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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Surgery, University of Miami, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Zhao-Jun
ZJ
Liu
Yurong
Y
Tan
Gary W
GW
Beecham
David M
DM
Seo
Runxia
R
Tian
Yan
Y
Li
Roberto I
RI
Vazquez-Padron
Margaret
M
Pericak-Vance
Jeffery M
JM
Vance
Pascal J
PJ
Goldschmidt-Clermont
Alan S
AS
Livingstone
Omaida C
OC
Velazquez
D000367:Age Factors; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D016922:Cellular Senescence; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D058226:Plaque, Atherosclerotic; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D040081:Protein Array Analysis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration; D014162:Transfection; D015854:Up-Regulation
D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D051880:Receptors, Notch