Nifedipine suppresses neointimal thickening by its inhibitory effect on vascular smooth muscle cell growth via a MEK-ERK pathway coupling with Pyk2

1 The aim of this study was to determine whether nifedipine could suppress an atherogenic process such as balloon-injured intimal thickening in vivo a nd the proliferation of vascular smooth muscle cells (VSMC) in vitro. 2 First, we examined the in vivo effect of nifedipine to determine whether it could suppress intimal thickening induced by balloon catheterization. Sp rague-Dawley (SD) rats were divided into three groups (L, nifedipine 0.3 mg kg(-1) day(-1); H, nifedipine 3 mg kg(-1) day(-1); C, no nifedipine), and Alzet(R) osmotic pumps were imp lanted in their backs for continuous administration. The neointimal layers were completely occupied by proliferated VSMC, and the area ratios of neoin tima/media treated with nifedipine significantly decreased dose-dependently compared to those of the control. Neither blood pressure nor lipid levels changed among the three groups. 3 We next evaluated the in vitro effect of nifedipine on the proliferation of cultured rat VSMC. Nifedipine decreased the values of [H-3]-thymidine incorporation and total cellular protein cont ent as well as the levels of phosphorylated extracellular signal-regulated protein kinase (ERK) 1/2, mitogen-activated protein kinase kinase (MEK) 1/2 , and even the phosphorylation of Pyk2, in dose-dependent fashions. In addi tion, nifedipine suppressed the levels of proliferative cell nuclear antige n (PCNA) dose-dependently in both VSMC and balloon-injured thoracic aortae. 4 These results indicate that nifedipine has an inhibitory effect on intima l thickening by attenuating intimal VSMC proliferation, suggesting that nif edipine could be effective for preventing the progression of atheroscleroti c plaque as in restenosis after angioplasty.