LOX-1: A potential target for therapy in atherosclerosis; an &ITin vitro&IT study

Pro-inflammatory signal generated from the interaction of oxLDL with its cognate receptor LOX-1 has been attenuated successfully by a novel combination siRNA (siLOX-1(Omega)) targeting unique regions of Homo sapien LOX- 1 mRNA. Signalling via LOX-1R was studied in a potentially pro-atherogenic arena recreated in a metabolic, pulse-chase set up. An initial pulse of oxLDL (20 mu g/mL;5 h) was chased (without oxLDL) on a temporal scale upto 72 h. Our study shows that the pro-inflammatory signal generated via oxLDL-LOX-1R interaction was mediated in two rungs, an initial sustained increase in LOX-1R expression up to 12 h, and a renewal after 48 h. TNF-alpha acted as a primary mediator of LOX-1R signalling, presumably also stimulating CD40 and MMP-9. Both TNF-alpha and IL-6 were involved in the second rung of LOX-1R signalling; maximum secretion of both was detected at 48 h. Our study suggests a temporal sustenance of LOX-1R signalling by pro-inflammatory cytokines even on withdrawal of oxLDL. Also, siLOX-1(Omega) successfully abated LOX-1R expression along with its signalling inter mediates, NO and NF-kB. Overall, LOX-1 signalling and the crucial role of cytokines in sustaining it is reported. Attenuation of this receptor may be of therapeutic value in atherosclerosis.