Arjuman Albina, Chandra Nimai C
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
Int J Biochem Cell Biol. 2017 Oct;91(Pt A):65-80. doi: 10.1016/j.biocel.2017.08.013. Epub 2017 Aug 30.
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) 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 (20μg/mL;5h) was chased (without oxLDL) on a temporal scale upto 72h. 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 12h, and a renewal after 48h. 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 48h. Our study suggests a temporal sustenance of LOX-1R signalling by pro-inflammatory cytokines even on withdrawal of oxLDL. Also, siLOX-1 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.
氧化型低密度脂蛋白（oxLDL）与其同源受体凝集素样氧化低密度脂蛋白受体1（LOX-1）相互作用产生的促炎信号已被一种新型组合小干扰RNA（siLOX-1）成功减弱，该小干扰RNA靶向智人LOX-1信使核糖核酸（mRNA）的独特区域。通过在代谢性脉冲追踪实验中重建的潜在促动脉粥样硬化环境中研究了经由LOX-1R的信号传导。对oxLDL（20μg/mL；5小时）的初始脉冲进行追踪（无oxLDL），时间长达72小时。我们的研究表明，经由oxLDL-LOX-1R相互作用产生的促炎信号通过两个阶段介导，最初是LOX-1R表达持续增加直至12小时，然后在48小时后再次增加。肿瘤坏死因子-α（TNF-α）作为LOX-1R信号传导的主要介质，可能还刺激了CD40和基质金属蛋白酶-9（MMP-9）。TNF-α和白细胞介素-6（IL-6）都参与了LOX-1R信号传导的第二阶段；两者的最大分泌量在48小时时检测到。我们的研究表明，即使在撤除oxLDL后，促炎细胞因子仍能使LOX-1R信号在一段时间内持续存在。此外，siLOX-1成功降低了LOX-1R的表达及其信号传导中间体一氧化氮（NO）和核因子-κB（NF-κB）。总体而言，报道了LOX-1信号传导以及细胞因子在维持该信号传导中的关键作用。该受体的减弱可能在动脉粥样硬化治疗中具有治疗价值。
