Increased atherosclerosis and vascular smooth muscle cell activation in AIF-1 transgenic mice fed a high-fat diet

• Published in: Atherosclerosis Vol. 220; no. 1; pp. 45 - 52
• Main Authors: Sommerville, Laura J, Kelemen, Sheri E, Ellison, Stephen P, England, Ross N, Autieri, Michael V
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.01.2012; Elsevier
• Subjects: Allograft inflammatory factor-1; allografting; Animals; Aorta, Abdominal - metabolism; Aorta, Abdominal - pathology; Aortic Diseases - etiology; Aortic Diseases - genetics; Aortic Diseases - metabolism; Aortic Diseases - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; arteries; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Blood vessels and receptors; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cardiology. Vascular system; Cardiovascular; CD36 Antigens - metabolism; Cell Movement; Cells, Cultured; Diet, High-Fat; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; gene expression; genetically modified organisms; high fat diet; Humans; Lipoproteins, LDL - metabolism; low density lipoprotein; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 9 - genetics; Medical sciences; messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Muscle Proteins - genetics; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; myocytes; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; NF-kappa B - metabolism; Nuclear factor kappa B; Oxidized LDL; Promoter Regions, Genetic; RNA, Messenger - metabolism; signal transduction; smooth muscle; Time Factors; transcription factor NF-kappa B; Transfection; Vascular smooth muscle cell; Vertebrates: cardiovascular system; Vascular smooth muscle cell; Oxidized LDL; Allograft inflammatory factor-1; Atherosclerosis; Nuclear factor kappa B; Rodentia; Homograft; Smooth muscle; Cardiovascular disease; Vascular disease; Lipoprotein LDL; Vertebrata; Mammalia; Mouse; Animal
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.07.095

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.