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Abstract

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.

Voltage‐gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A

“…Expression of I Na could be found in parts of the cells examined in this study, which may also support this notion. However, these changes may be occurred under various pathophysiological conditions such as vascular injury, atherosclerosis and asthma [29–32]. Therefore, the possible expression of I Na under these conditions is worth considering, and further studies are necessary to clarify the physiological significance of the channel.…”

Decorin Mimic Regulates Platelet-Derived Growth Factor and Interferon-γ Stimulation of Vascular Smooth Muscle Cells

“…11−13 PDGF, which has been demonstrated to increase SMC proliferation and migration in vitro and in vivo, as well as upregulate SMC extracellular matrix synthesis, has been associated with the onset of intimal hyperplasia in arterial-injury models. 8,14,14,15 While PDGF is pro-stenotic, the function of IFN-γ with respect to regulating SMC activity is more complex, with both pro- and antistenotic activities identified, calling into question the role of the cytokine on SMC proliferation, migration, and protein synthesis. 16 While IFN-γ exhibits conflicting biological activities, the cytokine has a range of influence on disease progression, with recent work providing evidence of an association of IFN-γ with the onset of intimal hyperplasia.…”

Inhibition of Apoptotic Signaling and Neointimal Hyperplasia by Tempol and Nitric Oxide Synthase following Vascular Injury

“…Antioxidants have served as useful tools in demonstrating a causal role for ROS in the formation of neointima. Whereas previous animal studies using the antioxidant probucol have highlighted the benefits of antioxidant therapy with respect to the inhibition of neointima formation [9, 13, 14], probucol had to be administered as much as 4 weeks prior to vascular injury in order to be effective. The data presented here demonstrate that, in contrast, tempol administration 1 day prior to injury and continued during the experimental period is sufficient to decrease ROS levels, inhibit the initial phase of medial SMC apoptosis, and attenuate neointima formation.…”