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The p17 cleaved form of caspase-3 is present within viable macrophages in vitro and in atherosclerotic plaque.
Title | The p17 cleaved form of caspase-3 is present within viable macrophages in vitro and in atherosclerotic plaque. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Nhan, TQ, W Liles, C, Chait, A, Fallon, JT, Schwartz, SM |
Journal | Arterioscler Thromb Vasc Biol |
Volume | 23 |
Issue | 7 |
Pagination | 1276-82 |
Date Published | 2003 Jul 1 |
ISSN | 1524-4636 |
Keywords | Amino Acid Chloromethyl Ketones, Animals, Antigens, CD95, Apoptosis, Arteriosclerosis, Caspase 3, Caspase Inhibitors, Caspases, Cysteine Proteinase Inhibitors, DNA Fragmentation, Enzyme Activation, Enzyme Inhibitors, Fas Ligand Protein, Foam Cells, In Situ Nick-End Labeling, Lipoproteins, LDL, Macrophages, Peritoneal, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Oligopeptides |
Abstract | 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. |
DOI | 10.1161/01.ATV.0000078602.54433.07 |
Alternate Journal | Arterioscler. Thromb. Vasc. Biol. |
PubMed ID | 12763761 |