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

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish
Pages (from-to)1276-1282
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume23
Issue number7
DOIs
StatePublished - 1 Jul 2003

Keywords

  • Apoptosis
  • CD95
  • Caspases
  • LDL
  • Macrophages

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