A role for the apoptosis inhibitory factor AIM/Spalpha/Api6 in atherosclerosis development.
Macrophages play a central role in the development of atherosclerosis through the accumulation of oxidized LDL (oxLDL). AIM (Spalpha/Api6) has previously been shown to promote macrophage survival; however, its function in atherogenesis is unknown. Here we identify AIM as a critical factor that protects macrophages from the apoptotic effects of oxidized lipids. AIM protein is induced in response to oxLDL loading and is highly expressed in foam cells within atherosclerotic lesions. Interestingly, both expression of AIM in lesions and its induction by oxidized lipids require the action of LXR/RXR heterodimers. AIM-/- macrophages are highly susceptible to oxLDL-induced apoptosis in vitro and undergo accelerated apoptosis in atherosclerotic lesions in vivo. Moreover, early atherosclerotic lesions in AIM-/-LDLR-/- double knockout mice are dramatically reduced when compared to AIM+/+LDLR-/- controls. We conclude that AIM production facilitates macrophage survival within atherosclerotic lesions and that loss of AIM decreases early lesion development by increasing macrophage apoptosis.
Arai
Satoko
S
Center for Immunology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard NA7200, Dallas, Texas 75390, USA.
Shelton
John M
JM
Chen
Mingyi
M
Bradley
Michelle N
MN
Castrillo
Antonio
A
Bookout
Angie L
AL
Mak
Puiying A
PA
Edwards
Peter A
PA
Mangelsdorf
David J
DJ
Tontonoz
Peter
P
Miyazaki
Toru
T
D000818:Animals; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000502:physiology*; D011973:Receptors, LDL / Q000172:deficiency; D047490:Retinoid X Receptor alpha / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D051116:Receptors, Scavenger
D004268:DNA-Binding Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D047490:Retinoid X Receptor alpha; C099252:oxidized low density lipoprotein; C117272:Cd5l protein, mouse; D051017:Apoptosis Regulatory Proteins; D051116:Receptors, Scavenger