清道夫受体,氧化低密度脂蛋白和动脉粥样硬化

Scavenger Receptors, Oxidized LDL, and Atherosclerosis

AGNES BOULLIER, DAVID A. BIRD, MI-KYUNG CHANG, EDWARD A. DENNIS, PETER FRIEDMAN, KRISTIN GILLOTTE-TAYLOR, SOHVI HÖRKKÖ,

WULF PALINSKI, OSWALD QUEHENBERGER, PETER SHAW,

DANIEL STEINBERG, VALESKA TERPSTRA, AND JOSEPH L. WITZTUM Department of Medicine, University of California, San Diego, La Jolla,

California 92093, USA

A BSTRACT: Oxidized LDL (OxLDL) competes with oxidatively damaged and

apoptotic cells for binding to mouse peritoneal macrophages, implying the

presence of one or more common domains. However, the nature of the ligands

involved has not been determined. Studies in this laboratory over the last sev-

eral years provide evidence that oxidized phospholipids, present in OxLDL and

also in the membrane of apoptotic cells, represent one such ligand. These oxi-

dized phospholipids, either in the lipid phase of OxLDL or becoming attached

covalently to apoprotein B during LDL oxidation, have been shown to play a

major role in the binding of OxLDL to CD36 and to SR-B1 expressed in trans-

fected cells. The lipid and protein moieties compete with each other to some ex-

tent, indicating that they are binding to at least one common site. A monoclonal

antibody selected because of its reactivity with OxLDL proved to be an anti-

body against oxidized phospholipids (but not native phospholipids). This anti-

body (EO6) blocked the uptake of OxLDL by CD36 and by SR-B1 in

transfected cells by as much as 80%; it also inhibited macrophage phagocytosis

of apoptotic cells by about 40%. Thus, the persistence of receptors for OxLDL

during evolution is probably accounted for by their role in recognition of

ligands on the surfaces of oxidatively damaged or apoptotic cells. This has im-

portant implications in biology generally and specifically in atherogenesis, be-

cause apoptosis is a prominent feature of late lesions.

K EYWORDS: scavenger receptors; oxidized LDL; atherosclerosis; apoptotic

cells

INTRODUCTION

Most of the lipid-laden “foam cells” in early atherosclerotic lesions represent monocyte/macrophages that have taken up lipoproteins in the subendothelial space. This is not the result of the uptake of native LDL, which cannot induce cholesterol accumulation in monocyte/macrophages, but rather it is due to the uptake of one or more modified forms of LDL. The best studied modification that can cause choles-terol accumulation is oxidative modification. The large body of evidence implicating Address for correspondence: Daniel Steinberg, M.D., Ph.D., Department of Medicine, Univer-sity of California San Diego, La Jolla, CA 92093-0682. Voice: 858-534-0569; fax: 858-534-2005.

dsteinberg@

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