Notch activation induces endothelial cell senescence and pro-inflammatory response: Implication of Notch signaling in atherosclerosis

• Published in: Atherosclerosis Vol. 225; no. 2; pp. 296 - 303
• Main Authors: Liu, Zhao-Jun, Tan, Yurong, Beecham, Gary W., Seo, David M., Tian, Runxia, Li, Yan, Vazquez-Padron, Roberto I., Pericak-Vance, Margaret, Vance, Jeffery M., Goldschmidt-Clermont, Pascal J., Livingstone, Alan S., Velazquez, Omaida C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.12.2012; Elsevier
• Subjects: Age Factors; Animals; aorta; Aorta - metabolism; Aorta - pathology; Aortic Diseases; Aortic Diseases - genetics; Aortic Diseases - metabolism; Aortic Diseases - pathology; Apolipoproteins E; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; blood; Blood and lymphatic vessels; Blood vessels and receptors; Blotting, Western; Cardiology. Vascular system; Cardiovascular; Cellular Senescence; coronary artery disease; Coronary Artery Disease - genetics; Coronary Artery Disease - metabolism; Coronary Artery Disease - pathology; Coronary Vessels; Coronary Vessels - metabolism; Coronary Vessels - pathology; Cytokines; Cytokines - metabolism; deficiency; Disease Models, Animal; EC senescence; endothelial cells; Endothelial cells (EC); Endothelial Cells - metabolism; Endothelial Cells - pathology; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; genes; genetics; genotyping; HEK293 Cells; Humans; immunohistochemistry; inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators; Inflammation Mediators - metabolism; interleukin-6; Leukocytes; Leukocytes - metabolism; Medical sciences; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; NIH 3T3 Cells; Notch; pathogenesis; pathology; patients; Plaque, Atherosclerotic; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Protein Array Analysis; Receptors, Notch; Receptors, Notch - genetics; Receptors, Notch - metabolism; risk; secretion; Signal Transduction; Signal Transduction - genetics; single nucleotide polymorphism; Time Factors; Transendothelial and Transepithelial Migration; Transfection; Up-Regulation; Vascular inflammation; Vertebrates: cardiovascular system; Endothelial cells (EC); Vascular inflammation; Notch; Atherosclerosis; EC senescence; Vascular disease; Endothelial cell; Senescence; Cardiovascular disease; Inflammation; Inflammatory cell
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2012.04.010

Notch signaling plays pivotal roles in the pathogenesis of vascular disease. However, little is known about its role in atherosclerosis. We sought to investigate the potential involvement of the Notch signaling in atherosclerosis. Expression of Notch pathway components in mouse and human aorta with or without atherosclerosis plaque was examined by immunohistochemistry. Expression of Notch target genes in young versus aged human endothelial cells (EC) was examined by PCRArray and immunoblot. In vitro loss- and gain-of-function approaches were utilized to evaluate the role of Notch signaling in inducing EC senescence and secretion of pro-inflammatory cytokines by ProteinArray. Notch gene profile was studied in 1054 blood samples of patients with coronary artery disease (CAD). Genotyping was performed using the Genome-Wide Single Nucleotide Polymorphism (SNP) Array. Notch pathway components were upregulated in luminal EC at atherosclerotic lesions from mouse and human aortas. In addition, the Notch pathway was activated in aged but not young human EC. Enforced Notch activation resulted in EC senescence and significantly upregulated expression of several molecules implicated in the inflammatory response (IL-6/IL-8/IL-1α/RANTES/ICAM-1). The upregulated IL-6 was partially responsible for mediating leukocyte transendothelial migration. Genetic association analysis detected, of 82 SNPs across 6 Notch pathway genes analyzed, 4 SNPs with nominal association with CAD burden. Notch pathway is activated in luminal EC at atherosclerotic plaques and results in pro-inflammatory response and senescence of EC. Notch signaling may be linked to human CAD risk. These findings implicate a potential involvement of Notch signaling in atherosclerosis. ► Notch signaling pathway is activated in luminal endothelial cells at atherosclerotic plaques. ► Notch pathway activation results in pro-inflammatory response and senescence of endothelial cells. ► Genetic association analyses suggest that the Notch signaling may be linked to human coronary artery disease (CAD) risk.