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J Am Coll Cardiol, 2002; 39:1429-1435 © 2002 by the American College of Cardiology Foundation |
* Division of Cardiovascular Medicine, Department of Internal Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA
Manuscript received September 10, 2001; revised manuscript received February 7, 2002, accepted February 14, 2002.
* Reprint requests and correspondence: Dr. Jawahar L. Mehta, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 532, Little Rock, Arkansas 72205, USA.
mehtajl{at}uams.edu
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Abstract |
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 Top Abstract Activators of LOX-1LOX-1 and endothelial cell...Role of LOX-1 in...ConclusionsReferences |
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Oxidized LDL leads to endothelial activation, dysfunction and injury. Endothelial activation is believed to be a very early step in the evolution of atherosclerosis. Activation of endothelial cells results in expression of a variety of genes, such as endothelin, tissue factor, cyclo-oxygenase, nitric oxide synthase (NOS), growth factors and monocyte chemoattractant protein-1 (MCP-1). It also leads to expression of adhesion molecules to which inflammatory cells attach, followed by a cascade of events, including cell rolling, separation of the intercellular junction and subendothelial migration of inflammatory cells (7–12). Oxidized LDL also induces apoptosis in endothelial cells (13).
How endothelial cells endocytose ox-LDL is a subject of intense investigation. In 1997, Sawamura et al. (14) identified a lectin-like receptor for ox-LDL (LOX-1) in bovine aortic endothelial cells. Since then, a number of groups have confirmed the presence of this specialized receptor and have defined its regulation. A definition and understanding of the regulation of this receptor allows the opportunity to intervene at endothelial phase in disease states in which ox-LDL plays a central role.
Lectin-like ox-LDL receptor is a type II membrane protein (
50 kDa) with a C-type lectin-like extracellular domain and a short cytoplasmic tail. Lectin-like ox-LDL receptor is present in the endothelium of human coronary arteries, rabbit and rat aortae and bovine endothelial cells (14–18). A small amount of LOX-1 has also been identified in macrophages, platelets and smooth muscle cells (19–21).
In human coronary artery endothelial cells (HCAECs), there is a single class of LOX-1 receptors with a Bmax of 30 ng/mg protein and KD of 1.7 x 10–8 mol/l, as determined by radioligand-binding studies (16,17). An excess of unlabeled ox-LDL inhibits iodine-125 labeled ox-LDL binding to LOX-1, and native LDL has no effect.
Activation of LOX-1 can be blocked in a nonspecific manner by polyinosinic acid and carrageenan, but not by the SR blocker fucoidin (16). Recently, a specific antisense phosphorothioate oligodeoxynucleotide directed at the 5"-coding sequence of human LOX-1 messenger ribonucleic acid (mRNA) has been designed (22,23). This antisense blocks the expression of LOX-1 in response to ox-LDL. Antibodies to the ox-LDL receptor have also been developed (15).
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Activators of LOX-1 |
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TopAbstractActivators of LOX-1LOX-1 and endothelial cell...Role of LOX-1 in...ConclusionsReferences |
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A recent study by Chen et al. (24) showed that the lectin-like domain of LOX-1 is essential for ligand binding, but the neck domain is not. In particular, the large loop between the third and fourth cysteine of the lectin-like domain plays a crucial role for ox-LDL binding, as well as C-terminal end-residues. Alanine-directed mutagenesis of the basic amino acid residues around this region revealed that all of the basic residues are involved in ox-LDL binding. Simultaneous mutations of these basic residues almost abolished the ox-LDL-binding activity of LOX-1. An electrostatic interaction between basic residues in the lectin-like domain of LOX-1 and negatively charged ox-LDL is critical for the binding activity of LOX-1.
Moriwaki et al. (25) reported that LOX-1 binds and degrades ox-LDL, but not acetylated LDL. Fucoidin and maleylated bovine serum albumin, which inhibit ox-LDL binding to class A SRs, do not inhibit ox-LDL binding or degradation in LOX-1–expressing cells (LOX-1-CHO). Polyinosinic acid and carrageenan, in contrast, significantly reduce ox-LDL binding to LOX-1-CHO. Oxidized LDL and delipidated and untreated LDL bind and are degraded similarly in LOX-1-CHO. Taken together, these observations show that LOX-1 is a receptor for ox-LDL, but not for acetylated LDL. LOX-1 recognizes protein moiety of ox-LDL, and its ligand specificity is distinct from that of other receptors for ox-LDL, including class A and B scavenger receptors (25). It is not known whether oxidized phospholipids and minimally oxidized LDL bind to LOX-1.
