current concepts of the role of oxidized ldl receptors in atherosclerosis

CORONARY HEART DISEASE (J FARMER, SECTION EDITOR)

Current Concepts of the Role of Oxidized LDL Receptorsin Atherosclerosis

Tanu Goyal & Sona Mitra & Magomed Khaidakov &

Xianwei Wang & Sandeep Singla & Zufeng Ding &

Shijie Liu & Jawahar L. Mehta

Published online: 29 January 2012# Springer Science+Business Media, LLC 2012

Abstract Atherosclerosis is characterized by accumulationof lipids and inflammatory cells in the arterial wall. Oxi-dized low-density lipoprotein (ox-LDL) plays important rolein the genesis and progression of atheromatous plaque.Various scavenger receptors have been recognized in thepast two decades that mediate uptake of ox-LDL leadingto formation of foam cells. Inhibition of scavenger receptorA and CD36 has been shown to affect progression of ath-erosclerosis by decreasing foam cell formation. Lectin-typeoxidized LDL receptor 1 (LOX-1) participates at varioussteps involved in the pathogenesis of atherosclerosis, and in

experimental studies its blockade has been shown to affectthe progression of atherosclerosis at multiple levels. In thisreview, we summarize the role of ox-LDL and scavengerreceptors in the formation of atheroma with emphasis oneffects of LOX-1 blockade.

Keywords Atherosclerosis . Scavenger receptors . SRA-1 .

CD36 . LOX1

Introduction

Oxidized low-density lipoprotein (ox-LDL) is implicated inthe pathogenesis of atherosclerosis as it causes endothelialdysfunction, which is followed by accumulation of foamcells, inflammation, and proliferation of vascular smoothmuscle cells in the subintimal space. Several scavengerreceptors (SR), such as CD36, SR-A and lectin-type oxi-dized LDL receptor 1 (LOX1), are responsible for uptake ofox-LDL and thus play role in the formation of atheroma.LOX-1 not only internalizes modified lipid, but also hasbeen shown to cause endothelial dysfunction/apoptosis, in-flammation and smooth muscle cell proliferation, and thuscontribute to the process of atheroma formation at multiplelevels.

Atherogenesis

Atherosclerosis is an inflammatory disease. Inflammationplays a crucial role in all stages of atherogenesis, from theformation of fatty streak to its progression, and finally in itsclinical complications. The first step in atherogenesis is theformation of fatty streaks, which are small subendothelialdeposits of lipid-laden macrophages. Various risk factors for

T. Goyal : S. Mitra :M. Khaidakov :X. Wang : S. Singla :Z. Ding : S. Liu : J. L. MehtaUniversity of Arkansas for Medical Sciences and Central ArkansasVeterans Health System,Little Rock, AR, USA

T. Goyale-mail: [email protected]

S. Mitrae-mail: [email protected]

M. Khaidakove-mail: [email protected]

X. Wange-mail: [email protected]

S. Singlae-mail: [email protected]

Z. Dinge-mail: [email protected]

S. Liue-mail: [email protected]

T. Goyal : S. Mitra :M. Khaidakov :X. Wang : S. Singla :Z. Ding : S. Liu : J. L. Mehta (*)Cardiovascular Division, UAMS,Little Rock, AR 72212, USAe-mail: [email protected]

Curr Atheroscler Rep (2012) 14:150–159DOI 10.1007/s11883-012-0228-1

atherosclerosis, such as elevated LDL, hypertension, smok-ing, diabetes, elevated homocysteine, infections, or combi-nations of these factors, alter normal homeostasis ofendothelium, causing endothelial dysfunction and produc-tion of reactive oxygen species (ROS) [1, 2].

Endothelial dysfunction, related to loss of constitutivenitric oxide synthetase (cNOs or eNOS), in response to ox-LDL and other triggers, is a first step in the development offatty streak formation. Endothelial activation results in theexpression of a number of adhesion molecules on endothe-lial cells. Circulating monocytes roll along the activatedendothelial layer and then move in between endothelial cellsto the subendothelial region in response to chemotacticsignals. Macrophage colony-stimulating factor and othergrowth factors stimulate the differentiation of these mono-cytes into macrophages and expression of various scavengerreceptors that internalize modified lipids. This processresults in formation of foam cells; deposition of these cellsin the intima is a hallmark of early atherosclerotic lesion.These foam cells release additional proinflammatory cyto-kines and growth factors, amplifying local inflammatoryresponse. Ox-LDL also triggers CD40/CD40L signalingpathway, which activates inflammatory reactions. Chemo-kines such as interferon (IFN)-! and eotaxin present in theatheroma lead to recruitment of T lymphocytes and mastcells [3].

This nascent atheroma develops into a more complexlesion, leading to various clinical manifestations. Growthfactors released by macrophages stimulate migration andmultiplication of smooth muscle cells and deposition ofextracellular matrix, leading to continuous and gradualgrowth of plaque with time and forming an advanced ath-erosclerotic plaque [1]. As the lesion grows, arterial lumennarrows, decreasing the blood flow with resultant clinicalsyndromes of tissue ischemia. Physical disruption of plaqueleads to a discontinuous and sudden burst in the growth ofplaque, precipitating massive ischemia, such as myocardialinfarction and stroke [4]. This disruption of plaque resultsfrom local inflammatory reaction and release of matrixmetalloproteinases (MMPs), which degrade the subendothe-lial basement membrane leading to loss of endothelium.This disruption of endothelium or erosion of the surfaceleads to platelet-rich thrombus formation. The rupture orerosion-prone plaque is also associated with large numberof small capillaries (ie, angiogenesis). Thrombosis of thesenewly formed fragile microvessels in the plaque can alsolead to sudden plaque expansion. Thrombin present in theplaques stimulates smooth muscle migration, proliferation,and deposition of collagen by release of platelet-derivedgrowth factor (PDGF) and tissue growth factor-" (TGF-")from platelets. IFN-! leads to a decrease in production ofnew collagen by smooth muscles and increased expressionof MMPs, resulting in degradation of collagen and thus

forming a weak and friable fibrous cap. Fissure in thisfibrous cap is the most common mechanism of plaquerupture, which exposes thrombogenic tissue factor in thelipid core to coagulation factors [3], although erosion is alsooften seen in many blood vessels where a clot is formed [5].

Role of Ox-LDL in Atherogenesis

Ox-LDL plays a central proatherogenic role in the arterialwall [2, 6] .Various known risk factors for atherosclerosislead to a state of oxidative stress characterized by excessiveproduction of ROS that is not neutralized by the body’santioxidant defenses [2]. Kita et al. [7] have shown theatheroprotective effects of the antioxidant probucol in Wata-nabe Heritable Hyperlipidemic (WHHL) rabbits, as it limit-ed oxidation of LDL and prevented foam cell formation.This work established the significance of ox-LDL in athero-sclerosis. Now it is well known that the ox-LDL–inducedpro-oxidant state is present in all stages of atherosclerosis,from the beginning to the acute thrombotic events. Ox-LDLinhibits the expression of the constitutive endothelial en-zyme nitric oxide synthetase (cNOS), which inhibits a num-ber of steps in involved in atherogenesis [8]. In addition, itresults in generation of ROS from endothelial cells [8, 9•],vascular smooth muscle cells [10], and macrophages [11•].Release of ROS also induces expression of adhesion mole-cules on endothelial cells [12], proliferation of macrophages[13], stimulates collagen formation in fibroblasts [14], leadsto proliferation [15, 16] and migration [17•] of vascularsmooth muscle cells, and activation of platelets [18]. Ox-LDL is also responsible for the disruption of fibrous cap viarelease of MMPs and formation of platelet clot in narrowedarteries, resulting in clinical syndromes of tissue ischemia[19, 20].

Circulating levels of ox-LDL and anti–ox-LDL antibod-ies are being studied as biomarkers of cardiovascular dis-ease. The plasma levels of ox-LDL were found to bemarkedly elevated in patients with acute myocardial infarc-tion than in patients with stable and unstable angina byEhara et al. [21]. They also reported that the culprit coronarylesions leading to death in patients with acute myocardialinfarction contained abundant macrophage-derived foamscells with distinct immunopositivity for ox-LDL and its recep-tors. Elevated ox-LDL levels were found to be closely related toan angiographically detected complex and thrombotic coronaryartery lesion morphology in unstable angina patients [22]. Inaddition, high ox-LDL and higher anti–ox-LDL antibody titershave been shown to correlate with stable coronary artery dis-ease [23•]. Ox-LDL and immunoglobulin M (IgM) ox-LDLantibodies have been shown to have temporal elevation follow-ing acute coronary syndrome, especially myocardial infarction[24]. These observations suggest that increased levels of ox-

Curr Atheroscler Rep (2012) 14:150–159 151

LDL in the plaque relates to plaque instability. The precisemechanism by which ox-LDL leads to plaque instability andinduces thrombosis of small blood vessels or apoptosis remainsunclear.

Receptors for Ox-LDL

Over the past decade, several receptors for ox-LDL havebeen identified. These receptors are also termed as scaven-ger receptors for their role in scavenging modified forms oflipid. These receptors have been classified into eight classes(Class A through H). They bind to a range of ligands such aspathogenic organisms and modified self proteins, and ox-LDL is one of them [25]. Only class B scavenger receptorsbind to native lipids and play a role in cholesterol homeo-stasis. All scavenger receptors bind to modified LDL exceptSCARA-5 (Class A) and LAMP (Class D). SR-A andMACRO (Class A), CD36 and SR-B (Class B), and SREC -I(Class F) bind to both ox-LDL and acetylated LDL (ac-LDL).SCRL-1 (Class A), CD68 (Class D), LOX-1 (Class E), andSR-PSOX (Class G) recognize only ox-LDL, whereas FEEL-I(Class H) binds to only ac-LDL (Table 1) [25].

Certain scavenger receptors have been studied extensivelyto determine their relationship to foam cell formation andatherogenesis (Table 2, Fig. 1). SR-A type I and II, CD36,and LOX-1 receptors have been implicated in receptor-mediated uptake of modified LDL and thus in the formationof foam cells. CD68 (macrosialin), which is expressed intra-cellularly on late endosomes and lysosomes of macrophages,is responsive to ox LDL but does not function as receptor forox-LDL on cell surface [26]. In vitro studies have shown thatSR-A and CD36 account for 75% to 90% of degradation of

ac-LDL and ox-LDL [27]. SR-A expression is mainly restrict-ed to myeloid cells but can be expressed by smooth musclecells and endothelial cells in the presence of oxidative stressand growth factors. These receptors are widely expressed inatherosclerotic lesions [28]. SR-A deletion has been shown tohave significantly smaller atherosclerotic lesions in apolipo-protein E (apoE)-null mice, and macrophages form SR-AI–and SR-AII–deficient mice show a 60% decrease in uptake ofmodified LDL (ac-LDL>ox-LDL]. SR-A deletion has alsobeen shown to reduce atherosclerosis-like lesions in C57BL/6 mice [30]. But the deletion of SR-A has been shown todecrease lesion size by only 20% in LDL-null mice [31].Peritoneal macrophages isolated from transgenic mice over-expressing human SR-A have increased foam cell formationand degradation of ac-LDL in vitro but do not affect itsclearance in vivo [32].

CD36 is present on monocyte/macrophages, platelets andadipocytes, and some endothelial cells [25]. CD36-mediatedbinding and uptake of modified lipids by macrophages leadsto foam cell formation [33] via activation of JNK1 and 2[34]. Podrez et al. [35, 36] have shown that in contrast toSR-AI and II, which have higher affinity for ac-LDL, CD36can recognize nitrogen dioxide (NO2)-LDL, which has moresignificant role in foam cell formation than ac-LDL. CD36and apoE double-knockout mouse models have shown asignificant reduction in aortic lesion size. Further, macro-phages isolated from these animals were defective in ox-LDL uptake and foam cell formation both in vitro and invivo [37]. Similarly, macrophages isolated from humanslacking CD36 have shown a 40% decrease in binding anduptake of ox LDL [38]. However, the combined absence ofboth SR-A I/II and CD36 has been shown to provide noadditional protection from atherosclerosis than absence of

Table 1 Ox-LDL, Ac-LDL, andnative LDL as ligands forvarious scavenger receptors

Ac-LDL acetylated low-densitylipoprotein; LDL low-densitylipoprotein; ox-LDL oxidizedlow-density lipoprotein

Scavenger receptor Ox-LDL Ac-LDL Native LDL

Class A SR-A I and II + + !

