A role for the apoptosis inhibitory factor AIM/Spalpha/Api6 in atherosclerosis development |
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Authors: | Arai Satoko Shelton John M Chen Mingyi Bradley Michelle N Castrillo Antonio Bookout Angie L Mak Puiying A Edwards Peter A Mangelsdorf David J Tontonoz Peter Miyazaki Toru |
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Institution: | Center for Immunology, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard NA7200, Dallas, Texas 75390, USA. |
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Abstract: | Macrophages play a central role in the development of atherosclerosis through the accumulation of oxidized LDL (oxLDL). AIM (Spα/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. |
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