TW96, a synthetic 1,4-naphthoquinone, differentially regulates vascular and endothelial cells survival

Vascular smooth muscle cell (VSMCs) proliferation is an essential factor in cardiovascular diseases, such as primary atherosclerosis and in-stent restenosis. In this study, we examined the effects of the novel synthetic naphthoquinone, 2-pyrrilidino-3-(p-hydroxyphenylamino)-1,4-naphthoquinone (TW-96), on cultured VSMCs and endothelial cells (ECs). Pharmacological concentrations of the derivative TW96 were found to induce VSMCs death, probably by increasing ROS levels while decreasing mitochondrial potential (ΔΨ_m) without affecting ECs. Treatment of tissue cultures with ROS is known to induce MAPK activity. Our observations showed prolonged phosphorylation and perinuclear accumulation of ERK1/2 and p38 simultaneously with an inhibition of MKP1. Increased expression of Bax found in TW96-stimulated VSMCs was inhibited by the NADPH oxidase inhibitor diphenyliodonium (DPI). An examination of the suppressive effects of TW96 on PDGF-BB-stimulated VSMCs cycle progression showed that TW96 leads to migration arrest at concentrations lower than LC₅₀. We hope that this prototype derivative will establish the basis for creating more specific naphthoquinone derivatives aimed at preventing the VSMCs proliferation associated with stenosis and restenosis.