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Review
. 2013 Aug;70(16):2859-72.
doi: 10.1007/s00018-012-1194-z. Epub 2012 Nov 3.

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Suowen Xu  1 , Sayoko Ogura, Jiawei Chen, Peter J Little, Joel Moss, Peiqing Liu
Affiliations
Review

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Suowen Xu et al. Cell Mol Life Sci. 2013 Aug.

Abstract

Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.

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Conflict of interest statement

None declared.

Figures

Fig. 1
Fig. 1
Schematic diagram illustrating the pivotal role of scavenger receptor LOX-1 in atherosclerotic plaque formation and destabilization. Functions of LOX-1 in EC, SMC, monocytes/macrophages, platelets, and plaque instability are summarized. After binding to LOX-1, oxLDL stimulates endothelial injury, senescence, apoptosis, and oxLDL uptake, also promotes EC to produce adhesion molecules, and recruits leukocytes to the site of injury. Persisted endothelial dysfunction leads to enhanced permeability allowing adherent monocytes to penetrate the lining EC. Differentiated macrophages in the sub-intimal space accumulate oxLDL and convert it to lipid-laden foam cells, which form the necrotic core of the plaque. Intensified inflammation and oxLDL accumulation may result in the proliferation, migration, and foam-cell formation of SMC. As the atherosclerotic plaques develop to the advanced stage, LOX-1 mediates platelet aggregation as well as platelet–endothelium interaction. Finally, LOX-1 leads to plaque destabilization by modulating plaque components (MMP expression, the content of collagen and SMC, and the apoptosis of SMC). EC endothelial cells, SMC smooth muscle cells, RCT reverse cholesterol transport, MMP matrix metalloproteinase. Question mark represents important aspects remaining unknown
Fig. 2
Fig. 2
Positive feedback loop involving the oxLDL/LOX-1 signaling pathway and LOX-1 modulators. LDL is oxidized within the vascular wall under atherogenic conditions to form oxLDL. The binding of oxLDL to LOX-1 activates the NADPH oxidase on the cell membrane that results in the quick increase of intracellular ROS formation. Increased ROS activates the redox-sensitive NF-κB signaling pathway, generating three responses: (1) increases binding to LOX-1 promoter, therefore, increases LOX-1 expression and amplifies LOX-1-mediated oxLDL uptake; (2) enhances Ang-II type 1 receptor expression; (3) augments downstream pro-inflammatory cytokine and chemokine expression, such as P-selectin, E-selectin, VCAM-1, ICAM-1, and MCP-1, resulting in increased recruitment of monocytes to endothelial cells. LOX-1 modulators are demonstrated to function at each critical step of this feedback loop. oxLDL oxidized LDL, ROS reactive oxygen species, AT 1 R Ang-II type 1 receptor, NF-κB nuclear factor-kappa B
Fig. 3
Fig. 3
LOX-1 signaling mechanistically links atherosclerosis, hypertension, and diabetes. oxLDL binding to LOX-1 affects NO catabolism by two mechanisms: (1) increased ROS production, which not only reacts with intracellular NO, resulting in the formation of cytotoxic peroxynitrite (ONOO−) but also down-regulates eNOS, thereby decreasing NO bioavailability; (2) oxLDL, through LOX-1 receptor activates arginase II, competing with eNOS for use of the substrate l-arginine, thus, down-regulating NO formation, and contributing to vascular dysfunction. Persistently increased ROS can activate multiple signaling pathways within vascular cells, such as PI3K/Akt, MAPK (p38, ERK and JNK), PKA, PKC, PTK, and p66Shc. These pathways further activate the redox-sensitive NF-κB pathway, increase NF-κB binding to LOX-1 promoter, and orchestrate LOX-1 expression in atherosclerosis. Alternatively, SIRT1 de-acetylates NF-κB to suppress the expression of LOX-1. LOX-1 is also the target gene of other transcription factors, such as AP-1, Oct-1, and PPAR-γ. AGEs act as a ligand of LOX-1 and can upregulate LOX-1 expression via PI3K/mTORC2/Akt pathway. In light of the cross-talk between AT1R and LOX-1, and potentially between RAGE and LOX-1, LOX-1 may provide a mechanistic link between atherosclerosis, hypertension, and diabetes. Ang-II angiotensin-II, oxLDL oxidized LDL, AGEs advanced glycation end-products, AT 1 R Ang-II type 1 receptor, RAGE receptor of advanced glycation end-products, NO nitric oxide, eNOS endothelial NO synthase, SIRT1 sirtuin-1, mTORC2 mammalian target of rapamycin complex 2, PI3K phosphatidylinositol 3-kinases, MAPK mitogen-activated protein kinases, ERK extracellular regulated protein kinases, JNK c-Jun N-terminal kinase, PKA protein kinase A, PKC protein kinase C, PTK protein tyrosine kinase, p66Shc 66-kDa isoform of Shc adaptor proteins, NF-κB nuclear factor-kappa B, AP-1 activator protein-1, Oct-1 octamer-binding protein 1, PPAR-γ peroxisome proliferator-activated receptor-gamma
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