Targeting LOX‐1 in atherosclerosis and vasculopathy: current knowledge and future perspectives

Abstract

LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1; also known as OLR1) is the dominant receptor that recognizes and internalizes oxidized low-density lipoproteins (ox-LDLs) in endothelial cells. Several genetic variants of LOX-1 are associated with the risk and severity of coronary artery disease. The LOX-1-ox-LDL interaction induces endothelial dysfunction, leukocyte adhesion, macrophage-derived foam cell formation, smooth muscle cell proliferation and migration, and platelet activation. LOX-1 activation eventually leads to the rupture of atherosclerotic plaques and acute cardiovascular events. In addition, LOX-1 can be cleaved to generate soluble LOX -1 (sLOX-1), which is a useful diagnostic and prognostic marker for atherosclerosis-related diseases in human patients. Of therapeutic relevance, several natural products and clinically used drugs have emerged as LOX-1 inhibitors that have antiatherosclerotic actions. We hereby provide an updated overview of role of LOX-1 in atherosclerosis and associated vascular diseases, with an aim to highlighting the potential of LOX-1 as a novel theranostic tool for cardiovascular disease prevention and treatment.

Oleacein and Foam Cell Formation in Human Monocyte-Derived Macrophages: A Potential Strategy against Early and Advanced Atherosclerotic Lesions

“…The interaction of LOX-1 and oxLDL induces several processes such as endothelial dysfunction, macrophage-derived foam cell formation, leukocyte adhesion. Current studies have proven, that LOX-1 activation eventually leads to the rupture of atherosclerotic plaques and acute cardiovascular events [29]. LOX-1 is a type II membrane protein belonging to the C-type lectin family of molecules and classified as an E class scavenger receptor.…”

Identification of potential biomarkers or therapeutic targets of mesenchymal stem cells in multiple myeloma by bioinformatics analysis

“…As for OLR1 gene, it is a novel PPAR-γ target gene playing a critical role in the regulation of adipocyte lipid metabolism [37]. High level of OLR1 expression was linked to obesity and dyslipidemia [37][38][39]. PPAR-γ was well established as a prime inducer of adipogenesis, which was demonstrated to regulate the differentiation of MSCs into adipocytes [40].…”

C‐type lectin receptors of the Dectin‐1 cluster: Physiological roles and involvement in disease

“…LOX‐1 is able to recognise a broad range of ligands including bacterial products, C‐reactive protein, and advanced glycation end products, but is best known for its ability to bind oxidised LDL (ox‐LDL). LOX‐1 can internalize its ligands through a cytoplasmic tripeptide (DDL) motif, and induce intracellular signalling that results in a variety of cellular responses including the production of ROS, chemokines and cytokines, upregulation of adhesion molecules, apoptosis, as well as activation of the NALP3 inflammasome and NF‐ κ B . How LOX‐1 mediates intracellular signalling is unclear, but recent evidence implicates the membrane N‐terminal fragments in these activities, and their regulation by the signal peptide peptidase–like 2a and b (SPPL2a/b) .…”

“…Notably, in humans, polymorphisms and alternative splice variants of LOX‐1 gene are associated with either promotion or protection from disease . Moreover, the levels of sLOX‐1 can be used as a prognostic and diagnostic marker for cardiovascular disease, and possibly stoke, in patients . Given its detrimental activities, there is considerable interest in developing novel therapeutics that target LOX‐1.…”