Summary
Proliferation of vascular smooth muscle cells (VSMCs) is postulated to be one of the
key events in the pathogenesis of atherosclerosis and restenosis. We investigated
whether YD-3, a lowmolecular weight, non-peptide compound, could modulate proliferation
of VSMCs in vitro and restenosis after balloon angioplasty in vivo. We examined the effect of YD-3 on thrombininduced VSMC proliferation by [3H]thymidine incorporation assay. The data demonstrated that YD-3 inhibited VSMC proliferation
in a concentration-dependent manner. To define the mechanisms of YD-3 action, we found
that YD-3 showed a profound inhibition on thrombin-induced Ras and ERK1/2 activities
by using Western blotting analysis. Furthermore, oral administration of YD-3 exhibited
a marked reduction in neointimal thickness using the carotid injury model in rats.
Using immunochemical detection, our experiments also revealed that YD-3 significantly
suppressed expression of the PAR-1 receptor, and markedly inhibited PAR-1-activating
peptide (SFLLRN)-induced VSMC proliferation in a concentration-dependent manner. These
results suggest that YD-3 inhibits thrombin-induced VSMC growth via the Rasand ERK1/2-mediated
signaling pathway. Moreover, YD-3 also shows a developmental potential in the treatment
of atherosclerosis and restenosis after vascular injury.
Keywords
YD-3 - vascular smooth muscle cells - thrombin - restenosis - signal transduction