LOX-1 Mediated Pathways in Cardiovascular Diseases

Lectin-like oxidised low-density lipoprotein receptor 1 (LOX-1) is a transmembrane glycoprotein expressed on endothelial cells, macrophages and vascular smooth muscle cells. By binding and internalising oxidised low-density lipoprotein (ox-LDL), LOX-1 initiates pro-inflammatory and pro-oxidative signalling cascades, including activation of NF-κB, upregulation of adhesion molecules and enhanced generation of reactive oxygen species (ROS). These events compromise endothelial function, promote foam cell formation and drive smooth muscle proliferation, leading to atherosclerotic plaque development and instability. Cleavage of membrane LOX-1 releases soluble LOX-1 (sLOX-1) into the circulation, where its levels mirror receptor activation and plaque vulnerability. Emerging data link LOX-1 dysregulation not only to coronary atherosclerosis but also to myocardial infarction, diabetic vasculopathy and post-infarct remodelling. Targeted inhibition of the receptor or its downstream effectors represents a promising therapeutic strategy to quell arterial inflammation and reduce adverse cardiovascular outcomes.

Research from Nature Portfolio

Structure-based approaches have provided proof of principle that selective blockade of the LOX-1 lectin domain can modulate early atherogenic events. Virtual screening identified small molecules that bind the ox-LDL recognition site on LOX-1, reducing ox-LDL uptake in human endothelial cells and suppressing downstream activation of ERK1/2 and p38 MAP kinases. These inhibitors also decreased endothelial expression of vascular cell adhesion molecule-1 and monocyte adhesion, demonstrating the feasibility of directly targeting LOX-1 to interfere with plaque initiation.

LOX-1 Mediated Pathways in Cardiovascular Diseases publication trend

The graph below shows the total number of articles in lox-1 mediated pathways in cardiovascular diseases across all publications each year (not limited to Nature Index journals).

Technical terms

LOX-1 (lectin-like oxidised low-density lipoprotein receptor 1): A cell-surface receptor that binds and internalises oxidised LDL, triggering inflammatory and oxidative responses in the vessel wall.

Oxidised LDL (ox-LDL): Low-density lipoprotein particles modified by reactive oxygen species, which are recognised by scavenger receptors and drive foam cell formation.

Endothelial dysfunction: Impaired ability of the vascular endothelium to regulate vasodilation, barrier function and anti-inflammatory responses, often preceding atherosclerosis.

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen that, in excess, induce oxidative damage and signalling in vascular cells.

Soluble LOX-1 (sLOX-1): A proteolytic fragment of LOX-1 released into the bloodstream, serving as a circulating marker of receptor activation and plaque instability.

References

1. Liraglutide ameliorates oxidized LDL-induced endothelial dysfunction by GLP-1R-dependent downregulation of LOX-1-mediated oxidative stress and inflammation. Redox Report (2023).
2. Radical Oxygen Species, Oxidized Low-Density Lipoproteins, and Lectin-like Oxidized Low-Density Lipoprotein Receptor 1: A Vicious Circle in Atherosclerotic Process. Antioxidants (2024).
3. LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review. International Journal of Molecular Sciences (2024).
4. Serum Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor-1 (sLOX-1) Is Associated with Atherosclerosis Severity in Coronary Artery Disease. Biomolecules (2023).
5. Elevated soluble LOX-1 predicts risk of first-time myocardial infarction. Annals of Medicine (2023).
6. Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein. Scientific Reports (2015).