Inhibition of aortic allograft vasculopathy by local delivery of platelet-derived growth factor receptor tyrosine-kinase blocker AG-1295.
BACKGROUND
Signal transduction through the platelet-derived growth factor (PDGF)/PDGF-receptor (PDGFR) system has been linked to vascular smooth muscle cell migration and proliferation leading to allograft vasculopathy. This study describes the effect of the tyrphostin AG-1295, a specific PDGFR tyrosine-kinase inhibitor, on neointimal formation in this disease.


RESULTS
Rat aortic allografts transplanted from dark agouti (RT1 ) donors to Wistar-Furth (RT1 ) recipients were assessed in a new treatment model for local drug delivery from polymeric carrier matrices precoated with AG-1295. Matrices were wrapped around the graft immediately after transplantation. The recipients received no background immunosuppression. At day 80 posttransplantation, intimal thickness in AG-1295-treated grafts was reduced when compared to controls (11.8+/-9.1% intimal thickness vs. 23.7+/-6.4% intimal thickness; P=0.042). This finding corresponded to inhibition of intimal PDGFR-beta expression in AG-1295-treated grafts at day 20 posttransplantation (P =0.029 vs. allogeneic controls).


CONCLUSIONS
The tyrphostin AG-1295 reduces neointimal formation in aortic allograft vasculopathy by inhibition of PDGFR-beta-triggered tyrosine phosphorylation. Local drug release of specific tyrosine-kinase inhibitors from perivascularly co-implanted polymeric carrier matrices is effective in the prophylaxis of allograft vasculopathy under selected experimental conditions.
Karck
Matthias
M
Department of Cardiothoracic Surgery, Hannover Medical School, Hannover, Germany. Karck@thg.mh-hannover.de.
Meliss
Rolf
R
Hestermann
Michael
M
Mengel
Michael
M
Pethig
Klaus
K
Levitzki
Alexander
A
Banai
Shmuel
S
Golomb
Gershon
G
Fishbein
Ilia
I
Chorny
Michael
M
Haverich
Axel
A
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D014184:Transplantation, Homologous / Q000009:adverse effects; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology*; D014652:Vascular Diseases / Q000517:prevention & control*
C407689:6,7-dimethoxy-2-phenylquinoxaline; D004791:Enzyme Inhibitors; D020032:Tyrphostins; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta