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 is characterized by neointimal hyperplasia caused by proliferation of smooth muscle cells (SMCs), which increases the expression of Platelet-derived growth factor (PDGF)-A and SMemb. SMemb, a non-muscle-type myosin heavy chain most predominantly expressed in embryonic smooth muscle, can be used as a good molecular marker for dedifferentiated SMC. The aim of this study was to analyze the effect of probucol on neointimal 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 weeks prior to carotid balloon injury to the time of killing (2 or 4 weeks after balloon injury). Intimal area was determined histologically using a computerized morphometry program. For quantification of SMC proliferation, alpha-actin-positive cells and proliferating cell nuclear antigen (PCNA)-labeled cells were counted. The expression of PDGF-A and SMemb mRNA was analyzed by the RNase protection assay. SMemb expression was also examined by immunohistochemistry. Probucol remarkably decreased intimal area by 70% and the number of SMC and PCNA-labeled cells in the intima. The expression of PDGF-A mRNA was significantly increased after balloon injury in untreated rabbits, whereas it was markedly suppressed with probucol treatment. The expression of SMemb was significantly increased in injured arteries at mRNA and protein levels. However, probucol did not suppress SMemb expression. Probucol is effective in preventing SMC proliferation, which is possibly due to a decrease in the expression of PDGF.
Department of Cardiology, Juntendo University School of Medicine, Tokyo, Japan.
K
K
Miyauchi
M
M
Aikawa
T
T
Tani
K
K
Nakahara
S
S
Kawai
R
R
Nagai
R
R
Okada
H
H
Yamaguchi
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D020212:Carotid Artery Injuries; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D018995:Myosin Heavy Chains / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D011341:Probucol / Q000627:therapeutic use*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits
D000924:Anticholesteremic Agents; D010982:Platelet-Derived Growth Factor; D020033:Protein Isoforms; D012333:RNA, Messenger; D018995:Myosin Heavy Chains; D011341:Probucol