MACRO + + !

SCARA5 ! ! !

SRCL + ! !

Class B CD36 + + +

SR-BI + + +

Class C dSR-CI (No homologous receptor in eukaryotes; binds to Ac-LDLin Drosophila)

Class D CD68 (Expression responsive to ox-LDL but does not act as receptor)

LAMP, I, II, III ! ! !

Class E LOX1 + ! !

Class F SRECI + + !

SRECII (Acts only as sensor, unable to internalize modified LDL)

Class G SP-PSOX + ! !

Class H FEEL-I ! + !

FEEL-II ! + !

152 Curr Atheroscler Rep (2012) 14:150–159

CD36 alone [39]. Further, RNA-mediated silencing of eitherSR-A or CD36 leads to decrease in atherogenesis in mice,but silencing of both CD36 and SR-A is found to be inef-fective, as silencing one receptor reciprocally upregulatesthe other receptor [25, 40•]. Contrary to these reports,Moore et al. [41] have shown increase in size of atheroscle-rotic plaques following deletion of SR-A and CD36 recep-tors. In addition, absence of SR-A in apoE-3 Leiden miceled to development of more severe lesions as compared toapoE-3 Leiden/SR-A wild-type mice [42].

In addition to internalizing modified lipids, these recep-tors mediate macrophage adhesion. CD36 has been shownto mediate adhesion between macrophages and activatedplatelets and collagen-1 [43, 44], and SR-A contributes toadhesion of macrophages to the extracellular matrix [45],which may play a role in the recruitment and retention ofmacrophages at the site of vascular injury. CD36 has alsobeen identified as an antiangiogenic receptor [46], andblocking of angiogenesis has been shown to decrease plaqueprogression in murine models [47].

LOX-1 is the only member of the class E scavengerreceptors and consists of a cytoplasmic, transmembrane,

Table 2 Role of SR-A, CD36, and LOX-1 in atherogenesis

Scavengerreceptor

Role in atherogenesis

SR-A Increases foam cell and atheroma formation [29, 30, 32, 42, 81]

Mediates adhesion of macrophages to extracellular matrix [45]

CD36 Increases foam cell and atheroma formation [33, 38, 82]

Mediates adhesion between macrophages and platelets [43]

Mediates adhesion between macrophages and collagen [44]

Decreases angiogenesis [46]

LOX-1 Induces endothelial apoptosis and adhesion moleculeexpression [55, 67]

Impairs eNOS activity and decreases NO production [70]

Increases foam cell and atheroma formation [70]

Increases in inflammatory infiltrate in atheroma [67, 70]

Leads to SMC proliferation and migration [69]

Increases collagen formation [14, 68]

Platelet aggregation and thrombus formation [18]

Increases MMP expression [66]

eNOS endothelial nitric oxide synthase; LOX-1 lectin-type oxidizedLDL receptor 1;MMP matrix metalloproteinase; NO nitric oxide; SMCsmooth muscle cell; SR-A scavenger receptor A

Fig. 1 Lectin-type oxidized LDL receptor (LOX-1) receptors presenton the endothelium mediate uptake of oxidized low-density lipoprotein(ox-LDL), which further upregulates the expression of LOX-1 recep-tors and adhesion molecules. Circulating monocytes roll along theendothelial cells and move through inter-endothelial space into thesubendothelial space and become transformed into tissue macrophages.