Oxidized LDL and lysophosphotidylcholine. Mehta and Li (16) and later on Aoyama et al. (26) described upregulation of LOX-1 mRNA in cultured endothelial cells by ox-LDL in a time-dependent fashion, with peak at 12 to 24 h of incubation in vitro. This effect of ox-LDL was concentration-dependent (10 to 40 µg/ml), with a decline at higher concentrations, probably a reflection of cell death at higher concentrations (80 to 100 µg/ml) (13). In contrast to ox-LDL, incubation of cells with native-LDL had no effect on the expression of LOX-1. The induction of LOX-1 protein is associated with an increase in mRNA, suggesting transcriptional upregulation of LOX-1 by ox-LDL. The upregulation of LOX-1 in response to ox-LDL can be blocked by a specific antisense to LOX-1 mRNA (22,23).
Lysophosphotidylcholine, which has been implicated in atherogenesis, also induces mRNA and protein expression of LOX-1 (26). Because lysophosphotidylcholine does not change the half-life of LOX-1 mRNA, the upregulation of LOX-1 appears to occur at transcriptional levels.
Tumor necrosis factor-alpha (TNF-alpha). The cytokine TNF-alpha is a pro-inflammatory cytokine. Its expression is increased in atherosclerosis, and excess production of TNF-alpha influences plaque vulnerability (27–29). Kume et al. (30) showed that TNF-alpha increases LOX-1 cell-surface expression in a concentration-dependent manner, with a peak time to expression of 8 to 12 h. Tumor necrosis factor-alpha appeared to activate the transcription of LOX-1, as measured by nuclear run-off assay. Another cytokine, interferon-gamma, however, does not increase the expression of LOX-1. It is noteworthy that TNF-alpha can induce the expression of class A SRs in cultured vascular smooth muscle cells (31,32), but it suppresses the expression of class A SRs in macrophages (33).
Fluid shear stress. Shear stress modulates the expression of various genes in endothelial cells and is an important determinant of endothelial cell function. Shear stress in the physiologic range (1 to 15 dynes/cm2) was shown by Murase et al. (34) to upregulate LOX-1 mRNA and protein in a time-dependent fashion, with a peak at 4 and 8 h, respectively. Chelation of intracellular Ca++ reduced shear stress-induced LOX-1 mRNA expression, and the Ca++ ionophore ionomycine enhanced LOX-1 mRNA expression.
Upregulation of LOX-1 expression in response to fluid shear stress may be important in endothelial cell injury and activation.
Angiotensin II. Activation of the renin-angiotensin system (RAS), resulting in the formation of angiotensin II, is a critical factor in atherogenesis. Inhibition of RAS by the angiotensin-converting enzyme has been shown to be effective in limiting atherosclerosis (35) and decreasing cardiac events associated with atherosclerosis (36). Most of the effects of angiotensin II are thought to be mediated by activation of the angiotensin II type 1 (AT1) receptor. Angiotensin II, like ox-LDL, causes endothelial apoptosis, decreases NOS expression, stimulates reactive oxygen species (ROS) formation and induces expression of adhesion molecules in endothelial cells (37–40).
Angiotensin II markedly increases LOX-1 mRNA and protein expression (17). The increase in LOX-1 expression occurs in a concentration-dependent manner. Angiotensin II causes an increase in ox-LDL uptake by endothelial cells, again in a concentration-dependent manner. Angiotensin II causes endothelial cell injury and potentiates ox-LDL–mediated cell injury. Most importantly, these effects of angiotensin II can be blocked by specific AT1 receptor blockers, but not by AT2 receptor blockers. Other studies suggest that ox-LDL upregulates angiotensin II AT1 receptor expression (41). Several studies show that hypercholesterolemia is associated with enhanced AT1 receptor expression (42,43).
These observations collectively imply the presence of the phenomenon of cross-talk between ox-LDL and RAS in atherosclerosis. Each of these mediators recruits the other, and together, the two systems cause extensive cell activation, dysfunction and injury.
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LOX-1 and endothelial cell injury |
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TopAbstractActivators of LOX-1LOX-1 and endothelial cell...Role of LOX-1 in...ConclusionsReferences |
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It is important to note that apoptosis is a common occurrence in atherosclerosis (44) and in a number of other atherosclerosis-related disease processes, such as myocardial ischemia (45).
A recent study (46) from our group demonstrated that ox-LDL decreases the expression of endothelial constitutive NOS (eNOS) and increases the expression of the following adhesion molecules in HCAECs: E- and P-selectins, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1. Importantly, we found that LOX-1 plays a crucial role in this setting, because inhibition of LOX-1 by LOX-1 antisense reduces the effect of ox-LDL on the expression of eNOS and adhesion molecules. These observations, taken together, indicate that LOX-1 plays a major role in endothelial dysfunction and injury, leading to the initiation and progression of atherosclerosis.
