Oxidized low-density lipoprotein induces calcium influx in polymorphonuclear leukocytes.
Polymorphonuclear leukocytes (PMN) have been suggested to play a role in atherosclerosis, but intracellular signaling after stimulation with oxidized low-density lipoprotein (LDL) is unknown. We investigated mechanistic aspects of oxidized LDL-induced superoxide production by human PMN, with special emphasis on intracellular Ca(2+) concentration ([Ca(2+)](i)). Oxidized LDL, but not native LDL, evoked an early but sustained increase in [Ca(2+)](i) and a delayed production of superoxide. The increase in [Ca(2+)](i) could be reduced by fucoidan and completely prevented by U73122, suggesting involvement of the scavenger receptor and coupling to the phospholipase C signal transduction pathway. Furthermore, we provide evidence that the increase in [Ca(2+)](i) partly results from protein kinase C-dependent Ca(2+) influx. The relevance of this Ca(2+) entry for oxidized LDL-stimulated effects is illustrated by the finding that superoxide production was markedly reduced in the absence of external Ca(2+). Finally, inhibition of phagocytosis by cytochalasin B abolished oxidized LDL-stimulated superoxide production without affecting, however, the Ca(2+) mobilization. These effects of oxidized LDL on [Ca(2+)](i) and on respiratory burst of PMN may underlie the occurrence of elevated levels of [Ca(2+)](i) of resting PMN in hypercholesterolemia and represent a mechanism by which PMN can amplify processes in the early phase of atherosclerosis.
van Tits
L J
LJ
Department of Medicine, Division of General Internal Medicine, Nijmegen, The Netherlands. b.vantits@aigazn.nl
Hak-Lemmers
H L
HL
Demacker
P N
PN
Stalenhoef
A F
AF
Willems
P H
PH
D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008163:Luminescent Measurements; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D010084:Oxidation-Reduction; D013481:Superoxides / Q000378:metabolism
D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D013481:Superoxides