title: Increased atherosclerosis and vascular smooth muscle cell activation in AIF-1 transgenic mice fed a high-fat diet.
abstract: Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, scaffold signal transduction protein constitutively expressed in inflammatory cells, but inducible in vascular smooth muscle cells (VSMCs) in response to injury or inflammatory stimuli. Although several basic science and population studies have reported increased AIF-1 expression in human and experimental atherosclerosis, a direct causal effect of AIF-1 expression on development of atherosclerosis has not been reported. The purpose of this study is to establish a direct relationship between AIF-1 expression and development of atherosclerosis. AIF-1 expression is detected VSMC in atherosclerotic lesions from ApoE(-/-) mice, but not normal arteries from wild-type mice. AIF-1 expression can be induced in cultured VSMC by stimulation with oxidized LDL (ox-LDL). Transgenic mice in which AIF-1 expression is driven by the G/C modified SM22 alpha promoter to restrict AIF-1 expression to VSMC develop significantly increased atherosclerosis compared with wild-type control mice when fed a high-fat diet (P=0.022). Cultured VSMC isolated from Tg mice demonstrated significantly increased migration in response to ox-LDL compared with matched controls (P<0.001). VSMC isolated from Tg mice and cultured human VSMC which over express AIF-1 demonstrated increased expression of MMP-2 and MMP-9 mRNA and protein and increased NF-κB activation in response to ox-LDL as compared with wild-type control mice. VSMC which over express AIF-1 have significantly increased uptake of ox-LDL, and increased CD36 expression. Together, these data suggest a strong association between AIF-1 expression, NF-κB activation, and development of experimental atherosclerosis.
authors.affiliation: Department of Physiology, Independence Blue Cross Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, United States.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Sommerville
authors.forename: Sheri E
authors.initials: SE
authors.lastname: Kelemen
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ellison
authors.forename: Ross N
authors.initials: RN
authors.lastname: England
authors.forename: Michael V
authors.initials: MV
authors.lastname: Autieri
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018955:CD36 Antigens / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C491049:Aif1 protein, mouse; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002135:Calcium-Binding Proteins; D008077:Lipoproteins, LDL; D008840:Microfilament Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; C051615:transgelin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse