Cytocidal effects of atheromatous plaque components: the death zone revisited.
OBJECTIVE
Earlier we suggested that atheroma lesions constitute a "death zone" containing toxic materials that may cause dysfunction and demise of invading macrophages to prevent the removal of plaque materials. Here we have assessed the cytotoxic effects of nonfractionated gruel and insoluble (ceroid-like) material derived from advanced human atheroma.


RESULTS
The insoluble material within advanced atherosclerotic plaque was isolated following protease K digestion and extensive extraction with aqueous and organic solvents. FTIR, Raman, and atomic absorption spectroscopy suggested that, despite its fluorescent nature, this material closely resembled hydroxyapatite and dentin, but also contained a significant amount of iron and calcium. When added to J774 cells and human macrophages in culture, this insoluble substance was phagocytosed, and progressive cell death followed. However, an even more cytotoxic activity was found in the atheromatous "gruel" that contains abundant carbonyls/aldehydes. Cell death caused by both crude gruel and ceroid could be blocked by preincubating cells with the lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone, apoferritin, BAPTA/AM, or sodium borohydride, indicating that cellular iron, calcium, and reactive aldehyde(s) are responsible for the observed cytotoxicity.


CONCLUSIONS
Toxic materials within atheromatous lesions include both ceroid and even more cytotoxic lipidaceous materials. The cytotoxic effects of these plaque components may help explain the persistence of atherosclerotic lesions.
Li
Wei
W
Division of Experimental Pathology, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
Ostblom
Mattias
M
Xu
Li-Hua
LH
Hellsten
Anna
A
Leanderson
Per
P
Liedberg
Bo
B
Brunk
Ulf T
UT
Eaton
John W
JW
Yuan
Xi-Ming
XM
D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology*; D001157:Arterial Occlusive Diseases / Q000473:pathology; D050197:Atherosclerosis / Q000473:pathology*; D016923:Cell Death; D002460:Cell Line; D003470:Culture Media; D006801:Humans; D008264:Macrophages / Q000473:pathology*; D008323:Mammary Arteries / Q000473:pathology*; D051379:Mice; D011817:Rabbits
D003470:Culture Media