EFFECT OF PROBUCOL ON SMOOTH-MUSCLE CELL-PROLIFERATION AND DEDIFFERENTIATION AFTER VASCULAR INJURY IN RABBITS - POSSIBLE ROLE OF PDGF

We previously reported a clinical study in which probucol reduced the restenosis rate. The mechanism of this effect is unclear. Restenosis i s characterized by neointimal hyperplasia caused by proliferation of s mooth muscle cells (SMCs), which increases the expression of Platelet- derived growth factor (PDGF)-A and SMemb. SMemb, a non-muscle-type myo sin heavy chain most predominantly expressed in embryonic smooth muscl e, can be used as a good molecular marker for dedifferentiated SMC. Th e aim of this study was to analyze the effect of probucol on neointima l proliferation and the level of expression of PDGF-A and SMemb after balloon injury in rabbits. Probucol was given orally 1.3 g/d from 2 we eks prior to carotid balloon injury to the time of killing (2 or 4 wee ks after balloon injury). Intimal area was determined histologically u sing a computerized morphometry program. For quantification of SMC pro liferation, alpha-actin-positive cells and proliferating cell nuclear antigen (PCNA)-labeled cells were counted. The expression of PDGF-A an d SMemb mRNA was analyzed by the RNase protection assay. SMemb express ion was also examined by immunohistochemistry. Probucol remarkably dec reased intimal area by 70% and the number of SMC and PCNA-labeled cell s in the intima. The expression of PDGF-A mRNA was significantly incre ased after balloon injury in untreated rabbits, whereas it was markedl y suppressed with probucol treatment. The expression of SMemb was sign ificantly increased in injured arteries at mRNA and protein levels. Ho wever, probucol did not suppress SMemb expression. Probucol is effecti ve in preventing SMC proliferation, which is possibly due to a decreas e in the expression of PDGF.