CD36, scavenger receptor A (SRA), and LOX-1 receptors on macro-phages mediate ox-LDL uptake and formation of foam cells. Variousinflammatory cytokines and growth factors released by macrophagescause smooth muscle cell and fibroblast proliferation and eventuallyplaque rupture and platelet-rich thrombus formation


neck, and extracellular domain [48]. LOX-1 also exists in itssoluble form, corresponding to its extracellular domain [49].It was initially identified as a major receptor for ox-LDL inendothelial cells [48] but later was also found to beexpressed on macrophages [50], platelets [51, 52], cardiacmyocytes [53], and vascular smooth muscle cells (Table 3)[52]. It is interesting that ox-LDL can upregulate its ownreceptor at transcriptional level in human endothelial cells ina time- and concentration-dependent fashion [54].

SR-A and CD36 are expressed in minimal amounts onendothelial cells whereas LOX-1 is expressed largely onendothelial cells, which is the first line of cells affectedin the formation of atheroma (Table 3). This has led to avery prominent role of LOX-1 in atherogenesis as theendothelial lining is the first protective barrier againstentry of ox-LDL into the vessel wall. The role of SR-Aand CD36 is controversial in the pathogenesis of athero-sclerosis, as some studies have shown their atherogenicrole whereas others have proven otherwise. The role ofSR-A in atherogenesis has also been shown to vary withgenetic background of mouse models used in variousstudies. On the other hand, the contributory role ofLOX-1 in atherogenesis is supported by several lines ofevidence:

1. LOX-1 plays an important role in foam cell formationby binding, internalizing, and proteolytically degradingox-LDL [48]

2. Ox-LDL via activation of LOX-1 induces endothelialdysfunction and apoptosis [55], a major change in vas-cular biology seen at the beginning of atherogenesis

3. Other mediators of atherosclerosis, such as angiotensin II(Ang II), cytokines, sheer stress, and advanced glycationend-products [AGE], all upregulate LOX-1 [56–58]

4. LOX-1 expression is dynamically upregulated in path-ologic conditions such as diabetes, hypertension, anddyslipidemia [59–61]

5. LOX-1 is present in atheroma-derived cells and is seenin large amounts in human and animal atheroscleroticlesions in vivo [52]

6. Serum levels of soluble LOX-1 (sLOX-1) have beenreported to rise before troponin T in acute coronarysyndrome, reflecting the instability of plaque [62], and

have also been associated with prognosis of acute cor-onary syndrome [63••]

7. In stable coronary artery disease, sLOX1 levels areassociated with markers of oxidative stress as its levelshave been shown to be positively correlated with uri-nary 8-isoprostane and inversely with heparin-releasedextracellular superoxide dismutase (EC-SOD) [64••].

LOX-1 Blockade in Atherogenesis

Our laboratory has conducted a number of in vitro and invivo studies relating ox-LDL and LOX-1 to atherosclerosis.Results of these studies are summarized here.

Surrogates of Atherosclerosis

In early studies we showed that ox-LDL in a concentrationof 10 to 40 #g/mL had several effects on endothelial cells,including apoptosis, expression of adhesion molecules andeNOS, and release of collagens and MMPs [65–67]. Allthese effects of ox-LDL could be blocked by an antibodyor antisense to LOX-1. Subsequent studies showed that ox-LDL via LOX-1 activated platelets, monocytes/macro-phages, SMC proliferation and migration, and generationof collagen from fibroblasts [68, 69•, 70]. In other studies,LOX-1 inhibition was shown to inhibit ADP- and thrombin-induced platelet aggregation [18].

Decrease in Extent of Atherosclerosis

The definitive evidence of the role of LOX-1 in atherogen-esis came from recent studies in LOX-1–deletion experi-ments wherein an LDL receptor (LDLR) knockout mousemodel of high-cholesterol-diet atherosclerosis was used[70]. There was extensive intimal thickening in the LDLRknockout mice with large areas of proliferation, which inseveral sections appeared to totally occlude the vascularlumen. In contrast, the intimal thickening was much less inthe double knockout mice with relatively few occlusivelesions. Recently, liposome-conjugated anti–LOX-1 anti-bodies targeting rho-kinase have been shown to reach carot-id artery atherosclerotic lesions and significantly inhibit

Table 3 Expression of SR-A, CD36, and LOX-1 on different cell types

Macrophages Monocytes Endothelial cells Platelets SMCs Cardiomyocytes Adipocytes

SR-A ++ ! + + + ! !

