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 d evelopment of coronary atherosclerosis. However, it remains to be exam ined what morphologic and functional changes are induced in vivo by th e long-term treatment with PDGF itself or what pharmacologic intervent ions could suppress those changes in vivo. Our study was designed to a ddress these points. We examined the effects of long-term treatment wi th PDGF on the porcine coronary artery in vivo. Under aseptic conditio ns, the proximal segments of the left porcine coronary artery were gen tly wrapped with cotton mesh absorbing sepharose beads either with or without recombinant human PDGF-AA or -BB. Two weeks after the operatio n, 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 an d histologic changes of the coronary artery induced by PDGF were marke dly inhibited by cotreatment with ST 638, a specific inhibitor of tyro sine kinases. A Western blot analysis showed that ST 638 markedly supp ressed the PDGF-induced tyrosine phosphorylations in the coronary segm ent. 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 substant ially involved.