high levels of low density lipoprotein ( ldl ) represent a major risk factor for atherosclerosis , since the oxidation of ldl is a key process in the initiation and progression of atherosclerotic lesion development . oxidized ldl ( oxldl ) acts through the interaction with several scavenger receptors , expressed differentially on the surface of the cells of the arterial wall and inflammatory circulating cells involved in the atherosclerotic process . among these receptors , lectin - like oxidized low - density lipoprotein receptor-1 ( lox-1 ) has been identified as the main endothelial receptor for oxldl ; however , also macrophages and smooth muscle cells ( smcs ) express lox-1 . several proinflammatory stimuli , including tumor necrosis factor  ( tnf ) , c - reactive protein ( crp ) , interleukin-1 ( il-1 ) , angiotensin ii , and endothelin-1 , and proatherogenic conditions ( dyslipidemia , diabetes , hypertension ) increase lox-1 expression . through the interaction with lox-1 , oxldl activates endothelial cells and induces endothelial dysfunction , smc proliferation , and apoptosis ; participates in the transformation of macrophages into foam cells , and induces platelet activation . lox-1 is undetectable in healthy vessels but overexpressed in atherosclerotic lesions , where it actively participates in the initiation and progression of the disease , as demonstrated by lox-1 deletion or overexpression studies in animal models [ 4 , 5 ] . lox-1 is a type ii membrane protein belonging to the c - type lectin family . it contains 4 domains : a short n - terminal cytoplasmic domain , a transmembrane domain , a neck domain , and a lectin - like extracellular c - terminal domain which interacts with oxldl . the extracellular domain can be proteolytically cleaved and released as a soluble form ( slox-1 ) . the tumor necrosis factor- converting enzyme ( tace / adam17 ) appears to be involved in the cleavage and release of growth factors , adhesion molecules and receptors   and is believed to participate also in the slox-1 release   ( figure 1 ) . in addition , the inflammatory factor il-18 stimulates slox-1 cleavage from cell membrane , and adam10 ( a disintegrin and metalloproteinase domain - containing protein 10 ) appears to be one of the proteases involved in this process   ( figure 1 ) . as elevated plasma levels of soluble receptors may reflect the increased expression of membrane - bound receptors and disease activities , circulating slox-1 has been suggested as a potential cardiovascular disease biomarker . acute coronary syndrome ( acs ) , which derives from the rupture of atheromatous plaques followed by thrombus formation , is one of the major causes of death and morbidity in developed countries . atherosclerotic plaques with abundant lipid - rich macrophages and activated smcs appear to be more prone to rupture ; within these plaques , lox-1 is highly expressed mainly by smcs and macrophages , and participates in the induction of smc apoptosis and the production of metalloproteases from endothelial cells , suggesting the involvement of lox-1 in lesion destabilization . several studies have compared slox-1 levels with other biomarkers in patients with acs , and it appears that slox-1 may be a useful marker for early diagnosis of acs . in fact , when evaluated in subjects undergoing coronary angiography ( cag ) , serum slox-1 levels were significantly higher in acs patients compared to subjects without acs ( median , 2.91  ng / ml versus < 0.5  ng / ml ) . high - sensitivity crp ( hs - crp ) , an inflammation marker associated with acs , was higher in acs group and in non - acs subjects with acute noncardiac illness but not in non - acs subjects with intact coronary , controlled chd , or ischemic chd ( table 1 ) . these observations suggest the possibility that , although lox-1 expression is higher in atherosclerotic - related diseases and is increased by proinflammatory stimuli , slox-1 levels do not reflect only the presence of an atherosclerotic disease or an inflammatory status but rather the instability of an atherosclerotic plaque , thus discriminating acs from other cag groups . in agreement , both slox-1 and hs - crp were associated with acs ( odds ratios 1.51 , p < 0.001 and 1.40 , p < 0.05 , resp . ) , but no significant correlation was found between slox-1 and hs - crp in patients with acs . interestingly , peak levels of slox-1 were observed on admission of or after percutaneous coronary intervention ( pci ) , while troponin t , a marker of cardiac injury , peaked around day 1 ; again , no correlation was found between slox-1 and troponin t , reinforcing the hypothesis that slox-1 is not a marker of cardiac