CD36 ++ ++ + ++ + + ++

LOX-1 + + ++ + + +++ +

LOX-1 lectin-type oxidized LDL receptor 1; SR-A scavenger receptor A


intimal hypertrophy in rats [71••]. Other studies fromSawamura et al. [72] showed that over-expression ofLOX-1 in apoE-null mice resulted in events associated withincreases in atherosclerosis. Recent studies from this grouphave provided further provocative evidence in favor of aprominent role for LOX-1 in LDLR-null mice [73]. Theseauthors showed that overexpression of LOX-1 in liver wasassociated with uptake of ox-LDL by the liver and decreasein atherosclerotic plaques in the aortas of LDLR-null mice.

Decrease in Inflammatory Cell Accumulation

As mentioned earlier, monocyte adhesion and diapede-ses are key steps in the formation of atheroscleroticplaque. Ox-LDL and LOX-1 have been shown to playa significant role in monocyte adhesion, as antisense tohuman LOX-1 mRNA suppresses monocyte chemoat-tractant protein-1 (MCP-1) and monocyte adhesion tohuman coronary artery endothelial cells [67]. Further,LOX-1 deletion in LDLR-null mice resulted in fewareas of macrophage accumulation and marked decreasein CD68 expression, which is a marker of macrophageinfiltration when compared with LDLR knockout mice[70]. This was accompanied by decrease in basalexpression of transcription factor NF-$" and increasein anti-inflammatory cytokine interleukin-10 (IL-10)expression. Other work in these mice showed that in-flammatory cell accumulation occurs predominantly inthe early phases (4–8 weeks) of atherogenesis, peakingat about 12 to 16 weeks of feeding a high-cholesteroldiet, and the accumulation of inflammatory cells thendeclines significantly. In the later phase of atherogene-sis, accumulation of collagen becomes a dominantfeature [74].

Preservation of Nitric Oxide-Mediated Dilation

Nitric oxide (NO) is a very important endothelium-derivedvaso-relaxing factor. It is produced constitutively by theaction of endothelial nitric oxide synthetase (eNOS) on L-arginine in endothelial cells. It plays a role in the preventionof atherosclerosis by decreasing endothelial activation,platelet aggregation, vascular smooth muscle cell prolifera-tion, and leukocyte adhesion. Oxidative inactivation of NOby ROS is an important cause of its decrease in biologicalactivity [75]. Chemical reaction with superoxide radicalsleads to formation of cytotoxic peroxynitrite, which hasbeen recently found in human atherosclerotic lesions [76].Uncoupling of eNOS also generates ROS rather than NO,which in turn can oxidize native unmodified LDL to ox-LDL [77•]. Chemical inactivation and loss of eNOS activityin response to ox-LDL have been suggested to be mediatedvia LOX-1.

Incubation of bovine aortic endothelial cells with ox-LDL was shown to result in an increase in superoxidewith a parallel decrease in NO production, which wasprevented by preincubating bovine aortic endothelialcells with various antioxidants and anti-LOX monoclo-nal antibodies [8]. In another experiment, arterial seg-ments from LOX-1–null mice maintained NO-dependentvasorelaxation despite treatment with ox-LDL. Further,pretreatment of aortic rings of wild-type mice with anti–LOX-1 antibodies resulted in vaso-relaxation similar tothat with LOX-1 ablation, and thus protected them fromthe adverse effects of ox-LDL [70].

