed that demonstrates that the oxidized fatty acid moiety protrudes into the aqueous phase, rendering it accessible for receptor recognition. Receptors and signaling pathways for individual Ox-PL species are now determined and receptor independent signaling pathways identified. The effects of Ox-PL are mediated both by gene regulation and transcription independent processes. It has now become apparent that Ox-PL affects multiple genes and pathways some of which are pro-atherogenic and some are protective. However, at concentrations that are likely present in the vessel wall in atherosclerotic lesions, the effects promote atherogenesis. There have also been new insights on enzymes that metabolize Ox-PL and the significance of these enzymes for atherosclerosis. With the knowledge we now have on the regulation and effects of Ox-PL in different vascular cell types, it should be possible to design experiments to test the role of specific Ox-PL on the development of atherosclerosis.

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“…Therefore, positive reactivity to the antibody can be a useful indicator of the oxidation of phosphocholine phospholipids in cells and tissues. However, in most cells, oxidized phospholipids are readily removed, either by cytosolic enzymes with phospholipase A2 activity, which removes the oxidized sn -2 side chain, 269 or by the reduction of sn -2 aldehydes by aldose reductase. 270 Hence, the absence of oxidized phospholipids does not necessarily indicate a lack of lipid peroxidation, and the measured levels are reflective of a steady state achieved between the generation and the metabolism of these phospholipids.…”

Section: Measurement Of Lipid Peroxidationmentioning

confidence: 99%

Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System

Griendling¹,

Touyz²,

Zweíer³

et al. 2016

Circulation Research

Self Cite

346

247

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Reactive oxygen species and reactive nitrogen species are biological molecules that play important roles in cardiovascular physiology and contribute to disease initiation, progression, and severity. Because of their ephemeral nature and rapid reactivity, these species are difficult to measure directly with high accuracy and precision. In this statement, we review current methods for measuring these species and the secondary products they generate and suggest approaches for measuring redox status, oxidative stress, and the production of individual reactive oxygen and nitrogen species. We discuss the strengths and limitations of different methods and the relative specificity and suitability of these methods for measuring the concentrations of reactive oxygen and reactive nitrogen species in cells, tissues, and biological fluids. We provide specific guidelines, through expert opinion, for choosing reliable and reproducible assays for different experimental and clinical situations. These guidelines are intended to help investigators and clinical researchers avoid experimental error and ensure high-quality measurements of these important biological species.

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Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

Cited by 33 publications

References 59 publications

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Role of Phospholipid Oxidation Products in Atherosclerosis

Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System

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Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids

Cited by 33 publications

References 59 publications

Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Role of Phospholipid Oxidation Products in Atherosclerosis

Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System

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Product

Resources

About

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) as a therapeutic target to prevent retinal vasopermeability during diabetes

Lipoprotein-associated phospholipase A ₂ (Lp-PLA ₂ ) as a therapeutic target to prevent retinal vasopermeability during diabetes