LOX-1: Regulation, Signaling and Its Role in Atherosclerosis
Open Access
- 11 July 2019
- journal article
- review article
- Published by MDPI AG in Antioxidants
- Vol. 8 (7), 218
- https://doi.org/10.3390/antiox8070218
Abstract
Atherosclerosis has long been known to be a chronic inflammatory disease. In addition, there is intense oxidative stress in atherosclerosis resulting from an imbalance between the excess reactive oxygen species (ROS) generation and inadequate anti-oxidant defense forces. The excess of the oxidative forces results in the conversion of low-density lipoproteins (LDL) to oxidized LDL (ox-LDL), which is highly atherogenic. The sub-endothelial deposition of ox-LDL, formation of foamy macrophages, vascular smooth muscle cell (VSMC) proliferation and migration, and deposition of collagen are central pathophysiologic steps in the formation of atherosclerotic plaque. Ox-LDL exerts its action through several different scavenger receptors, the most important of which is LOX-1 in atherogenesis. LOX-1 is a transmembrane glycoprotein that binds to and internalizes ox-LDL. This interaction results in variable downstream effects based on the cell type. In endothelial cells, there is an increased expression of cellular adhesion molecules, resulting in the increased attachment and migration of inflammatory cells to intima, followed by their differentiation into macrophages. There is also a worsening endothelial dysfunction due to the increased production of vasoconstrictors, increased ROS, and depletion of endothelial nitric oxide (NO). In the macrophages and VSMCs, ox-LDL causes further upregulation of the LOX-1 gene, modulation of calpains, macrophage migration, VSMC proliferation and foam cell formation. Soluble LOX-1 (sLOX-1), a fragment of the main LOX-1 molecule, is being investigated as a diagnostic marker because it has been shown to be present in increased quantities in patients with hypertension, diabetes, metabolic syndrome and coronary artery disease. LOX-1 gene deletion in mice and anti-LOX-1 therapy has been shown to decrease inflammation, oxidative stress and atherosclerosis. LOX-1 deletion also results in damage from ischemia, making LOX-1 a promising target of therapy for atherosclerosis and related disorders. In this article we focus on the different mechanisms for regulation, signaling and the various effects of LOX-1 in contributing to atherosclerosis.Keywords
This publication has 102 references indexed in Scilit:
- LOX-1, OxLDL, and AtherosclerosisMediators of Inflammation, 2013
- Oxidized low density lipoprotein, stem cells, and atherosclerosisLipids in Health and Disease, 2012
- Chlamydia pneumoniae binds to the lectin-like oxidized LDL receptor for infection of endothelial cellsMicrobes and Infection, 2012
- LOX-1 Inhibition in ApoE KO Mice Using a Schizophyllan-based Antisense Oligonucleotide TherapyMolecular Therapy Nucleic Acids, 2012
- Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery diseaseJCI Insight, 2011
- OxLDL-dependent activation of arginase II is dependent on the LOX-1 receptor and downstream RhoA signalingAtherosclerosis, 2011
- Oxidized Low-Density LipoproteinPublished by Springer Science and Business Media LLC ,2009
- LOX-1 augments oxLDL uptake by lysoPC-stimulated murine macrophages but is not required for oxLDL clearance from plasmaJournal of Lipid Research, 2009
- Soluble lectin-like oxidized low density lipoprotein receptor-1 in type 2 diabetes mellitusJournal of Lipid Research, 2008
- Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injuryBiochemical and Biophysical Research Communications, 2006