6533b827fe1ef96bd1285d9b
RESEARCH PRODUCT
Fatty acids liberated from low-density lipoprotein trigger endothelial apoptosis via mitogen-activated protein kinases.
Hidenori IchijoMatthias HusmannSucharit BhakdiKatrin Derschsubject
Programmed cell deathp38 mitogen-activated protein kinasesBlotting WesternApoptosisDNA FragmentationBiologyFatty Acids NonesterifiedMAP Kinase Kinase Kinase 5p38 Mitogen-Activated Protein Kinaseschemistry.chemical_compoundHumansPhosphorylationMolecular BiologyCells CulturedCaspase 7Cell growthKinaseCaspase 3Cell BiologyCell biologyLipoproteins LDLchemistryBiochemistryApoptosisLow-density lipoproteinCaspasesPhosphorylationlipids (amino acids peptides and proteins)Endothelium VascularLipoproteinOleic Aciddescription
Enzymatic modification of low-density lipoprotein (LDL) as it probably occurs in the arterial intima drastically increases its cytotoxicity, which could be relevant for the progression of atherosclerotic lesions. LDL was treated with a protease and cholesterylesterase to generate a derivative similar to lesional LDL, with a high content of free cholesterol and fatty acids. Exposure of endothelial cells to the enzymatically modified lipoprotein (E-LDL), but not to native or oxidized LDL, resulted in programmed cell death. Apoptosis was triggered by apoptosis signal-regulating kinase 1 dependent phosphorylation of p38. Depletion and reconstitution experiments identified free fatty acids (FFA) as the triggers of this pathway. Levels of FFA in native LDL are low and the lipoprotein is therefore not cytotoxic; enzymatic cleavage of cholesterylesters liberates FFA that can rapidly trigger an apoptosis signaling cascade in neighboring cells. Blockade of this pathway can rescue cells from death.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2005-04-23 | Cell death and differentiation |