Abciximab inhibits the migration and invasion potential of human coronary artery smooth muscle cells.
In the EPIC trial, high-risk patients received the integrin receptor antagonist abciximab v placebo during and for 12 h following percutaneous coronary intervention with a significant 23% decrease of repeat revascularisation at 6 months. However, EPILOG and CAPTURE trials could not confirm these promising long-term results. Recently presented data from the EPISTENT trial suggested a beneficial effect of abciximab on restenosis in patients with diabetes. Based on these divergent results the aim of this study was to test whether alpha v beta 3 receptor blockade by abciximab could cause inhibition of human coronary smooth muscle cell (hcSMC) proliferation, migration, and invasion which represent crucial steps during restenosis development. In contrast to quiescent hcSMCs, proliferating cells were capable to migrate towards chemoattractive stimuli and even capable to invade through a basement membrane equivalent. Abciximab and LM609, an alpha v beta 3 specific inhibiting antibody, caused only a modest dose-dependent inhibition of hcSMC proliferation. On the contrary, the chemotactic and invasive potential of hcSMCs was significantly inhibited by abciximab administration 24 h prior to and during migration. (IC(50)=33.0 microg/ml for chemotaxis and IC(50)=0.5 microg/ml for invasion). For LM609 similar results were obtained. Administration of the drugs just during migration without pretreatment inhibited migration equally but invasion to a lower extent (abciximab: IC(50)=32.6 microg/ml for chemotaxis and IC(50)=44.9 microg/ml for invasion; LM609 IC(50)=3.1 microg/ml for chemotaxis and IC(50)=2.0 microg/ml for invasion). The attachment to the extracellular matrix proteins collagen I, collagen IV, laminin and vitronectin was not influenced. Pretreatment for 24 h with abciximab or LM609 did not cause a downregulation of the alpha v beta 3-integrin receptor. The results of this study indicate that the alpha v beta 3 antagonist abciximab is a potent inhibitor of hcSMC migration and invasion which could explain the observed lower reintervention rate after PTCA and stent implantation.
Blindt
R
R
Medical Clinic I and Interdisciplinary Center of Clinical Research BIOMAT, University of Aachen Hospital, Pauwelsstr 30, Aachen, 52074, Germany. ruediger.blindt@post.rwth-aachen.de
Bosserhoff
A K
AK
Zeiffer
U
U
Krott
N
N
Hanrath
P
P
vom Dahl
J
J
D000077284:Abciximab; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000925:Anticoagulants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002469:Cell Separation; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects; D009389:Neovascularization, Pathologic; D010919:Placebos; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D019096:Vitronectin / Q000378:metabolism
D000906:Antibodies; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D007797:Laminin; D010919:Placebos; D010975:Platelet Aggregation Inhibitors; D019096:Vitronectin; D003094:Collagen; D000077284:Abciximab