Oxidized LDL has also been well known to play a key role in the adherence of monocytes to the activated endothelium, an early step in atherogenesis (7). The intracellular processes involved include activation of protein kinase C and mitogen-activated protein kinase (MAPK) (47), as well as the subsequent upregulation of MCP-1 (47–49). In studies of HCAECs (23), we found that incubation of endothelial cells with ox-LDL increased the phosphorylation of MAPK. In these experiments, ox-LDL also upregulated MCP-1 expression (protein and mRNA) and monocyte adhesion to the endothelial cells through activation of LOX-1. The definitive evidence for the hypothesis that LOX-1 induces upregulation of MCP-1, with subsequent adhesion of monocytes to endothelial cells, through LOX-1 activation with activation of MAPK as a key signal transduction mechanism, came from experiments in which the antisense to LOX-1 mRNA completely blocked these processes in endothelial cells treated with ox-LDL.
LOX-1 and signaling pathways.
The signaling pathways for ox-LDL–mediated endothelial injury include the intracellularly generated ROS and activation of protein kinases and transcription factors (50–54). Cominacini et al. (49) showed that it is the binding of ox-LDL to LOX-1 that initiates nuclear factor-
B activation, as well as the increase in intracellular ROS formation. These effects of ox-LDL were blocked by a monoclonal antibody to LOX-1. Direct evidence for ox-LDL–mediated intracellular ROS formation in endothelial cells through activation of LOX-1 has recently been presented (50).
As mentioned earlier, treatment of HCAECs with ox-LDL resulted in the activation of MAPK and transcriptional nuclear factor-B, and subsequently expression of several genes (22). Further experiments showed that the antisense to LOX-1 mRNA inhibited these signal transduction pathways elicited by ox-LDL (22).
A recent study (55) showed that LOX-1 expression is associated with inactivation of the protein kinase B pathway. Protein kinase B, the cellular homologue of v-Akt, is a key signaling component downstream of phosphatidylinositide-3 kinase (56). Activation of protein kinase B appears to be vitally important in the expression of eNOS.
Upregulation of LOX-1, the signal conduction pathways in its biologic effects and the role of LOX-1 in steps leading to cell injury and ultimately atherosclerosis are summarized in Figure 1.
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Role of LOX-1 in disease states |
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TopAbstractActivators of LOX-1LOX-1 and endothelial cell...Role of LOX-1 in...ConclusionsReferences |
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Hypertension. In studies by Nagase et al. (61), spontaneously hypertensive rats, Wistar-Kyoto rats and Dahl salt-sensitive and salt-resistant rats were fed a salt-loaded or control diet. Lectin-like ox-LDL receptor mRNA, as determined by Northern blot analysis, was found to be minimal in the aorta and veins of Wistar-Koyoto rats, but was markedly upregulated in spontaneously hypertensive rats. Expression of LOX-1 was lower in the aorta of Dahl salt-resistant rats on both diets, but was higher in salt-loaded Dahl salt-sensitive rats. These investigators also suggested that LOX-1 expression in hypertensive rats might be dynamically regulated. This concept is further supported by the observations that angiotensin II upregulates LOX-1 gene expression in endothelial cells (17), and angiotensin-converting enzyme inhibitors markedly decrease LOX-1 gene expression (62). These findings suggest that LOX-1 expression is upregulated in hypertension and may contribute to its pathogenesis. It may be speculated that enhanced LOX-1 expression is the cause of increased ox-LDL uptake in endothelial cells, as well as diminished endothelium-dependent vasorelaxation in hypertension (63).
Atherosclerosis. Chen et al. (15) showed LOX-1 expression (protein and mRNA) to be upregulated in the aortae of eight-week-old Watanabe-heritable hyperlipidemic rabbits. Immunostaining showed that the augmented expression was primarily localized within the intima at the early stages of atherosclerosis. The most prominent staining effect was observed in the endothelial cells of atherosclerotic lesions; however, the endothelium of the areas without lesions in the rabbits’ aortae also demonstrated LOX-1 accumulation, suggesting that LOX-1 may be involved in the initiation of atherosclerosis.
We studied New Zealand White rabbits on a 10-week, high-cholesterol diet and observed upregulation of LOX-1 gene expression in the aortae of hypercholesterolemic rabbits, but not in the aortae of rabbits on a regular diet (64). Immunostaining showed that LOX-1 was present primarily in the neointima. Importantly, treatment of rabbits with the AT1 receptor blocker, losartan, not only decreased the extent of atherosclerosis, but also reduced LOX-1 expression (by reverse-transcription polymerase chain reaction and immunostaining). The vascular tissues in this model of atherosclerosis have previously been shown to over-express AT1 receptors (43). These observations collectively provide in vivo evidence for cross-talk between LOX-1 accumulation and AT1 receptor upregulation.
