Regulation of shear-induced nuclear translocation of the Nrf2 transcription factor in endothelial cells.
BACKGROUND
Vascular endothelial cells (ECs) constantly experience fluid shear stresses generated by blood flow. Laminar flow is known to produce atheroprotective effects on ECs. Nrf2 is a transcription factor that is essential for the antioxidant response element (ARE)-mediated induction of genes such as heme-oxygenase 1 (HO-1). We previously showed that fluid shear stress increases intracellular reactive oxygen species (ROS) in ECs. Moreover, oxidants are known to stimulate Nrf2. We thus examined the regulation of Nrf2 in cultured human ECs by shear stress.


RESULTS
Exposure of human umbilical vein endothelial cells (HUVECs) to laminar shear stress (12 dyne/cm2) induced Nrf2 nuclear translocation, which was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, a protein kinase C (PKC) inhibitor, and an antioxidant agent N-acetyl cysteine (NAC), but not by other protein kinase inhibitors. Therefore, PI3K, PKC, and ROS are involved in the signaling pathway that leads to the shear-induced nuclear translocation of Nrf2. We also found that shear stress increased the ARE-binding activity of Nrf2 and the downstream expression of HO-1.


CONCLUSIONS
Our data suggest that the atheroprotective effect of laminar flow is partially attributed to Nrf2 activation which results in ARE-mediated gene transcriptions, such as HO-1 expression, that are beneficial to the cardiovascular system.
Hsieh
Chung-Yu
CY
Department of Chemical Engineering, National Taiwan University, Taipei 106, Taiwan. r94524008@ntu.edu.tw
Hsiao
Huai-Yu
HY
Wu
Wan-Yi
WY
Liu
Ching-Ann
CA
Tsai
Yu-Chih
YC
Chao
Yuen-Jen
YJ
Wang
Danny L
DL
Hsieh
Hsyue-Jen
HJ
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D033081:Shear Strength; D013314:Stress, Mechanical
D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases