LOX-1: Regulation, Signaling and Its Role in Atherosclerosis

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.

Foam cells promote atherosclerosis progression by releasing CXCL12

“…AS has long been known as a progressive chronic inflammatory disease of the arteries [25]. The subendothelial deposition of oxidized LDLs (ox-LDLs), the formation of foamy macrophages, and the proliferation/migration of VSMCs are central pathophysiologic steps in the formation of atherosclerotic plaque [20]. The excessive uptake of ox-LDLs by monocyte-derived macrophages and a decrease in cholesterol outflow are factors that accelerate atherosclerotic plaque formation, and also key processes that determine the size of atherosclerotic plaque [28].…”

Role of the Scavenger Receptor CD36 in Accelerated Diabetic Atherosclerosis

“…However, CD36 is not the only mediator of oxLDL uptake. Other scavenger receptors for lipids, such as lectin-like oxidized LDL receptor-1 (LOX-1), low-density lipoprotein receptor-related protein (LRP1), and class A scavenger receptor (SR-A), internalize oxLDL and may be upregulated in VSMC by oxLDL [ 14 , 36 , 37 , 38 ]. On the contrary, the silencing of CD36 did not affect the upregulated expression of pro-inflammatory markers by HG and oxLDL, suggesting that the effects observed by the exposure to HG with or without the presence of oxLDL cannot be explained by the unique action of CD36-derived signaling.…”

Uremic Vascular Calcification Is Correlated With Oxidative Elastic Lamina Injury, Contractile Smooth Muscle Cell Loss, Osteogenesis, and Apoptosis: The Human Pathobiological Evidence

“…Emerging evidence have highlighted that UVC is a cell-mediated active process associated with VSMC death, maladaptation, and phenotypic modulation to promote UVC progression (11)(12)(13). Moreover, vascular oxidative injury is attributed to an imbalance between the excess reactive oxygen species (ROS) generation and inadequate anti-oxidant defense forces (14). Oxidative stress derived from uremic toxins initiates tissue injury by inducing damages in both proteins and DNA, suppressing VSMC repair functions, and a vicious circle in activation of mitochondrial ROS (15)(16)(17).…”