Kataoka et al. (65) examined human carotid artery endarterectomy specimens and showed positivity for LOX-1 expression in early atherosclerotic lesions, and the positivity was greater in recent compared with advanced lesions. They found that besides endothelial cells, macrophages and smooth muscle cells in the intima of advanced atherosclerotic plaques demonstrated LOX-1 positivity. In our laboratory, we have identified LOX-1 expression in the intima of the microvasculature of advanced human atherosclerotic lesions. Furthermore, we observed co-localization of LOX-1 in apoptotic cells on double immunostaining. The cells expressing apoptosis and LOX-1 were endothelial cells, smooth muscle cells and macrophages. Notably, Oka et al. (66) have shown that LOX-1 mediates phagocytosis of aged and apoptotic cells. These observations in atherosclerotic tissues collectively confirm the results of in vitro studies (13), and suggest that LOX-1 expression in the early stages of atherosclerosis may serve to facilitate the uptake of ox-LDL and activate endothelial cells to which inflammatory cells adhere. As the process of atherogenesis progresses, LOX-1 is expressed in the smooth muscle cells and monocytes and macrophages, where, in conjunction with expression of classic scavenger receptors, LOX-1 may serve to induce apoptosis and phagocytosis.
Thrombosis. Thrombosis is usually the early event that leads to acute manifestations of atherosclerosis, and platelets are the usual initiator cells in this process (67). Platelets have been shown to internalize ox-LDL, which serves to decrease type 3 NOS (eNOS) activity in platelets and enhance platelet aggregation (58). Recently, platelets have also been shown to express a modest amount of LOX-1 (19). Kakatani et al. (68), in preliminary studies, have shown that LOX-1 antibody decreases arterial thrombus formation in the rat. This observation provides a link between internalization of ox-LDL and platelet activation and thrombosis.
Myocardial ischemia. Thrombosis formed in the coronary arteries is often the most proximal cause of acute coronary syndromes (67). Oxidized LDL is present in the atherosclerotic tissues of rupture-prone segments (60). Furthermore, the degree of myocardial ischemia is characterized by the oxidative state, which facilitates oxidation of native LDL (60). An in vitro study showed that perfusion of ox-LDL significantly decreases myocardial contraction in the isolated heart of the rat in the Langendorff model (69). We recently examined LOX-1 expression in the myocardium of rats undergoing total coronary occlusion for 1 h, followed by reperfusion for 2 h. In these rat hearts, we observed extensive LOX-1 expression in the ischemic-reperfused myocardium, but not in the hearts of rats subjected to a sham operation. Ischemia alone did not cause a marked upregulation of LOX-1 expression. To examine the contributory role of LOX-1 in the determination of infarct size and cardiac function, a group of rats was treated with LOX-1 antibody before initiation of ischemia. We observed a marked decrease in the expression of LOX-1 in the myocardium of rats given the antibody. Further, there was 48% reduction in infarct size, as well as preservation of left ventricular function after ischemia-reperfusion in rats given the LOX-1 antibody.
These studies imply LOX-1’s important role during myocardial ischemia, in terms of determination of cardiac function and infarct size.
Diabetes mellitus. Diabetes is characterized by a state of oxidative stress, endothelial dysfunction and upregulated expression of adhesion molecules in inflammatory cells. In a rat model of diabetes in response to streptozocin, LOX-1 expression was found to be increased in the aorta of the diabetic rat, compared with that of the nondiabetic rat (70). Immunohistochemistry revealed that the most distinctive staining effect of LOX-1 was in the endothelial cells, especially in the region of bifurcation of the aorta. Furthermore, in cultured aortic endothelial cells, diabetic rat serum and advanced glycosylation end-products induced LOX-1 expression, whereas control rat serum, along with high glucose levels, did not. In addition, with a competitive inhibition assay, LOX-1 ligand activity was accumulated in the diabetic rat serum, mainly in the very-low-density lipoprotein/LDL fractions.
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Conclusions |
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TopAbstractActivators of LOX-1LOX-1 and endothelial cell...Role of LOX-1 in...ConclusionsReferences |
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A definition of the underlying signals leading to inflammatory cell deposits and activation provides an opportunity to understand the disease process and to design novel therapies in the management of atherosclerosis.
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is transcriptionally and post-transcriptionally regulated. J Biol Chem. 1996;271:7767–7773B. Circulation. 2000;102:1970–1976B through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000;275:12633–12638This article has been cited by other articles:
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