title: AIP1 suppresses atherosclerosis by limiting hyperlipidemia-induced inflammation and vascular endothelial dysfunction.
abstract: 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.
  
  
  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 nuclear factor-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 nuclear factor-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.
  
  
  CONCLUSIONS
  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.
authors: Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors: Qunhua
authors: Q
authors: Huang
authors: Lingfeng
authors: L
authors: Qin
authors: Shengchuan
authors: S
authors: Dai
authors: Haifeng
authors: H
authors: Zhang
authors: Satish
authors: S
authors: Pasula
authors: Huanjiao
authors: H
authors: Zhou
authors: Hong
authors: H
authors: Chen
authors: Wang
authors: W
authors: Min
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D007249:Inflammation / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000097:blood; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D020703:ras GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D016207:Cytokines; C561450:Dab2ip protein, mouse; D018836:Inflammation Mediators; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D014280:Triglycerides; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C099252:oxidized low density lipoprotein; D020703:ras GTPase-Activating Proteins; D002784:Cholesterol