Upregulation of endothelial adhesion molecules by lysophosphatidylcholine

Kim, Chul Han; Chung, Jong Il; Kim, Ji Y.; Chung, Sang Woon; Kim, Mi K.; Im, Dong‐Soon; Lee, Joo Young; Yu, Byung P.; Chung, Hae Young

doi:10.1111/j.1742-4658.2007.05792.x

Cited by 27 publications

(16 citation statements)

References 46 publications

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“…We identified GPR4 in an mRNA expression profiling screen as an endothelial cell-specific gene, in accordance with previous reports [5][6][7][8][9][10]. We further show that in primary human endothelial cells, GPR4 acts as a functional proton-sensing receptor, since the pH-dependent cAMP production could be blocked by GPR4-specific siRNAs and receptor antagonists ( Fig.…”

Section: Discussionsupporting

confidence: 91%

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Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor

et al. 2011

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The G protein-coupled receptor GPR4 is activated by acidic pH and recent evidence indicates that it is expressed in endothelial cells. In agreement with these reports, we observe a high correlation of GPR4 mRNA expression with endothelial marker genes, and we confirm expression and acidic pH dependent function of GPR4 in primary human vascular endothelial cells. GPR4-deficient mice were generated; these are viable and fertile and show no gross abnormalities. However, these animals show a significantly reduced angiogenic response to VEGF (vascular endothelial growth factor), but not to bFGF (basic fibroblast growth factor), in a growth factor implant model. Accordingly, in two different orthotopic models, tumor growth is strongly reduced in mice lacking GPR4. Histological analysis of tumors indicates reduced tumor cell proliferation as well as altered vessel morphology, length and density. Moreover, GPR4 deficiency results in reduced VEGFR2 (VEGF Receptor 2) levels in endothelial cells, accounting, at least in part, for the observed phenotype. Our data suggest that endothelial cells sense local tissue acidosis via GPR4 and that this signal is required to generate a full angiogenic response to VEGF.

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Section: Discussionsupporting

confidence: 91%

“…Earlier reports had already described an important role for GPR4 in endothelial cell function, but these findings were seen in relation to the presumed ligands sphingosylphosphorylcholine and lysophosphatidylcholine [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 80%

Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor

et al. 2011

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“…It is believed to be a critical factor underlying cardiovascular diseases,1,2 and several pathological conditions are associated with elevated LPC levels in the circulation 3-5. LPC has a broad-spectrum of pro-inflammatory activities, including promotion of cell growth,6 migration,7,8 secretion of chemokines and cytokines,9,10 generation of reactive oxygen species,11 and upregulation of adhesion molecules such as ICAM-1, VCAM-1, and selectins 12…”

Section: Introductionmentioning

confidence: 99%

Bioactive Lysophosphatidylcholine 16:0 and 18:0 Are Elevated in Lungs of Asthmatic Subjects

Yoder

Zhuge

Yuan

et al. 2014

Allergy Asthma Immunol Res

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PurposeAsthma is a chronic inflammatory disease of the airways, and is associated with upregulation of phospholipase A2 (PLA2), the enzyme that hydrolyzes phosphatidylcholine, producing lysophosphatidylcholine (LPC) and free fatty acids. LPC is a lipid mediator with known pro-inflammatory and pro-atherogenic properties, and is believed to be a critical factor in cardiovascular diseases. We postulate that asthmatic subjects have an elevated content of LPC in the lung lining fluids.MethodsEight non-asthmatic controls and seven asthmatic subjects were recruited for broncho-alveolar lavage fluids (BALF) collection for analysis of LPC by high performance liquid chromatography-tandem mass spectrometry.ResultsLPC16:0 and LPC18:0 were significantly elevated in the BALF of asthmatics with impaired lung function characteristic of moderate asthma, but not mild asthma. The increased LPC content in BALF was accompanied by increased PLA2 activity. Furthermore, qRT-PCR analysis of the BALF cell fraction indicated increased secretory PLA2-X (sPLA2-X).ConclusionsThe increased LPC content in the lung lining fluids is a potential critical lipid mediator in the initiation and/or progression of airway epithelial injury in asthma.

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“…Such pathological increases of LPC can significantly contribute to the inflammatory microenvironment in lungs. Abundant evidence indicates that LPC induces multiple pro-inflammatory activities, including promotion of cell growth,5 migration,6,7 secretion of chemokines and cytokines,8,9 generation of reactive oxygen species,10 and upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and selectins 11. Furthermore, studies show that exogenous administration of LPC into lungs induces infiltration of eosinophils12 and increased lung permeability 13,14.…”

Section: Introductionmentioning

confidence: 99%

Stimulated Bronchial Epithelial Cells Release Bioactive Lysophosphatidylcholine 16:0, 18:0, and 18:1

Zhuge

Yuan

Breemen

et al. 2014

Allergy Asthma Immunol Res

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PurposeIn human subjects and animal models with acute and chronic lung injury, the bioactive lysophosphatidylcholine (LPC) is elevated in lung lining fluids. The increased LPC can promote an inflammatory microenvironment resulting in lung injury. Furthermore, pathological lung conditions are associated with upregulated phospholipase A2 (PLA2), the predominant enzyme producing LPC in tissues by hydrolysis of phosphatidylcholine. However, the lung cell populations responsible for increases of LPC have yet to be systematically characterized. The goal was to investigate the LPC generation by bronchial epithelial cells in response to pathological mediators and determine the major LPC species produced.MethodsPrimary human bronchial epithelial cells (NHBE) were challenged by vascular endothelial growth factor (VEGF) for 1 or 6 h, and condition medium and cells collected for quantification of predominant LPC species by high performance liquid chromatography-tandem mass spectrometry (LC-MS-MS). The cells were analyzed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for PLA2. The direct effects of LPC in inducing inflammatory activities on NHBE were assessed by transepithelial resistance as well as expression of interleukin-8 (IL-8) and matrix metalloproteinase-1 (MMP-1).ResultsVEGF stimulation of NHBE for 1 or 6 h, significantly increased concentrations of LPC16:0, LPC18:0, and LPC18:1 in condition medium compared to control. The sPLA2-selective inhibitor (oleyloxyethyl phosphorylcholine) inhibited the VEGF-induced release of LPC16:0 and LPC18:1 and PLA2 activity. In contrast, NHBE stimulated with TNF did not induce LPC release. VEGF did not increase mRNA of PLA2 subtypes sPLA2-X, sPLA2-XIIa, cPLA2-IVa, and iPLA2-VI. Exogenous LPC treatment increased expression of IL-8 and MMP-1, and reduced the transepithelial resistance in NHBE.ConclusionsOur findings indicate that VEGF-stimulated bronchial epithelial cells are a key source of extracellular LPCs, which can function as an autocrine mediator with potential to induce airway epithelial inflammatory injury.

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Upregulation of endothelial adhesion molecules by lysophosphatidylcholine

Cited by 27 publications

References 46 publications

Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor

Reduced pathological angiogenesis and tumor growth in mice lacking GPR4, a proton sensing receptor

Bioactive Lysophosphatidylcholine 16:0 and 18:0 Are Elevated in Lungs of Asthmatic Subjects

Stimulated Bronchial Epithelial Cells Release Bioactive Lysophosphatidylcholine 16:0, 18:0, and 18:1

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