Fatty acids liberated from low-density lipoprotein trigger endothelial apoptosis via mitogen-activated protein kinases.
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.
Dersch
K
K
Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, 55131 Mainz, Germany.
Ichijo
H
H
Bhakdi
S
S
Husmann
M
M
D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D019301:Oleic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D005230:Fatty Acids, Nonesterified; D008077:Lipoproteins, LDL; D019301:Oleic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases