Minimally Oxidized Low-Density Lipoprotein Increases Expression of Scavenger Receptor A, CD36, and Macrosialin in Resident Mouse Peritoneal Macrophages

From the Department of Medicine, University of California, San Diego.

Correspondence to Daniel Steinberg, University of California at San Diego, Department of Medicine 0682, 9500 Gilman Dr, La Jolla, CA 92093-0682. E-mail dsteinberg{at}ucsd.edu

Abstract—Fully oxidized LDL (OxLDL) is believed to contribute to atherogenesis in part by virtue of uptake into macrophages via specific scavenger receptors. This phenomenon results in the formation of cholesterol-loaded foam cells, a major component of atherosclerotic lesions. The present study is directed at examining the effects of OxLDL and minimally oxidized LDL (MM-LDL) on scavenger receptor expression and activity in mouse peritoneal resident macrophages. Macrophages were preincubated with MM-LDL or OxLDL at concentrations of 25 or 50 µg/mL for 24 to 48 hours, after which their ability to bind and take up ¹²⁵I-OxLDL or ¹²⁵I-acetylated LDL (AcLDL) was determined. MM-LDL pretreatment induced a clear increase of cell association and degradation of ¹²⁵I-OxLDL and ¹²⁵I-AcLDL. Pretreatment with OxLDL also enhanced scavenger receptor activity, but to a lesser degree. Neither native LDL nor AcLDL had any effect. Scatchard analysis showed that preincubation with 50 µg/mL MM-LDL for 48 hours increased the B_max of ¹²⁵I-OxLDL and ¹²⁵I-AcLDL by 139% and 154%, respectively, without significantly changing their affinity. Lipids extracted from MM-LDL also significantly induced scavenger receptor activity, but to a lesser extent than did intact MM-LDL. MM-LDL pretreatment increased both mRNA levels and protein levels of scavenger receptor A, CD36, and macrosialin. On the other hand, OxLDL pretreatment increased expression of macrosialin only. These results, showing that MM-LDL can upregulate scavenger receptor expression in mouse resident peritoneal macrophages, suggest that clearance of OxLDL by macrophages in lesions is more effective, in part because the OxLDL precursor, MM-LDL, primes the macrophage for foam cell generation.

Key Words: minimally oxidized low density lipoprotein • scavenger receptor A • CD36 • macrosialin • mouse peritoneal resident macrophages

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