AIP1 Suppresses Atherosclerosis by Limiting Hyperlipidemia-Induced Inflammation and Vascular Endothelial Dysfunction
Objective—Apoptosis signal–regulating kinase 1–interacting protein-1 (AIP1) is a signaling adaptor molecule implicated in stress and apoptotic signaling induced by proinflammatory mediators. However, its function in atherosclerosis has not been established. In the present study, we use AIP1-null (AIP1−/−) mice to examine its effect on atherosclerotic lesions in an apolipoprotein E-null (ApoE−/−) mouse model of atherosclerosis.
Approach and Results—ApoE−/− control mice developed atherosclerosis in the aortic roots and descending aortas on Western-type diet for 10 weeks, whereas the atherosclerotic lesions are significantly augmented in ApoE−/−AIP1−/− double knockout (DKO) mice. DKO mice show increases in plasma inflammatory cytokines with no significant alterations in body weight, total cholesterol levels, or lipoprotein profiles. Aortas in DKO mice show increased inflammation and endothelial cell (EC) dysfunction with NF-κB activity, correlating with increased accumulation of macrophages in the lesion area. Importantly, macrophages from DKO donors are not sufficient to augment inflammatory responses and atherogenesis when transferred to ApoE-KO recipients. Mechanistic studies suggest that AIP1 is highly expressed in aortic EC, but not in macrophages, and AIP1 deletion in EC significantly enhance oxidized low-density lipoprotein–induced NF-κB signaling, gene expression of inflammatory molecules, and monocyte adhesion, suggesting that vascular EC are responsible for the increased inflammatory responses observed in DKO mice.
Conclusion—Our data demonstrate that loss of AIP1 in aortic EC primarily contributes to the exacerbated lesion expansion in the ApoE−/−AIP1−/− mice, revealing an important role of AIP1 in limiting inflammation, EC dysfunction, and atherosclerosis.
- apoptosis signal–regulating kinase 1–interacting protein-1
- endothelial cell
- lipids and lipoproteins
- Received September 28, 2012.
- Accepted January 29, 2013.
- © 2013 American Heart Association, Inc.