IAP Survivin Regulates Atherosclerotic Macrophage Survival

Abstract

Objectives-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. Methods and 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-␣, 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.

Oxysterols and mechanisms of apoptotic signaling: implications in the pathology of degenerative diseases☆

“…These findings comply with the literature as Smac/DIABLO is a well-known IAP antagonist. Blanc-Brude et al [136] revealed discrete IAP survivin expression in human aorta lipid streaks but virtually none in advanced atherosclerotic plaques. The authors deduced that dysregulation of survivin expression caused by re-current oxLDL exposure may favor apoptosis in advanced atherosclerotic plaques despite up-regulated cIAP-2 and XIAP.…”

Angiopoeitin-2 modulates Survivin expression in OxLDL-induced endothelial cell apoptosis

“…While IAP protein blocks apoptosis via inhibition of effector caspases, oxidized low density lipoprotein (OxLDL) differentially regulates the members of IAP family [3,4]. OxLDL has been reported to decrease the expression of cellular inhibitor of apoptosis protein 1 (cIAP-1) in endothelial cells [5], and prolonged OxLDL treatment down-regulated Survivin expression in macrophages [6]. In advanced atherosclerotic lesions, Survivin expression is absent despite an increase in both x-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 2 (cIAP2) [6].…”

“…OxLDL has been reported to decrease the expression of cellular inhibitor of apoptosis protein 1 (cIAP-1) in endothelial cells [5], and prolonged OxLDL treatment down-regulated Survivin expression in macrophages [6]. In advanced atherosclerotic lesions, Survivin expression is absent despite an increase in both x-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 2 (cIAP2) [6]. Whether OxLDL induces apoptosis via down-regulation of Survivin expression in vascular endothelial cells remains unknown.…”

Diabetes mellitus and apoptosis: inflammatory cells

“…In addition, these data highlight the complexity of atheropathogenesis, with the likelihood that a multiple hit hypothesis rather than a single event is important in terms of disease progression. Balancing pro-apototic factors are a series of inhibitors of this process which include: Bcl-2 [107], macrophage colony-stimulating factor (M-CSF) [108], tissue inhibitors of metalloproteinases (TIMPs) [109], survivin [108], TOSO [110], FLICE-like inhibitory protein (FLIP) [111], Bfl-1, and Mcl-1 [112]. The importance of considering the temporal aspects of macrophage apoptosis in atherosclerosis is illustrated by recent work on survivin, a caspase inhibitor of the inhibitors of apoptosis (IAP) family, which is transcribed specifically during mitosis and is usually absent in normal adult tissues.…”