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

•LOX-1 has been evaluated as a potential target for therapy in atherosclerosis.•A novel siRNA targeting all 3 LOX-1 mRNA variants has been generated successfully.•LOX-1 signalling is mediated in two rungs, initially by TNF-α and sustained by IL-6.•oxLDL signalling via LOX-1-NO-NFкB was successfully abolished by our siLOXΩ.

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-1Ω) 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 μg/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-α acted as a primary mediator of LOX-1R signalling, presumably also stimulating CD40 and MMP-9. Both TNF-α 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-1Ω successfully abated LOX-1R expression along with its signalling intermediates, 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.

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