LOX-1 and atherosclerosis: proof of concept in LOX-1-knockout mice.

An increased plasma level of low-density lipoprotein (LDL) is a well-known risk factor for endothelial dysfunction and atherosclerosis.1 The proatherosclerotic potential of LDL may even increase after oxidative modification to oxidized LDL (oxLDL),2 whose uptake by macrophage scavenger receptors is thought to be a key process in the formation of foam cells, the hallmark of atherosclerotic lesions. However, there is less clarity on oxLDL uptake regulation in endothelial cells and its role in early stages of atherosclerosis. A decade ago, Tatsuya Sawamura and colleagues discovered the lectin-like oxLDL receptor LOX-1 in endothelial cells.3 LOX-1 is a 50-kDa type II membrane glycoprotein and contains a short N-terminal cytoplasmic domain, a single transmembrane domain, a NECK domain or stalk, and an oxLDL-binding C-terminal extracellular C-type lectin-like domain. LOX-1 assembles on the cell surface in hexamer form or larger, comprising 3 homodimeric LOX-1 molecules bound to oxLDL.4 Although LOX-1 is expressed at very low levels in healthy endothelium, several lines of evidence support a role of LOX-1 in the pathogenesis of atherosclerosis.5 LOX-1 may be upregulated by its own ligand oxLDL or by proinflammatory cytokines in endothelial cells.6 Because proatherosclerotic angiotensin II7,8 and endothelin-19 vasoconstrictors increase endothelial LOX-1 expression and oxLDL uptake, LOX-1 has been suggested as a link between hypertension and atherogenesis.10 In line with these findings, a high-cholesterol diet induced intimal thickening and a marked increase in LOX-1 expression in the endothelium and neointima of rabbits, which was successfully reduced by an angiotensin II receptor type 1 antagonist.11,12 Further support for a proatherosclerotic role of LOX-1 arises from increased atheroma-like lesion areas in mice overexpressing LOX-1 in an apolipoprotein E–null background as compared with non–transgenic littermates after a high-fat diet.13 Nevertheless, there is still no proof of concept for a proatherosclerotic role of LOX-1 by a transgenic deletion model. In this issue of Circulation Research, Mehta, Sawamura, and colleagues report on the first LOX-1 knockout mice model showing reduced formation of atherosclerotic lesions in a proatherogenic genetic background under a high-cholesterol diet.14 LOX-1–knockout mice are homozygous-viable, possessing a preserved endothelial function after oxLDL treatment. After crossing LOX-1–knockout mice with LDL receptor (LDLR)–knockout mice and feeding the latter a high-cholesterol diet for 18 weeks, atherosclerotic lesion formation was significantly reduced in the aorta of double knockout mice compared with the LDLR-knockout mice. Furthermore, luminal obstruction and intima thickness were reduced in the double knockout mice. Proatherosclerotic and prooxidative signaling and inflammatory response, measured as vascular NFB and CD68 expression and p38 MAPK phosphorylation, was increased in LDLR–knockout mice, but not in double knockout animals. In contrast, antioxidative superoxide dismutase activity and antiinflammatory cytokine IL-10 were expressed at lower levels in LDLR-knockout mice compared with double knockout mice, whereas endothelial nitric oxide synthase expression (eNOS) was also preserved in the double knockout mice. These data suggest a LOX-1–dependent balance of proand antiatherosclerotic processes in the vessel wall (Figure), whereby deletion or low expression of LOX-1 is associated with low levels of atherosclerosis, low intimal thickness, NFB, CD68 expression, and p38 MAPK activation. Whereas endothelial function, eNOS, IL-10, and SOD activity is preserved in double knockout animals, a high-fat diet with high LOX-1 expression or with LOX-1 overexpression is associated with a proatherosclerotic, prooxidative, and proinflammatory gene expression pattern together with accelerated atherosclerosis. Therefore, this study provides the proof of concept of a proatherosclerotic role of LOX-1. In this context, it has to be considered that the human situation differs from the murine atherosclerosis model regarding lipoprotein metabolism and atherosclerotic lesion structure, although additional studies will be necessary to provide additional support for these findings. Indeed, genetic LOX-1 deletion led to detectable uptake of oxLDL in the vessel wall and atherosclerotic lesion formation in the current study, but apart from LOX-1, additional endothelial oxLDL receptors such as SR-AI/II, CD36, SR-BI, macrosialin/CD68, and SREC have also been discussed,15 and may be responsible for the oxLDL uptake observed in double knockout animals. Although endothelial LOX-1 is considered to play a major role in the initial phase of atherosclerosis, LOX-1 expression is not completely restricted to endothelial cells. LOX-1 can also be found on a lower but inducible level in vascular The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Germany. Correspondence to Henning Morawietz, PhD, Department of Vascular Endothelium and Microcirculation, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Fetscherstr. 74, D-01307 Dresden, Germany. E-mail [email protected] (Circ Res. 2007;100:1534-1536.) © 2007 American Heart Association, Inc.