Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis

Anaïs Briot, Mete Civelek, Atsuko Seki, Karen Hoi, Julia J. Mack, Stephen D. Lee, Jason Kim, Cynthia Hong, Jingjing Yu, Gregory A. Fishbein, Ladan Vakili, Alan M. Fogelman, Michael C. Fishbein, Aldons J. Lusis, Peter Tontonoz, Mohamad Navab, Judith A. Berliner, M. Luisa Iruela-Arispe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Although much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic pathways that counteract these events. Here we identified NOT CH1 as an antagonist of endothelial cell (EC) activation. NOT CH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high-fat diet. Furthermore, treatment of human aortic ECs (HAECs) with inflammatory lipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine [Ox-PAPC]) and proinflammatory cytokines (TNF and IL1β) decreased Notch1 expression and signaling in vitro through a mechanism that requires STAT3 activation. Reduction of NOT CH1 in HAECs by siRNA, in the absence of inflammatory lipids or cytokines, increased inflammatory molecules and binding of monocytes. Conversely, some of the effects mediated by Ox-PAPC were reversed by increased NOT CH1 signaling, suggesting a link between lipid-mediated inflammation and Notch1. Interestingly, reduction of NOT CH1 by Ox- PAPC in HAECs was associated with a genetic variant previously correlated to high-density lipoprotein in a human genome- wide association study. Finally, endothelial Notch1 heterozygous mice showed higher diet-induced atherosclerosis. Based on these findings, we propose that reduction of endothelial NOT CH1 is a predisposing factor in the onset of vascular inflammation and initiation of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)2147-2163
Number of pages17
JournalJournal of Experimental Medicine
Volume212
Issue number12
DOIs
StatePublished - Nov 16 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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