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Selected Publication:
Bochkov, VN; Mechtcheriakova, D; Lucerna, M; Huber, J; Malli, R; Graier, WF; Hofer, E; Binder, BR; Leitinger, N.
Oxidized phospholipids stimulate tissue factor expression in human endothelial cells via activation of ERK/EGR-1 and Ca(++)/NFAT.
Blood. 2002; 99(1):199-206
Doi: 10.1182/blood.V99.1.199
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- Co-authors Med Uni Graz
- Graier Wolfgang
- Malli Roland
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- Abstract:
- Activation of endothelial cells by lipid oxidation products is a key event in the initiation and progression of the atherosclerotic lesion. Minimally modified low-density lipoprotein (MM-LDL) induces the expression of certain inflammatory molecules such as tissue factor (TF) in endothelial cells. This study examined intracellular signaling pathways leading to TF up-regulation by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a biologically active component of MM-LDL. OxPAPC induced TF activity and protein expression in human umbilical vein endothelial cells (HUVECs). However, OxPAPC neither induced phosphorylation or degradation of I kappa B alpha nor DNA binding of nuclear factor-kappa B (NF-kappa B). Furthermore, OxPAPC-induced TF expression was not inhibited by overexpression of I kappa B alpha. These results strongly indicate that OxPAPC-induced TF expression is independent of the classical NF-kappa B pathway. However, OxPAPC stimulated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and expression of early growth response factor 1 (EGR-1). Inhibitors of mitogen-activated kinase/ERK (MEK) or protein kinase C (PKC) blocked elevation of both EGR-1 and TF. Furthermore, overexpression of NAB2, a corepressor of EGR-1, inhibited effects of OxPAPC. In addition, OxPAPC induced rapid and reversible elevation of free cytosolic Ca(++) levels and nuclear factor of activated T cells (NFAT)/DNA binding. Induction of TF expression by OxPAPC was partially inhibited by cyclosporin A, known to block calcineurin, a Ca(++)-dependent phosphatase upstream of NFAT. Treatment of OxPAPC with phospholipase A(2) destroyed its biologic activity and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine was identified as one biologically active component of OxPAPC that induces TF expression. Together, the results demonstrate that OxPAPC induces TF expression in HUVECs through activation of PKC/ERK/EGR-1 and Ca(++)/calcineurin/NFAT pathways rather than by NF-kappa B-mediated transcription. Thus, oxidized phospholipids may contribute to inflammation by activating pathways alternative to the classical NF-kappa B pathway.
- Find related publications in this database (using NLM MeSH Indexing)
- Calcineurin - antagonists and inhibitors
- Calcium - metabolism
- Cells, Cultured - metabolism
- Cyclosporine - pharmacology
- DNA - metabolism
- DNA-Binding Proteins - metabolism
- Early Growth Response Protein 1 - metabolism
- Endothelium, Vascular - drug effects
- Enzyme Activation - drug effects
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- I-kappa B Proteins - drug effects
- Immediate-Early Proteins - drug effects
- Mitogen-Activated Protein Kinase 1 - metabolism
- Mitogen-Activated Protein Kinase 3 - metabolism
- Mitogen-Activated Protein Kinases - metabolism
- NF-kappa B - metabolism
- NFATC Transcription Factors - metabolism
- Nuclear Proteins - metabolism
- Oxidation-Reduction - metabolism
- Phospholipases A - pharmacology
- Phospholipid Ethers - pharmacology
- Phosphorylation - pharmacology
- Thromboplastin - metabolism
- Transcription Factors - metabolism
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