damage but is an early diagnostic marker of acs , as suggested by the finding that slox-1 level on admission showed almost the peak values in acs patients . thus , it seems that serum slox-1 levels start to increase before the onset of acs . compared to subjects with stable coronary artery disease ( cad ) , patients with acs show higher levels of slox-1 ( 0.579  ng / ml versus 1.61  ng / ml , p < 0.01 ) ; patients with acs show also a significant positive correlation between slox-1 level increase and the number of complex lesions ( table 1 ) . slox-1 levels were independently associated with the presence of multiple complex coronary lesions ( odds ratio 1.967 , p < 0.05 ) , thus suggesting the possibility that they might predict vulnerable plaques . for patients who have no chance to undergo coronary angiography , slox-1 level measurement might thus help in identifying the presence of vulnerable atherosclerotic lesions . multiple complex lesions are often associated with adverse clinical outcomes in acs patients ; as slox-1 levels correlate with the presence of multiple complex lesions , it was hypothesized that slox-1 levels might predict the prognosis after acs . thus , in acs patients undergoing pci , slox-1 levels ( as well as other serum markers ) were measured before the followup . circulating slox-1 levels were higher in re - acs patients as compared to the event - free ones ( 6.60  ng / ml versus 2.54  ng / ml ) ( table 1 ) , while no differences in hs - crp or troponin t were found between the two groups . acs patients with the highest slox-1 values had more frequent and earlier acs recurrence or death . these observations reinforce the hypothesis that serum slox-1 levels may be a biomarker for the vulnerability of atherosclerotic plaque and predict acs recurrence in acs patients . in addition , it has been recently shown that slox-1 levels , but not hs - crp or hs - tnt , can differentiate acs with plaque rupture from those without . plasma slox-1 was significantly higher in acs with plaque rupture subjects ( p < 0.001 ) and in those without plaque rupture ( p = 0.002 ) than in subjects with stable angina pectoris , and it was significantly higher in the plaque rupture group than in the nonrupture group ( p < 0.001 ) ( table 1 ) . hs - crp differed only between the plaque rupture group and the stable group ( p = 0.048 ) , while hs - tnt was significantly higher in both acs groups ( p < 0.001 ) than in stable patients and tended to be lower in the rupture group than in the nonrupture group ( p = 0.055 ) . slox-1 , but not hs - crp or hs - tnt , was significantly associated with plaque rupture and inversely correlated with the fibrous cap thickness , thus reflecting plaque vulnerability . the diagnostic accuracy for acs is essential to identify high - risk patients and differentiate them from non - acs with similar chest pain and electrocardiogram anomalies ; the evaluation of serum cardiac markers , which include cardiac troponins , cardiac kinase - mb ( ck - mb ) , myoglobin , and heart - type fatty acid - binding protein ( h - fabp ) , plays a crucial role in the diagnosis of acs . although tnt , h - fabp , and slox-1 were all found to be higher in acs patients than in non - acs patients ( table 1 ) , slox-1 revealed a higher sensitivity and specificity than tnt and h - fabp and could detect acs in subjects with tnt values not significantly elevated ; in addition , in the acs group , h - fabp values significantly correlated with tnt values , while slox-1 values did not correlate with tnt or h - fabp , indicating the independence of slox-1 from these two acs biomarkers . slox-1 represents a biomarker for plaque rupture or vulnerability , but not for myocardial damage ; as plaque instability or rupture precedes cardiac damage in acute myocardial infarction , the slox-1 level increase is expected to precede the increase of biomarkers of cardiac injury . accordingly , plasma slox-1 levels were significantly higher in subjects with acute myocardial infarction ( ami ) than in non - ami subjects ( p < 0.001 ) , and they were significantly higher in subjects with st - elevation myocardial infarction ( stemi ) than in the non - stemi ( nstemi ) group ( p = 0.001 ) ( table 1 ) . in ami patients , slox-1 levels resulted elevated at the earliest stages of acute myocardial infarction ( 89 minutes from the symptom onset ) , persisted for 24  h after arrival at the emergency room , and declined to basal levels at 16 days after the onset of stemi . other biomarkers peaked later ( myoglobin and h - fabp after the termination of percutaneous coronary intervention , troponin t and ck - mb after 6  h ) and declined rapidly . these