TY - JOUR
T1 - Notch activation induces endothelial cell senescence and pro-inflammatory response
T2 - Implication of Notch signaling in atherosclerosis
AU - Liu, Zhao Jun
AU - Tan, Yurong
AU - Beecham, Gary W.
AU - Seo, David M.
AU - Tian, Runxia
AU - Li, Yan
AU - Vazquez-Padron, Roberto I.
AU - Pericak-Vance, Margaret
AU - Vance, Jeffery M.
AU - Goldschmidt-Clermont, Pascal J.
AU - Livingstone, Alan S.
AU - Velazquez, Omaida C.
N1 - Funding Information:
We thank Dr. D. Fraker for HMVECs and Dr. G. McNamara for quantification of IHC data. This work was supported by grants from the National Institutes of Health ( R01DK-071084 and R01GM081570 , to OCV).
PY - 2012/12
Y1 - 2012/12
N2 - 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. Conclusion: 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.
AB - 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. Conclusion: 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.
KW - Atherosclerosis
KW - EC senescence
KW - Endothelial cells (EC)
KW - Notch
KW - Vascular inflammation
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U2 - 10.1016/j.atherosclerosis.2012.04.010
DO - 10.1016/j.atherosclerosis.2012.04.010
M3 - Article
C2 - 23078884
AN - SCOPUS:84869500556
VL - 225
SP - 296
EP - 303
JO - Atherosclerosis
JF - Atherosclerosis
SN - 0021-9150
IS - 2
ER -