The β3 integrin antagonist m7E3 reduces matrix metalloproteinase activity and smooth muscle cell migration

被引:23
作者
Bendeck, MP
Nakada, MT
机构
[1] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada
[2] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada
[3] Centocor Inc, Malvern, PA 19355 USA
关键词
smooth muscle cell; matrix metalloproteinase; m7E3; av beta 3; integrin; arterial injury;
D O I
10.1159/000051095
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Treatment with c7E3 (abciximab, ReoPro) has been associated with a reduction in coronary events and the need for revascularization. Some of these beneficial effects may be due to blockade of the alphavbeta3 integrin receptor on smooth muscle cells (SMCs), however very little is known about the mechanisms involved. The current studies were designed to test the hypothesis that beta3 integrin antagonists inhibit the arterial response to injury by reducing matrix metalloproteinase (MMP) activity in the vessel wall. Male Sprague-Dawley rats were treated with daily intraperitoneal injections of the monoclonal antibody m7E3 at a dose of 6 mg/kg/day. MMP-9 activity was reduced by 73%, and MMP-2 activity by 75%, in the injured carotids of the m7E3-treated rats compared to saline-treated controls. By contrast, tissue inhibitor metalloproteinase (TIMP) activity was not changed. SMC migration assayed at 4 days after injury was reduced from 56.7 +/- 14 cells/mm(2) intimal surface area in controls to 17.5 +/- 5 cells/mm(2) in m7E3-treated rats (p = 0.02). Medial cell replication measured at 4 days and intimal cell replication measured at 7 days were not affected. Intimal cross-sectional area, measured 14 days after injury was reduced by 28% after m7E3 treatment (p = 0.05). Intimal smooth muscle cell number and the ratio of intima/media cross-section area were also reduced. By contrast, intimal SMC density was not affected by m7E3 treatment, indicating no effect on matrix accumulation. We conclude that treatment with m7E3 reduced SMC migration following vascular injury, possibly via an inhibitory effect on MMP activity, and this resulted in a decrease in intimal size at 14 days after injury. Copyright (C) 2001 S. Karger AG, Basel.
引用
收藏
页码:590 / 599
页数:10
相关论文
共 45 条
[31]  
Sassoli PM, 2001, THROMB HAEMOSTASIS, V85, P896
[32]   NF-κB mediates αvβ3 integrin-induced endothelial cell survival [J].
Scatena, M ;
Almeida, M ;
Chaisson, ML ;
Fausto, N ;
Nicosia, RF ;
Giachelli, CM .
JOURNAL OF CELL BIOLOGY, 1998, 141 (04) :1083-1093
[33]  
SEFTOR REB, 1993, CANCER RES, V53, P3411
[34]   7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1 [J].
Simon, DI ;
Xu, H ;
Ortlepp, S ;
Rogers, C ;
Rao, NK .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1997, 17 (03) :528-535
[35]   β3-integrins rather than β1-integrins dominate integrin-matrix interactions involved in postinjury smooth muscle cell migration [J].
Slepian, MJ ;
Massia, SP ;
Dehdashti, B ;
Fritz, A ;
Whitesell, L .
CIRCULATION, 1998, 97 (18) :1818-1827
[36]   Selective αvβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury:: Evidence for the functional importance of integrin αvβ3 and osteopontin expression during neointima formation [J].
Srivatsa, SS ;
Fitzpatrick, LA ;
Tsao, PW ;
Reilly, TM ;
Holmes, DR ;
Schwartz, RS ;
Mousa, SA .
CARDIOVASCULAR RESEARCH, 1997, 36 (03) :408-428
[37]   MECHANISM OF CELL-SURFACE ACTIVATION OF 72-KDA TYPE-IV COLLAGENASE - ISOLATION OF THE ACTIVATED FORM OF THE MEMBRANE METALLOPROTEASE [J].
STRONGIN, AY ;
COLLIER, I ;
BANNIKOV, G ;
MARMER, BL ;
GRANT, GA ;
GOLDBERG, GI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (10) :5331-5338
[38]   Abciximab (ReoPro, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and αvβ3 integrins [J].
Tam, SH ;
Sassoli, PM ;
Jordan, RE ;
Nakada, MT .
CIRCULATION, 1998, 98 (11) :1085-1091
[39]   Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta(3) blockade with percutaneous coronary intervention [J].
Topol, EJ ;
Ferguson, JJ ;
Weisman, HF ;
Tcheng, JE ;
Ellis, SG ;
Kleiman, NS ;
Ivanhoe, RJ ;
Wang, AL ;
Miller, DP ;
Anderson, KM ;
Califf, RM .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 1997, 278 (06) :479-484
[40]  
Topol EJ, 1997, NEW ENGL J MED, V336, P1689