Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits.
BACKGROUND
Crosstalk between pro-inflammatory cytokines and platelet-derived growth factor (PDGF) regulates smooth-muscle-cell proliferation in cardiac-allograft arteriosclerosis. In this study, we tested the effect of STI 571, a novel orally active protein tyrosine kinase (PTK) inhibitor selective for PDGF receptor (PDGF-R) on transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits.


METHODS
Cardiac allografts were transplanted heterotopically from Dutch Belted to New Zealand White rabbits. A 0.5% cholesterol diet was begun 4 days before transplantation. Recipients received STI 571 5 mg/kg per day or vehicle intraperitoneally throughout the study period of 6 weeks. Cyclosporine A was given as background immunosuppression.


RESULTS
In cardiac allografts of vehicle-treated rabbits, 76.2+/-2.1% of medium-sized arteries were affected by intimal thickening, and the percentage of arterial occlusion was 45.0+/-5.0%. Treatment with STI 571 reduced the incidence of affected medium-sized arteries to 41.2+/-8.1% (P <0.05) and the arterial occlusion to 27.6+/-5.0% ( P<0.05). In addition, we observed that STI 571 treatment reduced intimal lesion formation in proximal ascending aorta of transplanted hearts from 72.3+/-19.9 to 12.7+/-1.9 microm ( P<0.05). Our results also show that STI 571 significantly inhibited accelerated arteriosclerosis in medium-sized arteries of recipients' own hearts.


CONCLUSIONS
The results of the present study suggest that PDGF-R activation may regulate the development of transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. Thus, PTK inhibitors may provide new strategies for prevention of these fibroproliferative vascular disorders.
Sihvola
Roope K
RK
Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Tikkanen
Jussi M
JM
Krebs
Rainer
R
Aaltola
Eva M
EM
Buchdunger
Elisabeth
E
Laitinen
Outi
O
Koskinen
Petri K
PK
Lemström
Karl B
KB
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001013:Aorta, Thoracic; D001018:Aortic Diseases / Q000188:drug therapy* / Q000453:epidemiology / Q000517:prevention & control; D001549:Benzamides; D002791:Cholesterol, Dietary / Q000097:blood / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000517:prevention & control; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006937:Hypercholesterolemia / Q000188:drug therapy; D000068877:Imatinib Mesylate; D015994:Incidence; D008264:Macrophages / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011817:Rabbits; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous
D000970:Antineoplastic Agents; D001549:Benzamides; D002791:Cholesterol, Dietary; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C075278:platelet-derived growth factor A; D000068877:Imatinib Mesylate; D017479:Receptors, Platelet-Derived Growth Factor