Abstract
Objective:
Previous studies have shown that oxidized products of PAPC (Ox-PAPC) regulate cell transcription of interleukin-8, LDL receptor, and tissue factor. This upregulation takes place in part through the activation of sterol regulatory element-binding protein (SREBP) and Erk 1/2. The present studies identify vascular endothelial growth factor receptor 2 (VEGFR2) as a major regulator in the activation of SREBP and Erk 1/2 in endothelial cells activated by Ox-PAPC.
Methods and results:
Ox-PAPC induced the phosphorylation of VEGFR2 at Tyr1175 in human aortic endothelial cells. Inhibitors and siRNA for VEGFR2 decreased the transcription of interleukin-8, LDL receptor, and tissue factor in response to Ox-PAPC and the activation of SREBP and Erk 1/2, which mediate this transcription. We provide evidence that the activation of VEGFR2 is rapid, sustained, and c-Src-dependent.
Conclusions:
These data point to a major role of VEGFR2 in endothelial regulation by oxidized phospholipids which accumulate in atherosclerotic lesions and apoptotic cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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Cells, Cultured
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / physiology*
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Enzyme Activation / drug effects
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Humans
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Interleukin-8 / genetics
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Interleukin-8 / physiology
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / physiology
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Phosphatidylcholines / pharmacology*
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Phosphorylation / drug effects
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RNA, Small Interfering / pharmacology
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Receptors, LDL / genetics
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Receptors, LDL / physiology
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Sterol Regulatory Element Binding Proteins / genetics
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Sterol Regulatory Element Binding Proteins / physiology
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Thromboplastin / genetics
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Thromboplastin / physiology
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Transcription, Genetic / drug effects
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Transcription, Genetic / physiology
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Vascular Endothelial Growth Factor Receptor-2 / physiology*
Substances
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Interleukin-8
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Phosphatidylcholines
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RNA, Small Interfering
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Receptors, LDL
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Sterol Regulatory Element Binding Proteins
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oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine
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Thromboplastin
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Vascular Endothelial Growth Factor Receptor-2
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Mitogen-Activated Protein Kinase 3