Tyrosine kinase inhibitor markedly suppresses the development of coronary lesions induced by long-term treatment with platelet-derived growth factor in pigs in vivo.
Platelet-derived growth factor (PDGF) plays an important role in the development of coronary atherosclerosis. However, it remains to be examined what morphologic and functional changes are induced in vivo by the long-term treatment with PDGF itself or what pharmacologic interventions could suppress those changes in vivo. Our study was designed to address these points. We examined the effects of long-term treatment with PDGF on the porcine coronary artery in vivo. Under aseptic conditions, the proximal segments of the left porcine coronary artery were gently wrapped with cotton mesh absorbing sepharose beads either with or without recombinant human PDGF-AA or -BB. Two weeks after the operation, coronary hyperconstrictions to intracoronary serotonin or histamine were noted at the sites treated with PDGF-AA or -BB. Histologically, neointimal formation and geometric remodeling (reduction of the total vessel area) were noted at the PDGF-treated sites. These functional and histologic changes of the coronary artery induced by PDGF were markedly inhibited by cotreatment with ST 638, a specific inhibitor of tyrosine kinases. A Western blot analysis showed that ST 638 markedly suppressed the PDGF-induced tyrosine phosphorylations in the coronary segment. These results indicate that long-term treatment with PDGF induces neointimal formation, geometric remodeling, and vasospastic responses in vivo, for all of which, activation of tyrosine kinases is substantially involved.
Kozai
T
T
Research Institute of Angiocardiology, Kyushu University School of Medicine, Fukuoka, Japan.
Shimokawa
H
H
Fukumoto
Y
Y
Kobayashi
S
S
Owada
M K
MK
Kadokami
T
T
Ito
A
A
Kuwata
K
K
Egashira
K
K
Shiraishi
T
T
Kanaide
H
H
Takeshita
A
A
D000042:Absorption; D000704:Analysis of Variance; D000792:Angiography; D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced / Q000188:drug therapy*; D000077214:Becaplermin; D001682:Biological Availability; D002934:Cinnamates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003329:Coronary Vasospasm / Q000188:drug therapy*; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D008297:Male; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins / Q000633:toxicity; D013440:Sulfides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine
D002934:Cinnamates; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D013440:Sulfides; C075278:platelet-derived growth factor A; C060747:ST 638; D000077214:Becaplermin; D011505:Protein-Tyrosine Kinases