The effects of native LDL and oxidized LDL on EDRF bioactivity and nitric oxide production in vascular endothelium.
Low-density lipoprotein (LDL) and oxidized low-density lipoprotein (OxyLDL) have previously been shown to inhibit vasorelaxation caused by endothelium-derived relaxing factor (EDRF). The purpose of the present study was to directly determine the effects of LDL and OxyLDL on EDRF bioactivity and nitric oxide (NO) production in vascular endothelium to further understand the mechanism whereby lipoprotein alters vascular reactivity. Cultured bovine aortic endothelial cells were incubated with either LDL or OxyLDL for 1 hour. After washing the cells free of lipoprotein, agonist-stimulated (bradykinin; BK) EDRF bioactivity and NO content of the effluent were quantitated. These results were compared with control cells not exposed to lipoprotein. In a second series of experiments, the effects of LDL and OxyLDL on EDRF-mediated increases in cyclic guanosine monophosphate (cGMP) in a reporter fibroblast cell line were determined. Last, the direct effects of LDL on NO-induced vasodilation of isolated coronary artery rings were determined by using standard in vitro isometric recording methods. LDL and OxyLDL significantly decreased EDRF bioactivity but not NO production by endothelial cells. When expressed as percent relaxation of the biodetector per mole of NO produced, both LDL and OxyLDL resulted in the release of a significantly less-potent vasodilator than that derived from control cells. In the reporter fibroblast experiments, there was no significant difference in the amount of cGMP generated by fibroblasts in response to medium from control and lipoprotein-treated cells. In isolated ring experiments, LDL did not directly alter NO vasorelaxation. We conclude that both LDL and OxyLDL inhibit EDRF-induced vasorelaxation by complex mechanisms other than the direct inhibition of NO synthesis by endothelial cells or extracellular inactivation of EDRF. LDL and OxyLDL may result in the release of a less potent NO-containing relaxing factor by altering the metabolism of an endogenous nitrosovasodilator.
Harry S Truman Memorial Veterans Administration Hospital, Columbia, MO.
P R
PR
Myers
T F
TF
Wright
M A
MA
Tanner
R E
RE
Ostlund
D000818:Animals; D002417:Cattle; D006152:Cyclic GMP / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
D008074:Lipoproteins; D008077:Lipoproteins, LDL; D009569:Nitric Oxide; D006152:Cyclic GMP