IRF-1 and miRNA126 modulate VCAM-1 expression in response to a high-fat meal

Chongxiu Sun, Kenan Alkhoury, Ying I. Wang, Greg A. Foster, Christopher E. Radecke, Kayan Tam, Christina M. Edwards, Marc T. Facciotti, Ehrin J. Armstrong, Anne A Knowlton, John W. Newman, Anthony G. Passerini, Scott I. Simon

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1054-1064
Number of pages11
JournalCirculation Research
Volume111
Issue number8
DOIs
StatePublished - Sep 2012

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Keywords

  • atherosclerosis
  • endothelial dysfunction
  • fatty acids
  • hypertriglyceridemia
  • triglycerides

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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 VCAM-1 expression in response to a high-fat meal. Circulation Research, 111(8), 1054-1064. https://doi.org/10.1161/CIRCRESAHA.112.270314