findings , in agreement with previous data showing that the circulating slox-1 is a more sensitive and specific biomarker for acs than tnt and h - fabp and can detect acs in subjects with normal tnt levels , suggested that slox-1 may be a useful biomarker for diagnosing stemi , although the evaluation of these slox-1 and hs - tnt in combination might improve the accuracy of acs diagnosis . acute aortic dissection ( aad ) is the most common life - threatening disorder affecting the aorta and it has a high mortality rate if not correctly and rapidly diagnosed . d - dimer evaluation is the standard method to diagnose aad , but it is not specific , as it is elevated also in acute ischemic events . slox-1 levels were found to be significantly higher in aad patients and in non - st elevation acs ( nsteacs ) patients than in controls and significantly higher in aad patients than in nsteacs patients ( p < 0.001 ) ( table 1 ) , while tnt levels were higher in nsteacs patients than in aad patients ( p = 0.002 ) and controls ( p < 0.001 ) . these observations indicate the usefulness of slox-1 in combination with tnt to detect patients with aad and distinguish them from those with nsteacs . serum slox-1 levels are associated with acute coronary syndrome ; however , slox-1 appears to be a potential disease biomarker also in patients with stable cad . slox-1 as well as tnf , crp , and il-6 levels were significantly higher in cad patients than in controls ; slox-1 levels positively correlated with inflammatory markers including il-6 , tnf , and crp , with tnf being the only independent determinant of slox-1 levels . the serum levels of slox-1 were higher in subjects with three or four vessels involved than in subjects with one or two vessels involved ( 2143  pg / ml versus 611  pg / ml , p < 0.05 ) ( table 2 ) , suggesting that circulating slox-1 levels might be related to cad severity . atherosclerotic plaques of the proximal and mid segments of the left anterior descending ( lad ) artery are the most prone to rupture . in subjects with stable cad in fact , patients with proximal / mid segment lad lesions ( as established by coronary angiograms ) had significantly higher circulating slox-1 levels than those with distal segment lad lesions ( 1.07  0.33  ng / ml versus 0.70  0.17  ng / ml , p < 0.001 ) ( table 2 ) , suggesting that slox-1 levels may also represent a marker of atherosclerotic plaque localization in patients with stable cad and may thus predict vulnerable plaques . similarly to subjects with acs , in patients with stable cad , slox-1 levels were higher in subjects with complex lesions than in those with simple lesions ( 0.914  ng / ml versus 0.426  ng / ml ) ( table 2 ) and were a significant and independent predictor of lesion complexity ( odds ratio 1.964 , p < 0.05 ) . percutaneous coronary intervention ( pci ) is a common procedure for coronary revascularization in patients with stable cad . although the procedural complications and long - term outcomes have significantly improved , periprocedural myocardial infarction remains relatively frequent ( ~30% ) among patients undergoing pci , with the increase of cardiac enzymes  indicative of myocardial injury . in stable cad , patients who manifested myocardial infarction related to pci procedure , as confirmed by the increase of cardiac biomarkers , baseline preprocedural serum slox-1 levels were higher compared to subjects without myocardial damage ( 167  89 versus 99  68  pg / ml , p < 0.001 ) ( table 2 ) . slox-1 levels also positively correlated with ck , ck - mb , and tnt , suggesting that slox-1 levels might be a biomarker to predict the risk of periprocedural myocardial damage in stable patients undergoing pci . in addition , slox-1 levels were evaluated before and after the procedure to verify whether it could predict in - stent restenosis ( isr ) during the followup of patients with stable cad who underwent successful primary pci . baseline slox-1 levels were comparable ; pci significantly increased serum slox-1 levels at 24  h after stent implantation in all patients , which might reflect a high expression of lox-1 at the site of stenting . however , the increase was more robust in patients with isr at 6-month followup ( table 2 ) , and postprocedural levels are significantly associated with the risk and severity of isr after stent implantation . this suggests that stent implantation induces plaque disruption and upregulation of lox-1 in several cell types , including platelets , resulting in smc migration , platelet aggregation , and inflammatory cell recruitment leading to restenosis . circulating levels of slox-1 are significantly higher in metabolic disorders