Notch1 inhibition reduces low shear stress-induced plaque formation

• Published in: The international journal of biochemistry & cell biology 2016-03, Vol.72, p.63-72
• Main Authors: Qin, Wei-dong, Zhang, Fan, Qin, Xiao-jun, Wang, Juan, Meng, Xiao, Wang, Hao, Guo, Hai-peng, Wu, Qun-zheng, Wu, Da-wei, Zhang, Ming-xiang
• Format: Article
• Language: English
• Subjects: Activation; Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Apolipoproteins E - deficiency; Atherosclerosis; Carotid arteries; Caveolin 1 - deficiency; Caveolin 1 - genetics; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell signal transduction; Diamines - pharmacology; Formations; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Gene Silencing; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Inflammatory response; Inhibition; Intercellular Adhesion Molecule-1 - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Low shear stress; Mice; NF-kappa B - metabolism; Notch1 signaling; Phosphorylation - drug effects; Phosphorylation - genetics; Plaque formation; Plaque, Atherosclerotic - genetics; Plaque, Atherosclerotic - metabolism; Plaque, Atherosclerotic - pathology; Protease Inhibitors - pharmacology; Protein Domains; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - chemistry; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; RNA, Small Interfering - genetics; Secretions; Shear Strength - drug effects; Shear stress; Signal Transduction - drug effects; Signal Transduction - genetics; Stress, Mechanical; Thiazoles - pharmacology
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2016.01.007

Low shear stress (LSS) contributes to the pathogenesis of inflammatory diseases, such as atherosclerosis. Notch1 is a type I transmembrane receptor that critically determines the growth, differentiation, and survival of various cell types, but its role and mechanism in LSS-induced inflammatory response remains undetermined. Apolipoprotein E-deficient (ApoE−/−) mice were fed with high fat diet and administered intraperitoneally with DAPT (a γ-secretase inhibitor). Perivascular shear stress modifiers were placed around the right carotid arteries to induce LSS. The left carotid arteries with undisturbed shear stress (USS) were used as the control. LSS increased Delta-like 1 (DLL-1) protein expression and the expression of Notch1 and NICD, while DAPT administration reduced NICD expression. Compared with the LSS group, DAPT reduced LSS-induced plaque formation and intercellular adhesion molecule 1 (ICAM-1) expression. Human umbilical vein endothelial cells (HUVECs) were exposure to undisturbed shear stress (USS, 1Pa) or LSS (0.4Pa). Notch1 was inhibited by siRNA or DAPT. RT-PCR and western blotting analysis showed that LSS upregulated the expression of Notch1 in a time-dependent manner. Caveolin-1 (CAV1) inhibition by siRNA could reduce Notch1 and NICD expression. Compared with USS, LSS increased inflammatory response, including IL-1β and IL-6 secretion, ICAM-1 and inducible nitric oxide synthase (iNOS) expression, and THP-1 cells adhesion. Notch1 inhibition by siRNA or DAPT could reduce these inflammatory responses by reduction of NF-κB phosphorylation, upregulation of IkBα expression, and inhibition of nuclear translocation of NF-κB, while Notch1 activation by DLL-4 had an adverse effect. The Notch signaling system is therefore a potential target for modulating LSS-induced inflammation response during atherosclerosis.