Effect of selective or combined inhibition of integrins alpha(IIb)beta(3) and alpha(v)beta(3) on thrombosis and neointima after oversized porcine coronary angioplasty.
BACKGROUND
Thrombosis and neointima formation limit the efficacy of coronary angioplasty (PTCA). Clinical trials have implicated the adhesion molecules integrin alpha(IIb)beta(3) and integrin alpha(v)beta(3) in these processes. The roles of these molecules in vascular smooth muscle cell adhesion, platelet aggregation, and the thrombotic and neointimal response to oversize porcine PTCA was investigated by use of a selective alpha(IIb)beta(3) antagonist (lamifiban), a selective alpha(v)beta(3) antagonist (VO514), and a combined alpha(IIb)beta(3)/alpha(v)beta(3) antagonist (G3580).


RESULTS
In vitro, both alpha(v)beta(3) inhibitors caused dose-dependent inhibition of porcine vascular smooth muscle cell adhesion to vitronectin but not to collagen type IV, fibronectin, or laminin, whereas selective alpha(IIb)beta(3) inhibition had no effect. Intravenous infusions of either alpha(IIb)beta(3) inhibitor in swine profoundly inhibited ex vivo platelet aggregation to ADP, whereas selective alpha(v)beta(3) inhibition had no effect. In a porcine PTCA model, intravenous infusions of the integrin antagonists were administered for 14 days after oversized balloon angioplasty injury. After PTCA, there was regional upregulation of integrin alpha(v)beta(3) in the developing neointima, as assessed by immunohistochemistry. Six hours after PTCA, obstruction of lumen by thrombus was reduced significantly by alpha(IIb)beta(3) inhibition compared with either control or alpha(v)beta(3) inhibition (mean control, 18.7%; VO514, 18.5%; lamifiban, 6.4%; G3580, 7.9%). Twenty-eight days after PTCA, there was a significant reduction of neointima with inhibitors of either integrin (mean intima/media ratio: control, 3.08; VO514, 1.33; lamifiban, 0.97; G3580, 1.32).


CONCLUSIONS
We conclude that both integrin alpha(IIb)beta(3) and integrin alpha(v)beta(3) participate in neointima development after experimental angioplasty.
Cardiovascular Research Group, Division of Clinical Sciences (NGHT), University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield, UK. timchico@gene.com
T J
TJ
Chico
J
J
Chamberlain
J
J
Gunn
N
N
Arnold
S L
SL
Bullens
T R
TR
Gadek
S E
SE
Francis
S
S
Bunting
M
M
Horton
L
L
Shepherd
M T
MT
Lipari
C
C
Quan
J
J
Knolle
H U
HU
Stilz
A
A
Peyman
D C
DC
Crossman
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013552:Swine; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D017539:Tunica Intima / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*
D000085:Acetates; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; D014443:Tyrosine; C084062:lamifiban