Physiological effects of oxidized phospholipids and their cellular signaling mechanisms in inflammation

Greig, Fiona H.; Kennedy, Simon; Spickett, Corinne M.

doi:10.1016/j.freeradbiomed.2011.10.481

Cited by 101 publications

(86 citation statements)

References 187 publications

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“…In terms of the mechanism that links insertion of oxidized lipids to endothelial cell stiffening, our recent study demonstrates that for oxLDL and oxysterols, stiffening is mediated by the activation of the RhoA/Rock/PLCP/MLC2 pathway (56). oxPAPCs, however, were shown to activate two other members of the Rho-GTPase family, Rac1 and CDC42, while attenuating thrombin-induced RhoA activation (18,82). More recently, it has also been shown that the truncated oxPAPC products, POVPC and PGPC, may individually have effects opposite to those of the complete oxPAPC mixture.…”

Section: Impact Of Oxidized Lipids On Endothelial Membrane Lipid Packmentioning

confidence: 99%

“…A major biologically active oxPC is oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine (oxPAPC), a component of the minimally oxidized form of LDL that represents the early and highly reactive oxidation state (15)(16)(17). OxPAPC is known to exert multiple biological effects, including formation of pro-inflammatory chemokines and monocyte adhesion to endothelial cells, as well as regulation of the endothelial barrier function (16)(17)(18). More specifically, oxPAPC contains a mixture of oxidized phospholipids with various biological activities.…”

Section: Introductionmentioning

confidence: 99%

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Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

Ayee

LeMaster

Shentu

et al. 2017

Biophysical Journal

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The influence of two bioactive oxidized phospholipids on model bilayer properties, membrane packing, and endothelial cell biomechanics was investigated computationally and experimentally. The truncated tail phospholipids, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC), are two major oxidation products of the unsaturated phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-phosphocholine. A combination of coarse-grained molecular dynamics simulations, Laurdan multiphoton imaging, and atomic force microscopy microindentation experiments was used to determine the impact of POVPC and PGPC on the structure of a multicomponent phospholipid bilayer and to assess the consequences of their incorporation on membrane packing and endothelial cell stiffness. Molecular simulations predicted differential bilayer perturbation effects of the two oxidized phospholipids based on the chemical identities of their truncated tails, including decreased bilayer packing, decreased bilayer bending modulus, and increased water penetration. Disruption of lipid order was consistent with Laurdan imaging results indicating that POVPC and PGPC decrease the lipid packing of both ordered and disordered membrane domains. Computational predictions of a larger membrane perturbation effect by PGPC correspond to greater stiffness of PGPC-treated endothelial cells observed by measuring cellular elastic moduli using atomic force microscopy. Our results suggest that disruptions in membrane structure by oxidized phospholipids play a role in the regulation of overall endothelial cell stiffness.

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Section: Impact Of Oxidized Lipids On Endothelial Membrane Lipid Packmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

Ayee

LeMaster

Shentu

et al. 2017

Biophysical Journal

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“…Furthermore, oxidized phospholipid binding with apo(a) could induce pro-inflammatory IL-8 expression (Scipione et al 2015). Considering the formation of oxidized phospholipids by lipid peroxidation (Greig et al 2012) and the distinct regulatory functions of different oxidized phospholipids species on inflammation (Freigang 2016), it may be helpful to reveal the impact of oxidative stress on the profiles of oxidized phospholipids and the exact roles of specific oxidized lipid metabolites in the initiation and progression of CAVD.…”

Section: Modulementioning

confidence: 99%

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

Liu

Luo

Sun

et al. 2017

Tohoku J. Exp. Med.

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In our aging world, increasing numbers of people are suffering from calcific aortic valve disease (CAVD). In this study, we used integrated bioinformatics analysis to predict several key genes that are involved in the initiation and progression of CAVD. Expression profiles of 15 calcific and 14 normal human aortic valve samples were generated from two gene expression datasets (GSE12644 and GSE51472). Dataset GSE26953 from the human aortic valve fibrosa-derived endothelial cells cultured under laminar or oscillatory shear stress was also evaluated. Related R packages were used to process the data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for functional annotation. Hub genes were identified based on the protein-protein interaction network. CAVD-related gene modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). The predicted key genes were manually reviewed. In our present work, complex connections among mechano-response, oxidative stress, inflammation and extracellular remodeling pathways in the etiology of CAVD were revealed. The key genes, thus identified, encode a transcription factor KLF2 and phospholipid phosphatase 3 (PLPP3) that are involved in mechanoresponses; eNOS involved in oxidative stress; IL-8 involved in inflammation; and collagen triple helix repeat containing 1 (CTHRC1) and secretogranin II (SCG2) involved in extracellular remodeling. These gene products are predicted to play critical roles in CAVD development and progression. The present study provides valuable information for future research and drug development.

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“…The active forms of MPO as well as HOCl-modified LDL are present in human atherosclerotic plaques [12,13] and correlate with an increase in the intima-to-media ratio in human iliac arteries [14]. Phospholipid chlorohydrins have a multitude of biological effects [15,16]. Their high polarity can disrupt cell membranes and cause toxicity in myeloid and endothelial cells [17,18] and can also induce leucocyte adhesion by up-regulation of adhesion molecules [19].…”

Section: Apoementioning

confidence: 99%

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

et al. 2015

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The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. The present study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodelling processes. Vascular injury was induced in C57BL/6 mice and high fat-fed ApoE −/− (apolipoprotein E) mice by wire denudation and ligation of the left carotid artery (LCA). Neointimal and medial composition was assessed using immunohistochemistry and ESI-MS. Primary rabbit aortic SMCs (smooth muscle cells) were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima-to-media ratio, was significantly larger in wire-injured ApoE −/− mice (3.62 + − 0.49 compared with 0.83 + − 0.25 in C57BL/6 mice, n = 3) and there was increased oxidized low-density lipoprotein (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines (PCs) were also observed in wire-injured ApoE −/− carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration whereas chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum [154.8 + − 14.2 % of viable cells at 1 μM PGPC (1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine) compared with control, n = 6]. In conclusion, ApoE −/− mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect.

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Physiological effects of oxidized phospholipids and their cellular signaling mechanisms in inflammation

Cited by 101 publications

References 187 publications

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

Molecular-Scale Biophysical Modulation of an Endothelial Membrane by Oxidized Phospholipids

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation

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