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Published on: February 20, 2019
LOX-1: A potential target for therapy in atherosclerosis; an in vitro study
Albina Arjuman1, Nimai C Chandra1
1Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
Abstract:
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 (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-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.
Insights
A novel siRNA (siLOX-1Ω) successfully reduced pro-atherogenic signals from oxidized LDL (oxLDL) and its receptor LOX-1. This therapy targets sustained inflammatory responses mediated by cytokines, offering potential atherosclerosis treatment.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Immunology
Background:
- Oxidized low-density lipoprotein (oxLDL) interaction with the Lectin-like oxidized LDL receptor 1 (LOX-1) triggers pro-inflammatory signals.
- Sustained LOX-1 signaling contributes to atherosclerosis development.
- Novel therapeutic strategies are needed to attenuate oxLDL-induced inflammation.
Purpose of the Study:
- To investigate the temporal dynamics of LOX-1 signaling.
- To identify key mediators in the oxLDL-LOX-1 pathway.
- To evaluate the efficacy of a novel siRNA (siLOX-1Ω) in attenuating LOX-1 signaling.
Main Methods:
- A metabolic pulse-chase system was used to study LOX-1R signaling over 72 hours.
- Cells were treated with oxLDL and then chased without the stimulus.
- Expression of LOX-1R, TNF-α, IL-6, NO, and NF-kB was measured.
- A novel combination siRNA (siLOX-1Ω) was employed to target Homo sapien LOX-1 mRNA.
Main Results:
- LOX-1R expression showed a biphasic pattern, increasing initially and then renewing after 48 hours.
- Tumor necrosis factor-alpha (TNF-α) acted as a primary mediator, potentially stimulating CD40 and MMP-9.
- Interleukin-6 (IL-6) and TNF-α were involved in the second phase of signaling, peaking at 48 hours.
- siLOX-1Ω effectively reduced LOX-1R expression and downstream signaling intermediates like nitric oxide (NO) and nuclear factor-kappa B (NF-kB).
Conclusions:
- LOX-1 signaling is sustained by pro-inflammatory cytokines even after oxLDL withdrawal.
- siLOX-1Ω successfully abated LOX-1R expression and its associated inflammatory cascade.
- Targeting LOX-1 signaling via siLOX-1Ω presents a potential therapeutic avenue for atherosclerosis.
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