Hypersusceptibility of neutrophil granulocytes towards lethal action of free fatty acids contained in enzyme-modified atherogenic low density lipoprotein.
OBJECTIVE
The bulk of LDL entrapped in the arterial intima is modified by hydrolytic enzymes, leading to extensive cleavage of cholesterylesters and liberation of fatty acids. The latter induce apoptosis in endothelial cells but are far less cytotoxic towards macrophages. We have compared the cytotoxic effects of enzymatically modified LDL (E-LDL) on macrophages and polymorphonuclear granulocytes (PMN).


RESULTS
E-LDL displayed toxicity towards PMN at far lower concentrations than towards monocyte-derived macrophages. Native or oxidized LDL had no effect. Free fatty acids contained in E-LDL were the cause of the observed toxicity, which could be mimicked by linoleic acid, oleic acid and arachidonic acid. E-LDL provoked Ca(2+) influx and activated PMN, as witnessed by the generation of superoxide anions and peroxidase secretion. Inhibition of either oxidative burst or calcium influx did not diminish the cytotoxicity of E-LDL. Similar to free linoleic acid, E-LDL lysed red blood cells and rapidly rendered cells permeable to propidium iodide.


CONCLUSIONS
Possibly through their capacity to directly perturb cell membranes, free fatty acids contained in E-LDL exert potent cytotoxic effects on PMN. This may be one reason why PMN are not abundantly present in atherosclerotic lesions, and why PMN-depletion suppresses atherogenesis.
Institute of Medical Microbiology and Hygiene, Johannes Gutenberg-University Mainz, Hochhaus am Augustusplatz, 55131 Mainz, Germany.
Cornelia Aquilina
CA
Lux
Andreas
A
Koschinski
Katrin
K
Dersch
Matthias
M
Husmann
Sucharit
S
Bhakdi
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002463:Cell Membrane Permeability; D002470:Cell Survival; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D006461:Hemolysis; D006801:Humans; D006868:Hydrolysis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019787:Linoleic Acid / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D019301:Oleic Acid / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D016897:Respiratory Burst; D002787:Sterol Esterase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D005230:Fatty Acids, Nonesterified; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D013481:Superoxides; D016718:Arachidonic Acid; D019301:Oleic Acid; D000255:Adenosine Triphosphate; D019787:Linoleic Acid; D007770:L-Lactate Dehydrogenase; D009195:Peroxidase; D002787:Sterol Esterase; D010447:Peptide Hydrolases; D002118:Calcium