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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1276.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

The p17 Cleaved Form of Caspase-3 Is Present Within Viable Macrophages In Vitro and in Atherosclerotic Plaque

Thomas Q. Nhan; W. Conrad Liles; Alan Chait; John T. Fallon; Stephen M. Schwartz

From the Departments of Pathology (T.Q.N., W.C.L., S.M.S.) and Medicine (W.C.L., A.C.), School of Medicine, University of Washington, Seattle, and the Department of Pathology (J.T.F.), Mount Sinai School of Medicine, New York, NY.

Correspondence to Stephen M. Schwartz, 1959 NE Pacific Way, Health Science Bldg, I-420, Box 357335, Department of Pathology, University of Washington, Seattle, WA 98195. E-mail steves{at}u.washington.edu

Objective— In vitro studies of macrophage death in response to oxidized LDL (oxLDL) were undertaken as a model for the formation of the necrotic core of atherosclerotic plaque.

Methods and Results— Thioglycollate-elicited mouse peritoneal macrophages avidly incorporated both oxLDL and acetylated LDL (acLDL) to become foam cells. oxLDL-treated macrophages, but not acLDL-treated macrophages, showed nearly 100% death, with characteristics consistent with apoptosis, including cell surface phosphatidylserine exposure, intracellular caspase-3 activity, cleavage of caspase-3 substrates, and DNA fragmentation, as shown by TUNEL assay. The activated form of caspase-3 (p17 cleaved form) was present in attached, viable macrophages before exposure to oxLDL. This p17 form was also found in apparently viable as well as in TUNEL-positive cells within atherosclerotic lesions of chow-fed apolipoprotein E–deficient (ApoE^-/-) mice. The amount of p17 caspase-3 was reduced by in vitro blockade of FasL with an FasL-blocking antibody and was absent in macrophages from lpr/lpr mice, which lack functional Fas. Moreover, lpr/lpr macrophages resisted oxLDL cytotoxicity.

Conclusions— The naturally occurring Fas-FasL induction of caspase-3 cleavage after macrophage attachment may represent an important physiologic mechanism that primes for cytotoxicity by oxLDL and possibly, other death-inducing molecules.

Key Words: macrophages • CD95 • LDL • caspases • apoptosis

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