Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines

被引:101
作者
Zeiffer, U
Schober, A
Lietz, M
Liehn, EA
Erl, W
Emans, N
Yan, ZQ
Weber, C
机构
[1] Univ Technol, Dept Mol Cardiovasc Res, Aachen, Germany
[2] Univ Technol, Dept Cardiol, Aachen, Germany
[3] Univ Technol, Inst Mol Biotechnol, Aachen, Germany
[4] Univ Munich, Inst Prevent Cardiovasc Dis, Munich, Germany
[5] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden
关键词
restenosis; inflammation; cell adhesion molecules; smooth muscle cells; chemokines;
D O I
10.1161/01.RES.0000121105.72718.5C
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and "memory" T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-alpha and fractalkine, whereas "memory" T cell arrest was mediated by stromal cell - derived factor (SDF)-1alpha. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-kappaB activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-kappaB by adenoviral IkappaBalpha in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-kappaB-mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.
引用
收藏
页码:776 / 784
页数:9
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