TY - JOUR
T1 - Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2
AU - Fledderus, Joost O.
AU - van Thienen, Johannes V.
AU - Boon, Reinier A.
AU - Dekker, Rob J.
AU - Rohlena, Jakub
AU - Volger, Oscar L.
AU - Bijnens, Ann-Pascale J. J.
AU - Daemen, Mat J. A. P.
AU - Kuiper, Johan
AU - van Berkel, Theo J. C.
AU - Pannekoek, Hans
AU - Horrevoets, Anton J. G.
PY - 2007/5/15
Y1 - 2007/5/15
N2 - Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and proinflammatory gene expression, ultimately resulting in atherogenesis. KLF2 has recently been implicated as a transcription factor involved in mediating the anti-inflammatory effects of flow. We investigated the effect of shear on basal and TNF-alpha-induced genomewide expression profiles of human umbilical vein endothelial cells (HUVECs). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS, and thrombomodulin, whereas basal expression of TNF-alpha-responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-alpha-induced gene expression was mostly NF-kappa B dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared with endothelium at unaffected sites. In HUVECs, a dramatic reduction of nuclear binding activity of ATF2 was observed under shear and appeared to be KLF2 dependent. Reduction of ATF2 with siRNA potently suppressed basal proinflammatory gene expression under no-flow conditions. In conclusion, we demonstrate that shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression
AB - Absence of shear stress due to disturbed blood flow at arterial bifurcations and curvatures leads to endothelial dysfunction and proinflammatory gene expression, ultimately resulting in atherogenesis. KLF2 has recently been implicated as a transcription factor involved in mediating the anti-inflammatory effects of flow. We investigated the effect of shear on basal and TNF-alpha-induced genomewide expression profiles of human umbilical vein endothelial cells (HUVECs). Cluster analysis confirmed that shear stress induces expression of protective genes including KLF2, eNOS, and thrombomodulin, whereas basal expression of TNF-alpha-responsive genes was moderately decreased. Promoter analysis of these genes showed enrichment of binding sites for ATF transcription factors, whereas TNF-alpha-induced gene expression was mostly NF-kappa B dependent. Furthermore, human endothelial cells overlying atherosclerotic plaques had increased amounts of phosphorylated nuclear ATF2 compared with endothelium at unaffected sites. In HUVECs, a dramatic reduction of nuclear binding activity of ATF2 was observed under shear and appeared to be KLF2 dependent. Reduction of ATF2 with siRNA potently suppressed basal proinflammatory gene expression under no-flow conditions. In conclusion, we demonstrate that shear stress and KLF2 inhibit nuclear activity of ATF2, providing a potential mechanism by which endothelial cells exposed to laminar flow are protected from basal proinflammatory, atherogenic gene expression
UR - http://www.scopus.com/inward/record.url?scp=34248350010&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood-2006-07-036020
DO - https://doi.org/10.1182/blood-2006-07-036020
M3 - Article
C2 - 17244683
SN - 0006-4971
VL - 109
SP - 4249
EP - 4257
JO - Blood
JF - Blood
IS - 10
ER -