A role for the apoptosis inhibitory factor AIM/Spalpha/Api6 in atherosclerosis development

Cell Metab. 2005 Mar;1(3):201-13. doi: 10.1016/j.cmet.2005.02.002.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Arteriosclerosis / etiology*
  • Cell Line
  • DNA-Binding Proteins / physiology
  • Gene Expression Regulation
  • Lipoproteins, LDL / metabolism
  • Liver X Receptors
  • Macrophages / pathology*
  • Mice
  • Mice, Knockout
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / physiology*
  • Receptors, LDL / deficiency
  • Retinoid X Receptor alpha / physiology


  • DNA-Binding Proteins
  • Lipoproteins, LDL
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Immunologic
  • Receptors, LDL
  • Retinoid X Receptor alpha
  • SPalpha protein, mouse
  • oxidized low density lipoprotein