title: Notch1 inhibition reduces low shear stress-induced plaque formation.
abstract: 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.
authors.affiliation: The Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: season__202@163.com.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Qin
authors.affiliation: The Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: The Department of Gynecology, the Linyi Tumour Hospital of Shandong Province, Linyi, Shandong, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Qin
authors.affiliation: The Department of Cardiology, the Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Meng
authors.affiliation: The Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Hai-Peng
authors.initials: HP
authors.lastname: Guo
authors.affiliation: The Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Qun-Zheng
authors.initials: QZ
authors.lastname: Wu
authors.affiliation: The Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China. Electronic address: icuqwd@163.com.
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D002135:Calcium-Binding Proteins; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D000072417:Protein Domains; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D033081:Shear Strength / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013314:Stress, Mechanical; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C000612000:24-diamino-5-phenylthiazole; D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D051242:Caveolin 1; D003959:Diamines; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D013844:Thiazoles; D018799:Intercellular Adhesion Molecule-1; D053829:Amyloid Precursor Protein Secretases
keywords: Cell signal transduction; Inflammatory response; Low shear stress; Notch1 signaling; Plaque formation