IRF-1 and miRNA126 Modulate VCAM-1 Expression in Response to a High-Fat Meal

• Published in: Circulation research Vol. 111; no. 8; pp. 1054 - 1064
• Main Authors: Sun, Chongxiu, Alkhoury, Kenan, Wang, Ying I., Foster, Greg A., Radecke, Christopher E., Tam, Kayan, Edwards, Christina M., Facciotti, Marc T., Armstrong, Ehrin J., Knowlton, Anne A., Newman, John W., Passerini, Anthony G., Simon, Scott I.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 28.09.2012; Lippincott Williams & Wilkins
• Subjects: Aorta - cytology; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Adhesion - physiology; Cell Line; Dietary Fats - administration & dosage; Dietary Fats, Unsaturated - administration & dosage; Disorders of blood lipids. Hyperlipoproteinemia; Endothelial Cells - cytology; Endothelial Cells - physiology; Fundamental and applied biological sciences. Psychology; Humans; Hypertriglyceridemia - genetics; Hypertriglyceridemia - metabolism; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - metabolism; Medical sciences; Metabolic diseases; MicroRNAs - physiology; Monocytes - metabolism; NF-kappa B - metabolism; Postprandial Period - physiology; Protein Processing, Post-Translational - physiology; Transcription Factor AP-1 - metabolism; Tumor Necrosis Factor-alpha - metabolism; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism; Vertebrates: cardiovascular system; Metabolic diseases; Cardiovascular disease; Lipids; Hyperlipoproteinemia; Lipoprotein; triglycerides; Triglyceride; Enzymopathy; Fatty acids; Vascular disease; Vertebrata; Mammalia; Hypertriglyceridemia; Atherosclerosis; Fat; Endothelial dysfunction; Circulatory system; Dyslipemia
• DOI: 10.1161/CIRCRESAHA.112.270314
• ISSN: 0009-7330; 1524-4571

RATIONALE:A high-fat diet accompanied by hypertriglyceridemia increases an individual’s risk for development of atherosclerosis. An early event in this process is monocyte recruitment through binding to vascular cell adhesion molecule 1 (VCAM-1) upregulated 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 after consumption of a high-fat meal. METHODS AND RESULTS:Postprandial TGRL isolated from 38 subjects were categorized as proatherogenic or antiatherogenic according to their capacity to alter the inflammatory response of HAEC. Proatherogenic TGRL increased expression of VCAM-1, intercellular adhesion molecule 1 (ICAM-1), and E-selectin by ≈20% compared with stimulation with tumor necrosis factor-α alone, whereas antiatherogenic TGRL decreased VCAM-1 expression by ≈20% while still upregulating ICAM-1. The relative atherogenicity of TGRL positively correlated with particle density of TG, apolipoprotein (Apo)CIII, ApoE, and cholesterol. Ω3-PUFA mimicked the effect of antiatherogenic TGRL by downregulating VCAM-1 expression. TGRL exerted this differential regulation of VCAM-1 by reciprocally modulating expression and activity of the transcription factor interferon regulatory factor 1 (IRF-1) and expression of microRNA 126 (miR-126). Overexpression or silencing of IRF-1 or miR-126 expression recapitulated the proatherogenic or antiatherogenic regulation of VCAM-1. CONCLUSIONS:In response to a high-fat meal, TGRL bias the inflammatory response of endothelium via transcriptional and posttranscriptional editing of VCAM-1. Subjects with an anti-inflammatory response to a meal produced TGRL that was enriched in nonesterified fatty acids, decreased IRF-1 expression, increased miR-126 activity, and diminished monocyte arrest.