Acute effects of oxidized low density lipoprotein on metabolic responses in macrophages

^a Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, University of Leiden, Leiden, The Netherlands
^b CNS Pharmacology, Solvay Duphar, Weesp, The Netherlands

The immediate effects of oxidized low density lipoprotein (OxLDL) on the metabolic activity of cultured macrophages (RAW 264.7) were studied using a microphysiometer. Administration of OxLDL acutely induced a concentration-dependent increase in metabolic activity, with an EC₅₀ of 16 ± 3 µg/ml OxLDL and a maximal effect of 35% ± 4% (mean ± SEM; n=5). A biphasic response was measured after administration of 75 or 100 µg/ml OxLDL consisting of an initial sharp increase, followed by the induction of a long-lasting hypoactivity of 80% of the control value. Incubation of cells with polyinosinic acid (polyI; 100 µg/ml) for 30 min prior to OxLDL administration could completely block the effect of 25 µg/ml OxLDL. In addition, polyI acted as a full antagonist on the decrease of the biphasic response of cells generated by 75 and 100 µg/ml OxLDL. Macrophages used in this study possessed a specific binding site for OxLDL, with a dissociation constant (K_D) of 9 ± 2 µg/ml and a maximal binding of 610 ± 32 ng ¹²⁵I-OxLDL/mg cell protein. Binding of ¹²⁵I-OxLDL to macrophages could be completely competed for by unlabeled OxLDL, by polyI for 58%, and by AcLDL for 46%. In conclusion, OxLDL can acutely activate the metabolic state of macrophages by a receptor-mediated process in a concentration-dependent fashion, which could be antagonized by polyI. Metabolic responses to OxLDL may underlie the changes observed in macrophages in the early atherosclerotic plaque.—de Vries, H. E., Ronken, E., Reinders, J.-H., Buchner, B., van Berkel, T. J. C., and Kuiper, J. Acute effects of oxidized low density lipoprotein on metabolic responses in macrophages. FASEB J. 12, 111–118 (1998)

Key Words: microphysiometer • oxLDL • scavenger receptor • atheroclerosis

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