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 journalArticlepeer-review

62 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

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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