Characterisation of the differential response of endothelial cells exposed to normal and elevated laminar shear stress

SJ White, EM Hayes, S Lehoux, JY Jeremy, AJ Horrevoets, AC Newby

Research output: Contribution to journalArticle (Academic Journal)peer-review

75 Citations (Scopus)

Abstract

Most acute coronary events occur in the upstream region of stenotic atherosclerotic plaques that experience laminar shear stress (LSS) elevated above normal physiological levels. Many studies have described the atheroprotective effect on endothelial behaviour of normal physiological LSS (approximately 15 dynes/cm(2) ) compared to static or oscillatory shear stress (OSS), but it is unknown whether the levels of elevated shear stress imposed by a stenotic plaque would preserve, enhance or reverse this effect. Therefore we used transcriptomics and related functional analyses to compare human endothelial cells exposed to laminar shear stress of 15 (LSS15-normal) or 75 dynes/cm(2) (LSS75-elevated). LSS75 upregulated expression of 145 and downregulated expression of 158 genes more than 2-fold relative to LSS15. Modulation of the metallothioneins (MT1-G, -M, -X) and NADPH oxidase subunits (NOX2, NOX4, NOX5 and p67phox) accompanied suppression of reactive oxygen species production at LSS75. Shear induced changes in dual specificity phosphatases (DUSPs 1, 5, 8, and 16 increasing and DUSPs 6 and 23 decreasing) were observed as well as reduced ERK1/2 but increased p38 MAP kinase phosphorylation. Amongst vasoactive substances, endothelin-1 expression decreased whereas vasoactive intestinal peptide (VIP) and prostacyclin expression increased, despite which intracellular cAMP levels were reduced. Promoter analysis by rVISTA identified a significant over representation of ATF and Nrf2 transcription factor binding sites in genes upregulated by LSS75 compared to LSS15. In summary, LSS75 induced a specific change in behaviour, modifying gene expression, reducing ROS levels, altering MAP kinase signalling and reducing cAMP levels, opening multiple avenues for future study. © 2011 Wiley-Liss, Inc.
Translated title of the contributionCharacterisation of the differential response of endothelial cells exposed to normal and elevated laminar shear stress
Original languageEnglish
Pages (from-to)2841 - 2848
Number of pages8
JournalJournal of Cellular Physiology
Volume226
Issue number11
DOIs
Publication statusPublished - Nov 2011

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