including obesity   and type 2 diabetes mellitus . in obese postmenopausal women , slox-1 levels were significantly increased compared to both lean ( + 79% ) or overweight women ( + 44% ) , which may suggest an increased lox-1 expression in adipose tissue . plasma slox-1 levels were positively associated with body weight , bmi , and total body fat . weight loss resulted in a significant decrease of slox-1 levels ; women with the highest slox-1 levels at baseline had the greatest reductions in slox-1 with weight loss ( r = 0.80 , p < 0.0001 ) . similarly , in overweight men , serum slox-1 levels decreased significantly with body weight reduction ; changes in serum slox-1 levels positively correlated also with changes in body mass index ( bmi ) , total cholesterol , hs - crp , leptin , and tnf , suggesting that lox-1 induction may be related to adipocyte metabolism , inflammation , and immune response associated with obesity . the metabolic syndrome ( mets ) constitutes a complex disorder combining obesity , dyslipidemia , hyperglycemia , and hypertension , associated with an increased risk of cardiovascular diseases , especially cad . in subjects with mets , patients with cad showed a higher level of serum slox-1 compared to subjects without cad ( 0.925  ng / ml versus 0.207  ng / ml , p < 0.01 ) ; among the variables that showed an association with the presence of cad ( slox-1 , age , gender , and bmi ) , slox-1 represented a relevant independent predictor of angiographic cad . in addition , in patients with mets and cad , serum slox-1 levels significantly correlated with the angiographically determined severity of cad , in agreement with previous findings . slox-1 levels might thus be used as a biomarker for the detection and risk assessment of cad in subjects with mets . patients with type 2 diabetes , which is associated with increased oxidative stress and subclinical inflammation , had serum slox-1 levels significantly higher compared to nondiabetic subjects ( 111.4  ng / ml versus 102.5  ng / ml , p < 0.01 ) . both glucose and advanced glucose end - products ( ages ) were significant determinants of lox-1 expression , as glycemic control , which induces glucose and age lowering , leads to a reduction of circulating slox-1 . peripheral artery disease ( pad ) is characterized by an atherosclerotic occlusive disease of the lower extremities , and diabetes and smoking are the strongest risk factors for pad . in type 2 diabetic patients , serum slox-1 levels were significantly higher in subjects with pad than in those without pad ( 490.3  299.3  pg / ml versus 366.9  258.0  pg / ml , p < 0.05 ) . slox-1 levels were also inversely correlated with ankle - brachial index ( abi ) ( r = 0.197 , p < 0.0001 ) and were associated with pad , which suggests that serum slox-1 concentration could be a marker for pad in patients with type 2 diabetes . lox-1 expression is upregulated under several pathological conditions related to atherosclerosis . as a membrane - bound protein with a single c - terminal domain , it can be cleaved and released as a soluble form in the circulation , thus allowing its measurement in patients . slox-1 increases in plasma or serum of patients with acs or with cad compared to control subjects and , when combined with other serum biomarker levels , might have the potential to increase the diagnosis accuracy of acute coronary syndromes or to predict disease progression or the risk of future cardiovascular events .
lectin - like oxidized low density lipoprotein receptor-1 ( lox-1 ) , the main oxidized low - density lipoprotein ( oxldl ) in endothelial cells , is upregulated in atherosclerotic lesions and is involved in several cellular processes that regulate the pathogenesis of atherosclerosis . 
 the lox-1 expressed on the cell surface can be proteolytically cleaved and released in a soluble form ( slox-1 ) in the circulation under pathological conditions . 
 serum levels of slox-1 , in fact , are elevated at the early stages of acute coronary syndrome and are associated with coronary plaque vulnerability and with the presence of multiple complex coronary lesions . moreover , in subjects with stable cad , levels of serum slox-1 are associated with the presence of lesions in the proximal and mid - segments of the left anterior descending artery that are the most prone to rupture ; in subjects undergoing percutaneous coronary intervention , baseline preprocedural serum slox-1 levels are associated with the incidence of periprocedural myocardial infarction . 
 altogether , these findings suggest that circulating levels of slox-1 might be a diagnostic and prognostic marker for atherosclerotic - related events .