Effect of endothelial cell proliferation on atherogenesis: a role of p21(Sdi/Cip/Waf1) in monocyte adhesion to endothelial cells.
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 TNFalpha, 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 (C-C motif) ligand 5 (CCL5/RANTES), which stimulates leukocyte recruitment and is downregulated by ROS scavenging.


CONCLUSIONS
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.
Obikane
Hiyo
H
Department of Pathology, School of Medicine, Nihon University, 30-1 Kamicho, Oyaguchi, Itabashi-ku, Tokyo 173-8610, Japan.
Abiko
Yoshimitsu
Y
Ueno
Hikaru
H
Kusumi
Yoshiaki
Y
Esumi
Mariko
M
Mitsumata
Masako
M
D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D018920:Coculture Techniques; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D009000:Monocytes / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D016133:Polymerase Chain Reaction; D012039:Regional Blood Flow; D013314:Stress, Mechanical; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C483024:CCL5 protein, human; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D018946:Chemokine CCL5; D050759:Cyclin-Dependent Kinase Inhibitor p21; C486715:TXNIP protein, human; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D013879:Thioredoxins