title: LDL are oxidatively modified by platelets via GP91(phox) and accumulate in human monocytes.
abstract: Oxidative stress-mediated LDL modification has a key role in initiation of the atherosclerotic process. Platelets produce reactive oxidant species (ROS) upon stimulation with agonist, but it is uncertain whether they are able to oxidatively modify LDL. Human platelets taken from healthy subjects were incubated with LDL, then stimulated with collagen. Compared with unstimulated platelets, collagen-stimulated platelets induced LDL modification as shown by enhanced conjugated dienes and lysophosphatidylcholine formation, electrophoretic mobility, Apo B-100 degradation, and monocyte LDL uptake. Activated platelets also induced a marked reduction of vitamin E contained in LDL. A significant inhibition of LDL oxidation was observed in platelets treated with arachidonyl trifluomethyl ketone (AACOCF3), an inhibitor of phospholipase A2. The experiments reported above were also conducted in patients with hereditary deficiency of gp91phox, the central core of NADPH oxidase, and in patients with hypercholesterolemia. Platelets from gp91 phox-deficient patients produced a small amount of ROS and weakly modified LDL. Conversely, platelets from hypercholesterolemic patients showed enhanced ROS formation and oxidized LDL more than platelets from healthy subjects. This study provides evidence that platelets modify LDL via NADPH oxidase-mediated oxidative stress, a phenomenon that could be dependent on arachidonic acid activation. This finding suggests a role for platelets in favoring LDL accumulation within atherosclerotic plaque.
authors.affiliation: Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Carnevale
authors.forename: P
authors.initials: P
authors.lastname: Pignatelli
authors.forename: L
authors.initials: L
authors.lastname: Lenti
authors.forename: B
authors.initials: B
authors.lastname: Buchetti
authors.forename: V
authors.initials: V
authors.lastname: Sanguigni
authors.forename: S
authors.initials: S
authors.lastname: Di Santo
authors.forename: F
authors.initials: F
authors.lastname: Violi
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000302:isolation & purification; D008562:Membrane Glycoproteins / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein; D014810:Vitamin E; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases