Increased secretion of Gas6 by smooth muscle cells in human atherosclerotic carotid plaques

被引:33
作者
Clauser, Sylvain [1 ,2 ,3 ]
Meilhac, Olivier [4 ,5 ,6 ]
Bieche, Ivan [7 ,8 ]
Raynal, Pierre [9 ]
Bruneval, Patrick [8 ,10 ,11 ]
Michel, Jean-Baptiste [4 ,5 ,6 ]
Borgel, Delphine [2 ]
机构
[1] Hop Ambroise Pare, AP HP, Serv Hematol Immunol, F-92104 Boulogne, France
[2] Univ Paris 11, EA 4531, Chatenay Malabry, France
[3] Univ Versailles St Quentin, Fac Med, Guyancourt, France
[4] INSERM, U698, Paris, France
[5] CHU Xavier Bichat, AP HP, Paris, France
[6] Univ Paris Diderot, Paris, France
[7] INSERM, UMR S745, Fac Pharm, Paris, France
[8] Univ Paris 05, Paris, France
[9] Ctr Hosp Versailles, Le Chesnay, France
[10] INSERM, U970, Paris, France
[11] Hop Europeen Georges Pompidou, AP HP, Paris, France
关键词
Atherosclerosis; Gas6; vascular smooth muscle cells; TGF beta; RECEPTOR TYROSINE KINASE; ARREST-SPECIFIC GENE; GROWTH ARREST; ENDOTHELIAL-CELLS; PROTEIN-S; MER RECEPTOR; AXL; EXPRESSION; ASSOCIATION; PRODUCT;
D O I
10.1160/TH11-05-0368
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Vitamin K-dependent protein Gas6 (growth-arrest specific gene 6) plays a role in vascular smooth muscle cell (VSMC) survival and migration, as well as in endothelium and leukocyte activation, and could therefore be involved in atherosclerosis. However, the study of mouse models has led to contradictory results regarding the pro- or anti-atherogenic properties of Gas6, and relatively few data are available in human pathophysiology. To better understand the implication of Gas6 in human atherosclerosis, we studied Gas6 expression and secretion in vitro in human VSMC, and analysed the effect of Gas6 on inflammatory gene expression in these cells. We show that Gas6 secretion in VSMC is strongly induced by the anti-inflammatory cytokine transforming growth factor (TGF)beta, and that VSMC stimulation by recombinant Gas6 decreases the expression of inflammatory genes tumour necrosis factor (TNF)alpha and intracellular adhesion molecule (ICAM)-1. The study of Gas6 expression in human carotid endarterectomy samples revealed that Gas6 is mainly expressed by VSMC at all stages of human atherosclerosis, but is not detected in normal vessel wall. Analysis of plaque secretomes showed that Gas6 secretion is markedly higher in non-complicated plaques than in complicated plaques, and that TGF beta secretion pattern mirrors that of Gas6. We conclude that Gas6 is secreted in human atherosclerotic plaques by VSMC following stimulation by TGF beta, and that Gas6 secretion decreases with plaque complication. Therefore, we propose that Gas6 acts as a protective factor, in part by reducing the pro-inflammatory phenotype of VSMC.
引用
收藏
页码:140 / 149
页数:10
相关论文
共 47 条
[1]   Defective Mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis [J].
Ait-Oufella, Hafid ;
Pouresmail, Vahid ;
Simon, Tabassome ;
Blanc-Brude, Olivier ;
Kinugawa, Kiyoka ;
Merval, Regine ;
Offenstadt, Georges ;
Leseche, Guy ;
Cohen, Philip L. ;
Tedgui, Alain ;
Mallat, Ziad .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2008, 28 (08) :1429-1431
[2]   TNF-α, IL-6, and IL-1 expression is inhibited by GAS6 in monocytes/macrophages [J].
Alciato, Federica ;
Sainaghi, Pier Paolo ;
Sola, Daniele ;
Castello, Luigi ;
Avanzi, Gian Carlo .
JOURNAL OF LEUKOCYTE BIOLOGY, 2010, 87 (05) :869-875
[3]   Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis [J].
Angelillo-Scherrer, A ;
de Frutos, PG ;
Aparicio, C ;
Melis, E ;
Savi, P ;
Lupu, F ;
Arnout, J ;
Dewerchin, M ;
Hoylaerts, MF ;
Herbert, M ;
Collen, D ;
Dahlbäck, B ;
Carmeliet, P .
NATURE MEDICINE, 2001, 7 (02) :215-221
[4]   Role of Gas6 in erythropoiesis and anemia in mice [J].
Angelillo-Scherrer, Anne ;
Burnier, Laurent ;
Lambrechts, Diether ;
Fish, Richard J. ;
Tjwa, Marc ;
Plaisance, Stephane ;
Sugamele, Rocco ;
DeMol, Maria ;
Martinez-Soria, Eduardo ;
Maxwell, Patrick H. ;
Lemke, Greg ;
Goff, Stephen P. ;
Matsushima, Glenn K. ;
Earp, H. Shelton ;
Chanson, Marc ;
Collen, Desire ;
Izui, Shozo ;
Schapira, Marc ;
Conway, Edward M. ;
Carmeliet, Peter .
JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (02) :583-596
[5]  
Avanzi GC, 1997, EXP HEMATOL, V25, P1219
[6]   GAS6 inhibits granulocyte adhesion to endothelial cells [J].
Avanzi, GC ;
Gallicchio, M ;
Bottarel, F ;
Gammaitoni, L ;
Cavalloni, G ;
Buonfiglio, D ;
Bragardo, M ;
Bellomo, G ;
Albano, E ;
Fantozzi, R ;
Garbarino, G ;
Varnum, B ;
Aglietta, M ;
Saglio, G ;
Dianzani, U ;
Dianzani, C .
BLOOD, 1998, 91 (07) :2334-2340
[7]   Analysis of Gas6 in human platelets and plasma [J].
Balogh, I ;
Hafizi, S ;
Stenhoff, J ;
Hansson, K ;
Dahlbäck, B .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2005, 25 (06) :1280-1286
[8]  
Bièche I, 2001, CANCER RES, V61, P1652
[9]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[10]   Gas6-Axl receptor signaling is regulated by glucose in vascular smooth muscle cells [J].
Cavet, Megan E. ;
Smolock, Elaine M. ;
Ozturk, Oktay H. ;
World, Cameron ;
Pang, Jinjiang ;
Konishi, Atsushi ;
Berk, Bradford C. .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2008, 28 (05) :886-891