IAP survivin regulates atherosclerotic macrophage survival.
OBJECTIVE
Inflammatory macrophage apoptosis is critical to atherosclerotic plaque formation, but its mechanisms remain enigmatic. We hypothesized that inhibitor of apoptosis protein (IAP) survivin regulates macrophage death in atherosclerosis.


RESULTS
Western blot analysis revealed discrete survivin expression in human aorta lipid streaks but virtually none in advanced atherosclerotic plaques, despite increased XIAP and cIAP2 levels. Survivin was detected in CD68-positive macrophages infiltrating human lipid streaks by immunohistochemistry. In advanced atherosclerotic plaques, only rare macrophages outside the necrotic core or occasional fibrous cap smooth muscle cells expressed survivin. In vitro, macrophage colony-stimulating factor-stimulated mouse macrophage survivin expression, proliferation and resistance to apoptosis. Conversely, prolonged oxidized low-density lipoprotein treatment abolished macrophage survivin expression and triggered apoptosis after 12 hours, despite enhanced XIAP and cIAP2 expression. Adenoviral overexpression of survivin conferred macrophages with sustained resistance to apoptosis after oxidized low-density lipoprotein, tumor necrosis factor-alpha, or staurosporine challenge.


CONCLUSIONS
Survivin is a critical modulator of atherosclerotic macrophage apoptosis under dual control by growth factors and oxidized lipids accumulating in atheroma. In early lipid streaks, growth factor-stimulated survivin expression may contribute to macrophage accumulation and survival, but dysregulation of survivin expression caused by recurrent oxidized low-density lipoprotein exposure may favor apoptosis in advanced atherosclerotic plaques, despite upregulated cIAP2 and XIAP.
Blanc-Brude
Olivier P
OP
Centre de Recherche Cardiovasculaire Inserm-Lariboisère U689, Hôpital Lariboisière, 41 boulevard de la Chapelle, F-75475, Paris Cedex 10, France. olivier.blanc-brude@larib.inserm.fr
Teissier
Elisabeth
E
Castier
Yves
Y
Lesèche
Guy
G
Bijnens
Ann-Pascal
AP
Daemen
Mat
M
Staels
Bart
B
Mallat
Ziad
Z
Tedgui
Alain
A
D000328:Adult; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008077:Lipoproteins, LDL / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D000077022:Survivin; D014161:Transduction, Genetic; D015854:Up-Regulation
C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008077:Lipoproteins, LDL; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D000077022:Survivin; C099252:oxidized low density lipoprotein; D016173:Macrophage Colony-Stimulating Factor