Decrease in Smooth Muscle Proliferation

Another important characteristic feature of atheroma forma-tion is proliferation and migration of vascular smooth mus-cle cells. Ox-LDL–induced LOX-1 expression has beenshown to stimulate vascular smooth muscle cell growthand proliferation via NF-$" and JNK signaling pathwaysin cultured rat vascular smooth muscle cells [69, 78]. Eto etal. [78] demonstrated increased LOX-1 expression and ox-LDL in smooth muscle cells in media and neointima inhuman coronary artery restenosis after balloon angioplastyin a time-dependent manner. They have also shown that theeffect of LOX-1 on SMCs is suppressed by antisense directedat LOX-1 in cultured rabbit smooth muscle cells. High dosesof ox-LDL cause apoptosis of vascular smooth muscle cells,leading to plaque instability and rupture [10]. This is mediatedlargely by LOX-1, as this phenomenon can be prevented byanti–LOX-1 monoclonal antibodies [10, 78, 79].

Decrease in Collagen

LOX-1 plays an important role in Ang II-stimulated andtransforming growth factor- "1 (TGF-"1)-stimulated fibro-blast growth and collagen synthesis. In LDLR-null mice,deletion of LOX-1 resulted in a marked reduction in colla-gen accumulation in atherosclerotic plaque [68]. Similarly,use of specific anti-LOX1 antibodies led to decrease incollagen formation in mouse fibroblasts [14]. This decreasein collagen in association with a reduction in atherosclerosishas raised the issue of plaque instability as collagen deposi-tion declines. Fortunately, other commonly used agents suchas statins, aspirin, and peroxisome proliferator activatedreceptor ! (PPAR!) ligands also reduce collagen formationin atheromatous plaques in animals and humans withoutaffecting plaque stability.

Increase in Apoptosis

Apoptosis, also known as programmed cell death, is fre-quently observed in atherosclerotic plaque perhaps via


activation of cells by ox-LDL, Ang II, and other mediatorsinvolved in atherogenesis. Ox-LDL can induce apoptosis ina variety of cell types, including endothelial cells, smoothmuscle cells, cardiac myocytes, and macrophages [10, 53,55, 79, 80]. Ox-LDL–induced apoptosis involves downre-gulation of antiapoptotic proteins c-IAP-1and Bcl-2, releaseof cytochrome c and Smac, activation of proapoptotic sig-nals caspase-9 and caspase-3, and finally induction of apo-ptosis itself [65]. Apoptosis is a frequent feature of earlyatherosclerotic lesions as well as vulnerable plaques. Wehave observed increases in apoptosis by strategies that re-duce the overall extent of atherosclerosis. Although theprecise significance of apoptosis in atherosclerotic plaqueis not clear, it is likely that apoptosis represents a naturallyoccurring program that is designed to remove unhealthy anddying cells, which may be smooth muscle cells or macro-phages or foam cells that are swollen with the presence ofox-LDL. We have also observed that repeated exposure ofendothelial cells to ox-LDL attenuates their subsequentproapoptotic response to ox-LDL. This is most likely sec-ondary to altered methylation of pro- and antiapoptoticgenes in the promoter region, and treatment of these cellswith anti-LOX antibody prevented this alteration in geneexpression and methylation and hence altered the apoptoticresponse. The presence of large number of apoptotic cells inthe early stages of atherosclerosis may represent a strugglebetween growing and dying cells, whereas a decrease in thenumber of apoptotic cells in later stages may suggest astable process. Thus, strategies that lead to a reduction inatherosclerosis are associated with active programmed celldeath (apoptosis being one of them). Further work needs tobe done regarding the importance of the apoptotic process indetermination of extent of atherosclerotic process and itsvulnerability to rupture.

Conclusions

Ox-LDL plays a key role in the pathogenesis of atheroscle-rosis. LOX-1 mediates many of the effects of ox-LDL, suchas endothelial dysfunction, apoptosis, activation and adhe-sion of monocytes, and increase in smooth muscle cellproliferation and migration, all of which are critical featuresof atherosclerosis. Blockade of LOX-1 receptors decreasesatherosclerotic plaque size by decreasing inflammatorysmooth muscle cell proliferation and collagen as well asrestoring endothelial function. Thus, targeting LOX-1 canbe a potential alternative therapeutic or preventive strategy.

Disclosure No conflicts of interest relevant to this article werereported.

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current concepts of the role of oxidized ldl receptors in atherosclerosis

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