Document Detail

Silencing of the F11R gene reveals a role for F11R/JAM-A in the migration of inflamed vascular smooth muscle cells and in atherosclerosis.
MedLine Citation:
PMID:  20627246     Owner:  NLM     Status:  MEDLINE    
RATIONALE AND OBJECTIVE: Our previous studies have determined that the F11 receptor (F11R; aka JAM-A) exerts a critical force in the adhesion of human platelets to inflamed endothelial cells (ECs), and thus can play a significant role in the initiation of atherosclerotic plaque formation. In the present study, we focus on a subsequent event in plaque development--the migration of smooth muscle cells (SMCs) from the media to the intima of inflamed vessels. Here we report our investigation of the expression of F11R in atherosclerotic arteries of coronary artery disease (CAD) patients, and of the role of F11R in the migration of SMCs involved in atherogenesis.
METHODS AND RESULTS: Histological staining and specific-antibody immunofluorescence of excised, human atherosclerotic coronary arteries revealed the expression of F11R in the SMCs of the intima. RT-PCR and SDS-PAGE followed by immunoblotting procedures demonstrated that F11R mRNA and the F11R protein levels were enhanced by the stimulation of cultured human aortic SMCs with a combined treatment of proinflammatory cytokines (TNFalpha+INFgamma+IL-beta1). Neither the F11R message nor protein was expressed in non-stimulated SMCs. The functional role of F11R in SMCs' migration was studied in cytokine-stimulated SMCs by interference of F11R expression with siRNA. Silencing of the F11R gene of cytokines-treated SMCs inhibited the expression of both F11R mRNA and F11R protein. Functionally, silencing of the F11R gene blocked the proliferation and migration of these inflamed SMCs, both critical events in atherogenesis.
CONCLUSIONS: The new findings of this study are that F11R mRNA and F11R protein are expressed in SMCs of the intima (but not in the media) of atherosclerotic arteries of CAD patients, and that F11R is required for the proliferation and migration of inflamed SMCs. Based on these findings, we conclude that in addition to the previously reported role of F11R in the initiation of plaque formation, F11R plays also an important role in the subsequent growth of atherosclerotic plaques. Identification of drugs that interfere with these pathophysiologic actions of F11R thus represents an effective new approach for the prevention and treatment of atherosclerosis, heart attacks and stroke.
Bani M Azari; Jonathan D Marmur; Moro O Salifu; Erdal Cavusoglu; Yigal H Ehrlich; Elizabeth Kornecki; Anna Babinska
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Publication Detail:
Type:  Journal Article     Date:  2010-05-19
Journal Detail:
Title:  Atherosclerosis     Volume:  212     ISSN:  1879-1484     ISO Abbreviation:  Atherosclerosis     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-09-03     Completed Date:  2010-12-28     Revised Date:  2011-12-22    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  197-205     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Division of Cardiology, Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203-2098, USA.
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MeSH Terms
Aorta / immunology,  pathology
Cell Adhesion Molecules / genetics,  metabolism*
Cell Movement* / genetics
Cell Proliferation
Cells, Cultured
Coronary Artery Disease / genetics,  immunology*,  pathology
Coronary Vessels / immunology,  pathology
Cytokines / metabolism
Fluorescent Antibody Technique
Immunoglobulins / genetics,  metabolism*
Inflammation / genetics,  immunology,  pathology
Inflammation Mediators / metabolism
Microscopy, Confocal
Middle Aged
Muscle, Smooth, Vascular / immunology*,  pathology
Myocytes, Smooth Muscle / immunology*,  pathology
Polymerase Chain Reaction
RNA Interference*
RNA, Messenger / metabolism
Time Factors
Reg. No./Substance:
0/Cell Adhesion Molecules; 0/Cytokines; 0/F11R protein, human; 0/Immunoglobulins; 0/Inflammation Mediators; 0/RNA, Messenger

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