From the Heiden Department of Cardiology, Bikur Cholim Hospital (S.B.);
the Departments of Vascular Surgery (Y.W.), Anatomy and Cell Biology (L.P.,
S.D.G.), and School of Pharmacy (G.G., I.F., L.R.), Hebrew
University–Hadassah Medical School; the Departments of Biological
Chemistry, Institute of Life Sciences (A.L., A.G.) and Organic Chemistry,
Institute of Chemistry (A.G.), Hebrew University; the Joseph Lunenfeld Cardiac
Surgery Research Center (A.S., G.L.), Jerusalem, Israel; and the Department of
Internal Medicine II (Cardiology), Ulm University Medical Center, Germany
(J.W., R.H.).
Correspondence to Shmuel Banai, MD, Department of Cardiology, Bikur Cholim Hospital, PO Box 492, Jerusalem 91004, Israel. E-mail banais{at}mail.netvision.net.il
Background—Signaling through protein
tyrosine kinases (PTKs) is a major contributor to the transmission of
mitogenic stimuli to the interior of the cell and nucleus.
The present study was designed to determine the effect of the
tyrphostin AG1295, a selective blocker of PDGF-receptor PTK, on the
growth of porcine and human smooth muscle cells (SMCs) in culture, on
the outgrowth kinetics of SMCs from porcine and human
arterial explants, and on neointimal formation
after balloon injury in pigs.
Methods and Results—SMCs for culture were obtained from porcine
abdominal aortas, human internal mammary arteries, and
endarterectomy tissue from a single human carotid
artery. Addition of AG1295 to SMCs before PDGF stimulation completely
inhibited PDGF-ß-receptor tyrosine phosphorylation
without affecting the level of PDGF-ß-receptor. AG1295 resulted in a
selective, reversible inhibition of SMC proliferation in culture (76%)
with only mild (13.5%) inhibition of endothelial cell
proliferation. The number of SMCs accumulating around explants of
porcine carotid arteries and human endarterectomy
specimens 12, 15, 19, 22, and 24 days after plating was reduced by 82%
to 92% in AG1295-treated compared with nontreated specimens, and
initiation of SMC outgrowth was markedly delayed. The numbers of cells
accumulated 10 days after initiation of outgrowth were significantly
lower in treated versus control explants. Local intravascular delivery
of AG1295-impregnated polylactic acid–based nanoparticles (130±25 nm)
to the site of balloon injury to porcine femoral arteries resulted in
significant reductions in intima/media area ratio and luminal
cross-sectional area narrowing by neointima compared with
contralateral control arteries to which empty nanoparticles were
applied (0.15±0.07 versus 0.09±0.03, P=.046 and
20±4% versus 10±4%, P=.0009, n=6 for both).
Conclusions—The tyrphostin AG1295, a selective blocker of
PDGF-receptor kinase, exerts a marked inhibitory effect on
the activation, migration, and proliferation of porcine and human SMCs
in vitro and an
© 1998 American Heart Association, Inc.
Basic Science Reports
PDGF-Receptor Tyrosine Kinase Blocker AG1295 Selectively Attenuates Smooth Muscle Cell Growth In Vitro and Reduces Neointimal Formation After Balloon Angioplasty in Swine
50% inhibitory effect on
neointimal formation after balloon injury in porcine
femoral arteries when delivered via biodegradable nanoparticles.
Further studies appear to be warranted to evaluate the applicability of
this novel approach to the interventional setting.
Key Words: muscle, smooth • tyrosine kinase • tyrphostin • platelet-derived factors • restenosis
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