Involvement of Fas signalling in 7β-hydroxycholesterol-and cholesterol-5β,6β-epoxide-induced apoptosis

Abstract

The induction of apoptosis in cells of the arterial wall is a critical event in the development of atheroma. 7β-Hydroxycholesterol (7β-OH) and cholesterol-5β,6β-epoxide (β-epoxide) are components of oxLDL and have previously been shown to be potent inducers of apoptosis. However, the exact mechanisms through which these oxysterols induce apoptosis remains to be fully elucidated. The specific interaction of the Fas death receptor with Fas ligand (FasL) initiates a caspase cascade culminating in apoptosis. The purpose of the present study was to determine the involvement of Fas signalling in 7β-OH-and β-epoxide-induced apoptosis. To this end we employed the Fas/FasL antagonist, Kp7-6, and examined the effect of Fas inhibition on oxysterol-induced cell death in U937 cells. Fas levels were increased following 24 h exposure to 30 μM 7β-OH while treatment with 30 μM β-epoxide had no effect. Kp7-6 reduced the Fas content of 7β-OH-treated cells to control levels and partially protected against 7β-OH-induced apoptosis. This coincided with a decrease in cytochrome c release along with a reduction in caspase-3 and caspase-8 activity. Our data implicate Fas signalling in the apoptotic pathway induced by 7β-OH and also highlight differences between apoptosis induced by 7β-OH and β-epoxide. Copyright © American College of Toxicology.