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J. Biol. Chem., Vol. 280, Issue 38, 32746-32752, September 23, 2005

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Group V Secretory Phospholipase A₂-modified Low Density Lipoprotein Promotes Foam Cell Formation by a SR-A- and CD36-independent Process That Involves Cellular Proteoglycans^*

Boris B. Boyanovsky, Deneys R. van der Westhuyzen, and Nancy R. Webb1

From the Department of Internal Medicine and Veterans Affairs Medical Center, Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, Kentucky 40536-0200

Accumulating evidence indicates that secretory phospholipase A₂ (sPLA₂) enzymes promote atherogenic processes. We have previously showed the presence of Group V sPLA₂ (GV sPLA₂) in human and mouse atherosclerotic lesions, its hydrolysis of low density lipoprotein (LDL) particles, and the ability of GV sPLA₂-modified LDL (GV-LDL) to induce macrophage foam cell formation in vitro. The goal of this study was to investigate the mechanisms involved in macrophage uptake of GV-LDL. Peritoneal macrophages from C57BL/6 mice (wild type (WT)), C57BL/6 mice deficient in LDL receptor (LDLR^–/–), or SR-A and CD36 (DKO) were treated with control LDL, GV-LDL, oxidized LDL (ox-LDL) or LDL aggregated by vortexing (vx-LDL). As expected, ox-LDL induced significantly more cholesterol ester accumulation in WT and LDLR^–/– compared with DKO macrophages. In contrast, there was no difference in the accumulation of GV-LDL or vx-LDL in the three cell types. ¹²⁵I-ox-LDL exhibited high affinity, saturable binding to WT cells that was significantly reduced in DKO cells. Vx-LDL and GV-LDL showed low affinity, non-saturable binding that was similar for both cell types, and significantly higher compared with control LDL. GV-LDL degradation in WT and DKO cells was similar. Analyses by confocal microscopy indicated a distinct intracellular distribution of Alexa-568-labeled GV-LDL and Alexa-488-labeled ox-LDL. Uptake of GV-LDL (but not ox-LDL or vx-LDL) was significantly reduced in cells preincubated with heparin or NaClO₃, suggesting a role for proteoglycans in GV-LDL uptake. Our data point to a physiological modification of LDL that has the potential to promote macrophage foam cell formation independent of scavenger receptors.

Received for publication, February 23, 2005 , and in revised form, May 16, 2005.

^* This work was supported by National Institutes of Health Grant HL071098 (to N. R. W.) and HL-65730 (to D. R. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, University of Kentucky Medical Ctr., 535 CT Wethington Bldg., 900 S. Limestone St., Lexington, KY 40536-0200. Tel.: 859-323-4933 (ext. 81385); Fax: 859-257-3646; E-mail: nrwebb1{at}uky.edu.

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