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Title:   Author  item
                                            SUN, CHONXIU - University Of Californiaitem
                                            ALKHOURY, KENAN - University Of Californiaitem
                                            WANG, YING - University Of Californiaitem
                                            FOSTER, GREG - University Of Californiaitem
                                            RADECKE, CHRISTOPHER - University Of Californiaitem
                                            TAM, KAYAN - University Of Californiaitem
                                            EDWARDS, CHRISTINA - University Of Californiaitem
                                            FACCIOTTI, MARC - University Of Californiaitem
                                            ARMSTRONG, EHRIN - University Of Californiaitem
                                            KNOWLTON, ANNE - University Of Californiaitem
                                            Newman, Johnitem
                                            PASSERINI, ANTHONY - Dominican University Of Californiaitem
                                            SIMON, SCOTT - University Of California
  Submitted to: Circulation Research
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 8/7/2012
                                    Publication  Date: 8/8/2012
                                    Citation: Sun, C., Alkhoury, K., Wang, Y.I., Foster, G.A., Radecke, C.E., Tam, K., Edwards, C.M., Facciotti, M.T., Armstrong, E.J., Knowlton, A.A., Newman, J.W., Passerini, A.G., Simon, S.I. 2012. IRF-1 and miRNA126 modulate inflammatory VCAM-1 expression in response to a high fat meal. Circulation Research. 111:1054-1064.Interpretive Summary: High fat diets are associated with hypertriglyceridemia and an increased risk of atherosclerosis.  Vascular inflammation is an early event in atherosclerosis which results from white blood cell recruitment to the vascular surface mediated by vascular cellular adhesion molecule-1 (VCAM-1) expression.  In this study, the VCAM-1 expression of human endothelial cells was evaluated in response to triglyceride rich lipoproteins (TGRLs) isolated from human subjects after consumption of a high-fat meal.  Using VCAM-1 expression response in the presence of tumor necrosis fator alpha (TNFa), TGRLs were categorized into pro- (increased VCAM-1 ~20%) and anti-atherogenic classes (decreased VCAM-1 ~20%).   The relative atherogenicity of a subject’s TGRL positively correlated with the density of TG, ApoCIII, ApoE, and cholesterol. Treatment of HAEC with the long chain omega-3 fatty acid docosahexaenoic acid (DHA) mimicked the effect of anti-atherogenic TGRL by down-regulating VCAM-1 expression in a dose-dependent manner. Saturated fats had no effect on these parameters. TGRL exerted the differential regulation of VCAM-1 by modulating expression and activity of the transcription factor IRF-1 and expression of microRNA 126 (miR-126). Studies using cDNA and siRNA modulation of IRF-1 expression or inhibitor to miR-126 recapitulated the pro- or anti-atherogenic regulation of VCAM-1. To summarize, in response to a high-fat meal, TGRLs bias the inflammatory response of endothelium via transcriptional and post-transcriptional editing of VCAM-1. Subjects producing anti-atherogenic TGRL were enriched in non-esterified fatty acids that decreased IRF-1, increased miR-126 activity, and diminished monocyte arrest on the endothelial surface.
                                Technical Abstract: Rationale: High-fat diets accompanied by hypertriglyceridemia increase an individual’s risk for developing atherosclerosis. An early event in this process is monocyte recruitment through binding to VCAM-1 on inflamed arterial endothelium. Diets high in polyunsaturated fatty acids (PUFAs) may provide athero-protection by ameliorating this effect.
 
Objective: We investigated the acute regulation of VCAM-1 expression in human aortic endothelial cells (HAEC) in response to triglyceride rich lipoproteins (TGRL) isolated from subjects following consumption of a high-fat meal.
 
Methods and Results: Postprandial TGRL isolated from 38 subjects was categorized as pro- or anti-atherogenic according to its capacity to alter the inflammatory response of HAEC. Pro-atherogenic TGRL increased expression of VCAM-1, ICAM-1, and E-selectin by ~20% compared to stimulation with TNFa alone, while anti-atherogenic TGRL decreased VCAM-1 expression by ~20% while still upregulating ICAM-1. The relative atherogenicity of a subject’s TGRL positively correlated with the density of TG, ApoCIII, ApoE, and cholesterol. Treatment of HAEC with n3-PUFA mimicked the effect of anti-atherogenic TGRL by down-regulating VCAM-1 expression in a dose-dependent manner. TGRL exerted this differential regulation of VCAM-1 by reciprocally modulating expression and activity of the transcription factor IRF-1 and expression of microRNA 126 (miR-126). Studies using cDNA and siRNA modulation of IRF-1 expression or inhibitor to miR-126 recapitulated the pro- or anti-atherogenic regulation of VCAM-1. 
 
Conclusions:  In response to a high-fat meal, TGRLs bias the inflammatory response of endothelium via transcriptional and post-transcriptional editing of VCAM-1. Subjects producing anti-atherogenic TGRL were enriched in non-esterified fatty acids that decreased IRF-1, increased miR-126 activity, and diminished monocyte arrest.


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