title: Oxidized low-density lipoprotein inhibits endothelium-dependent vasodilation by an antioxidant-sensitive, lysophosphatidylcholine-independent mechanism.
abstract: Previous studies have shown that oxidized low-density lipoprotein (LDL) can impair endothelial function and that this can be overcome in vivo by administration of vitamin E. However, it is unclear whether this effect of oxidized LDL is due to lysophosphatidylcholine or other components of oxidized LDL, and it is also uncertain if the protective effect of vitamin E is related to its antioxidant action. The objectives of the current study were to define how much of the effect of extensively oxidized LDL on endothelium-dependent relaxation (EDR) was in fact due to lysophosphatidylcholine, to determine if the effect of oxidized LDL involved oxidant stress to the endothelium, and, if so, to ascertain if this could be blocked by oxyradical scavengers or antioxidants. Endothelial function was assessed by measuring vasodilation in preconstricted rat mesenteric artery rings in response to acetylcholine. In the presence of 100 microg/mL oxidized LDL, 25-fold higher concentrations of acetylcholine were required for the same degree of vasorelaxation. Similar concentrations of native LDL or acetyl LDL had no effect, but 100 microg/mL phospholipase A(2)-treated LDL or 20 microM lysophosphatidylcholine produced a similar inhibition of EDR. Removal of more than 90% of lysophosphatidylcholine from oxidized LDL did not affect its ability to inhibit EDR, nor did treatment of oxidized LDL with borohydride. This effect of oxidized LDL was blocked by preincubation of arterial rings with vitamin E, probucol, or BO-653 (a potent lipophilic antioxidant), but not by superoxide dismutase. In contrast, the inhibition of EDR by lysophosphatidylcholine was unaffected by antioxidants. Calphostin C prevented the inhibition of EDR by oxidized LDL and lysophosphatidylcholine. These studies demonstrate that at least part of the effect of oxidized LDL on EDR is independent of lysophosphatidylcholine, lipid peroxides, and superoxide release but appears to involve intracellular oxidative stress and protein kinase C activation.
authors.affiliation: Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Holman
authors.initials: H
authors.lastname: Chan
authors.forename: Marilee
authors.initials: M
authors.lastname: Lougheed
authors.forename: Ismail
authors.initials: I
authors.lastname: Laher
authors.forename: Urs P
authors.initials: UP
authors.lastname: Steinbrecher
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001894:Borohydrides / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D010741:Phospholipases A / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001894:Borohydrides; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D014665:Vasodilator Agents; C099252:oxidized low density lipoprotein; D009599:Nitroprusside; D002374:Catalase; D013482:Superoxide Dismutase; D010741:Phospholipases A; D000109:Acetylcholine