Lymphocyte resistance to lysophosphatidylcholine mediated apoptosis in atherosclerosis

Zurgil, Naomi; Afrimzon, Elena; Shafran, Yana; Shovman, Ora; Gilburd, Boris; Brikman, Haim; Shoenfeld, Yehuda; Deutsch, Mordechai

doi:10.1016/j.atherosclerosis.2006.02.013

Cited by 15 publications

(16 citation statements)

References 33 publications

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“…Neutrophils ROS generation: NAD(P)H oxidase activation and myeloperoxidase release [49] Functional responses: increased chemotaxis, elastase release [49] Monocytes/Macrophages Formation of inflammatory mediators: upregulation of cytokines (IL-1 , IL-8, VEGF, HB-EGF), Ca 2+ -dependent PLA2 enzymes, and arachidonic acid release [50,51] Functional responses: increased chemotaxis [52,53] Cytotoxicity: increased cellular permeability and apoptosis [54] T-lymphocytes Formation of inflammatory mediators: upregulation of cytokines (IL-2, IFN-, and ROS) [55,56] Functional responses: increased chemotaxis [49] Cytotoxicity: increased apoptosis [57] Endothelial cells Homing of inflammatory cells: upregulation of adhesion molecules (ICAM-1/VCAM-1), P-selectin, and MCP-1 [58][59][60] Formation of inflammatory mediators: activation of Ca 2+ -dependent PLA2 enzymes, upregulation of COX-2 and arachidonic acid release [61] Functional responses: impaired proliferation/migration and reduced NO-and EDHF-mediated vasodilation [19,[62][63][64][65] Cytotoxicity: increased apoptosis [66] Smooth muscle cells Homing of inflammatory cells: upregulation of MCP-1 [67] Oxidative stress: NAD(P)H oxidase activation [68] Functional responses: upregulation of growth factors and increased proliferation and migration [50,69] Cytotoxicity: increased apoptosis [70] the lesion and are particularly abundant in the shoulder region, where the atheroma grows [71]. Many of the immune cells exhibit signs of activation and produce inflammatory cytokines [3].…”

Section: Target Cells Effects Referencesmentioning

confidence: 99%

Role of Lysophosphatidylcholine (LPC) in Atherosclerosis

Matsumoto

Kobayashi²,

Kamata

2007

CMC

288

215

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Lysophosphatidylcholine (LPC) is a bioactive proinflammatory lipid generated by pathological activities. LPC is also a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL) and is implicated as a critical factor in the atherogenic activity of Ox-LDL. LPC is believed to play an important role in atherosclerosis and inflammatory diseases by altering various functions in a number of cell-types, including endothelial cells, smooth muscle cells, monocytes, macrophages, and T-cells. LPC activates several second messengers -- including protein kinase C, extracellular-signal-regulated kinases, protein tyrosine kinases, and Ca(2+) -- implicating the engagement of transduction mechanisms in its observed actions. Moreover, recent evidence suggests that in several cell-types, cloned orphan G-protein-coupled receptors may serve as the specific receptors via which LPC modulates second messenger pathways (although LPC may not be a direct ligand of such receptors). In addition, current evidence suggests that LPC impairs the endothelium-dependent relaxations mediated by endothelium-derived relaxing factors and directly modulates contractile responses in vascular smooth muscle. However, despite all this, and although elevated levels of LPC have been linked to the cardiovascular complications associated with atherosclerosis, ischemia, and diabetes, the precise pathophysiological roles played by LPC in several states remain to be established. In this review, we focus in some detail on the entirety of the signal-transduction system for LPC, its pathophysiological implications, and the vascular abnormalities associated with it.

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Section: Target Cells Effects Referencesmentioning

confidence: 99%

Role of Lysophosphatidylcholine (LPC) in Atherosclerosis

Matsumoto

Kobayashi²,

Kamata

2007

CMC

288

215

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“…To determine whether this model was sensitive to intervention strategies, compounds that prevented LPC toxicity in other cell types (Colles and Chisolm, 2000;Watanabe et al, 2006;Zurgil et al, 2007) were added simultaneously with LPC. The effect of the compounds on LPC toxicity was determined by MBP ELISA and CNPase activity assay (Fig.…”

Section: Prevention Of Lpc Toxicity In Rat Whole Brain Spheroids Cultmentioning

confidence: 99%

An in vitro model for de‐ and remyelination using lysophosphatidyl choline in rodent whole brain spheroid cultures

Vereyken

Fluitsma

Bolijn

et al. 2009

Glia

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The process of demyelination occurring in diseases as multiple sclerosis is usually investigated in animal models. A major drawback of animal models is that only one condition can be tested per animal, necessitating many animals and systemic effects are factors to be considered. The aim of the study was to develop a reproducible in vitro model for de- and remyelination using whole brain spheroid cultures and lysophosphatidyl choline (LPC). In spheroid cultures, single cell suspensions of embryonic day 15 rodent brain cells reaggregate under constant rotation. Three-dimensional contacts form between the central nervous system cell types present. Multilayered myelin is maximal in four-week old cultures. A week of repeated exposure to LPC led to 30% loss of MBP protein concentration and 2',3'-cyclic nucleotide 3'-phosphodiesterase activity measurements in both rat and mouse spheroids and 56% loss in the number of myelin sheets, with partial remyelination after a week of recovery. The number of dividing cells was increased after LPC exposure and oligodendrocytes were shown to be among the dividing cells. Microglia and astrocytes were not affected and neurons were relatively spared. This suggests that LPC toxicity is specific for myelin and oligodendrocytes. LPC toxicity could be decreased using cholesterol and simvastatin, suggesting that LPC works through altering membrane composition. Thus, in different rodent species and using different read-outs, we could reproducibly show de- and remyelination in spheroid cultures after LPC exposure. This model for demyelination with potential for remyelination offers possibilities for testing novel therapies and studying mechanisms of remyelination.

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“…LPC (a mixture of 16:0, 18:0 and 18:1, 5-50 µM) increases apoptosis and reactive oxygen species (ROS) generation in phytohemagglutinin (PHA)-activated but not in control human peripheral blood lymphocytes (Zurgil et al, 2007).…”

Section: Lymphocytesmentioning

confidence: 99%

“…Chemoattractant (McMurray et al, 1993;Ryborg et al, 1994;Radu et al, 2004) IL-2Rα↑/thymidine uptake↑ (Asaoka et al, 1991;Asaoka et al, 1992) HB-EGF↑ (Nishi et al, 1997), IFN-γ↑ CD40 ligand↑ (Sakata-Kaneko et al, 1998), CXCR4↑, IL-2↑ (Han et al, 2004) Antibody formation↑, most notably IgA (Huang et al, 1999) Apoptosis↑/ROS generation↑ (Zurgil et al, 2007) p56 lck and ZAP 70 phosphorylation↑, [Ca2+] i ↑ in Jurkat cells (Legradi et al, 2004) Monocyte/macrophage Chemoattractant (Quinn et al, 1988) Activates p38 and p42/44 MAPKs in THP-1 cells (Jing et al, 2000) Mitogenic effects of acetylated LDL↑ (Sakai et al, 1994) Mature dendritic cell generation↑/CD86↑ (Coutant et al, 2002) Adhesion↑/activation of CD11b (Weber et al, 1995) IFN-γ↑ (Nakano et al, 1994), IL-1 β↑ (Liu-Wu et al, 1998), TNF-α↑ (Huang et al, 1999), MIP2↑ in RAW264.7 cells (Olofsson et al, 2008), arachidonic acid ↑ in THP-1 and Mono Mac6 cells (Oestvang et al, 2003) Phospholipase D (PLD) activity ↑ (Gómez- Muñoz et al, 1999) Extracellular acidification ↑ in RAW264.7 cells (De Vries et al, 1998) EC-SOD ↑ in U937 cells (Yamamoto et al, 2002) Ca 2+ influx ↑ in U937 human monocytes (Yun et al, 2004) De-ramification of murine microglia↑/nonselective cation current↑, calcium-activated potassium current↑/ hyperpolarization↑ (Schilling et al, 2004) …”

Section: Lymphocytementioning

confidence: 99%