Inhibition of coronary thrombosis and local inflammation by a noncarbohydrate selectin inhibitor.
We tested the hypothesis that selectin inhibition with blocking antibodies or a small-molecular-weight inhibitor of L-, P-, and E-selectin, methoxybenzoylpropionic acid (MBPA), prevents thrombus formation in a canine coronary Folts' model. Cyclic flow variations (CFVs) were induced by crush injury and constriction of the left anterior descending coronary artery in dogs. Systemic infusion of antibodies to P- and L-selectin abolished CFVs, respectively, in 50% and 17% of treated dogs [P = not significant (NS)]. The combination of P- and L-selectin antibodies suppressed CFVs in 60% of treated dogs (P = NS). In contrast, systemic selectin blockade by intravenous infusion or local adventitial application of MBPA markedly reduced CFVs and, in addition, reduced myocardial myeloperoxidase (MPO) activity. We conclude that inhibition of L-, P-, and E-selectin binding by a small-molecular-weight, noncarbohydrate compound markedly reduces arterial thrombosis, whereas systemic administration of antibodies to L- and P-selectin fail to reproduce this antithrombotic effect. These results underscore the role of selectins in the pathogenesis of arterial thrombosis under high shear stress and suggest that inhibition of P- and L- selectin may not suffice to prevent thrombus formation in this model. The role of E-selectin in thrombus formation in this model awaits further testing.
Zoldhelyi
P
P
Wafic Said Molecular and Gene Therapy Research Laboratory, Texas Heart Institute, Houston, Texas, USA.
Beck
P J
PJ
Bjercke
R J
RJ
Ober
J C
JC
Hu
X
X
McNatt
J M
JM
Akhtar
S
S
Ahmed
M
M
Clubb
F J
FJ
Chen
Z Q
ZQ
Dixon
R A
RA
Yeh
E T
ET
Willerson
J T
JT
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001772:Blood Cell Count; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000276:immunology* / Q000517:prevention & control; D003331:Coronary Vessels / Q000293:injuries / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D019040:E-Selectin / Q000276:immunology; D005260:Female; D007275:Injections, Intravenous; D019041:L-Selectin / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008297:Male; D009500:Neutralization Tests; D009504:Neutrophils / Q000276:immunology; D019007:P-Selectin / Q000276:immunology; D010647:Phenyl Ethers; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D011422:Propionates / Q000494:pharmacology*; D019087:Selectins / Q000276:immunology*; D014657:Vasculitis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control
C118761:3-(4-methoxybenzoyl)propionic acid; D000911:Antibodies, Monoclonal; D019040:E-Selectin; D019007:P-Selectin; D010647:Phenyl Ethers; D011422:Propionates; D019087:Selectins; D019041:L-Selectin