Journal
ATHEROSCLEROSIS
Volume 212, Issue 1, Pages 116-122Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2010.05.029
Keywords
Atherosclerosis; Endothelial cells; Shear stress; p21(Sdi/Cip/Waf1); Proliferation; Monocyte adhesion; Redox balance
Funding
- Nihon University Multidisciplinary Research
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Grants-in-Aid for Scientific Research [21390497] Funding Source: KAKEN
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Objective: Uniform laminar shear stress (LS) and disturbed turbulent shear stress (DS) are thought to play opposite roles in preventing or inducing atherosclerosis. Endothelial cell (EC) growth and monocyte adhesion to ECs, an early event in atherosclerosis, are also oppositely regulated by LS and DS. However, how atherogenesis is affected by the regulation of growth by blood flow is unknown. Here we examined the role of p21(Sdi/Cip/Waf1) (p21), a growth inhibitor induced by LS, in monocyte adhesion to ECs. Methods: p21 was overexpressed by transfecting a p21-expressing adenoviral vector into ECs. Factors linking EC growth, monocyte adhesion, and p21 were examined by microarray analysis, PCR and Western blotting. Results: Compared with DS, in the presence or absence of TNF alpha, LS significantly inhibited EC growth and monocyte adhesion to ECs. Both EC proliferation and monocyte adhesion induced by DS were inhibited by p21-overexpression. LS suppressed the expression of thioredoxin-interacting protein (TXNIP). Thioredoxin (TRX) activity, which is suppressed by TXNIP, was therefore higher under LS than DS, as reported previously. p21-overexpression significantly suppressed the DS-induced TXNIP expression, and inhibited the expression of vascular cell adhesion molecule 1 and chemokine (CC motif) ligand 5 (CCL5/RANTES), which stimulates leukocyte recruitment and is downregulated by ROS scavenging. Conclusion: p21 may function to prevent atherogenesis by regulating the redox balance, which leads to the inhibition of adhesion molecule and chemokine expression in ECs under LS. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
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