Plasma Lipoprotein-associated Phospholipase A2 in Patients with Metabolic Syndrome and Carotid Atherosclerosis
Lipids in Health and Diseasevolume 10, Article number: 13 (2011)
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a recently identified and potentially useful plasma biomarker for cardiovascular and atherosclerotic diseases. However, the correlation between the Lp-PLA2 activity and carotid atherosclerosis remains poorly investigated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the potential role of Lp-PLA2 as a comprehensive marker of metabolic syndrome in individuals with and without carotid atherosclerosis.
We documented 118 consecutive patients with MetS and 70 age- and sex-matched healthy subjects served as controls. The patients were further divided into two groups: 39 with carotid plaques and 79 without carotid plaques to elucidate the influence of Lp-PLA2 on carotid atherosclerosis. The plasma Lp-PLA2 activity was measured by using ELISA method and carotid intimal-media thickness (IMT) was performed by ultrasound in all participants.
Lp-PLA2 activity was significantly increased in MetS subgroups when compared with controls, and was higher in patients with carotid plaques than those without plaques (P < 0.05). Furthermore, we found that significant difference in Lp-PLA2 was obtained between patients with three and four disorders of metabolic syndrome (P < 0.01). Age (β = 0.183, P = 0.029), LDL-cholesterol (β = 0.401, P = 0.000) and waist-hip ratio (β = 0.410, P = 0.000) emerged as significant and independent determinants of Lp-PLA2 activity. Multiple stepwise regression analysis revealed that LDL-cholesterol (β = 0.309, P = 0.000), systolic blood pressure (β = 0.322, P = 0.002) and age (β = 0.235, P = 0.007) significantly correlated with max IMT, and Lp-PLA2 was not an independent predictor for carotid IMT.
Lp-PLA2 may be a modulating factor for carotid IMT via age and LDL-cholesterol, not independent predictor in the pathophysiological process of carotid atherosclerosis in patients with MetS.
The metabolic syndrome (MetS) is a constellation of atherogenic risk factors including abdominal obesity, hypertension, insulin resistance, dyslipidemia, proinflammatory, and prothrombotic state . Recent publications have probed that patients with MetS are at higher risk of cardiovascular morbidity and mortality  and are more prone to atherosclerosis than normal subjects, even in the young adults [3, 4]. Although the relationship between MetS and the risk of cardiovascular disease is still a matter of debate, MetS has been associated with carotid plaque formation and intima-media thickening . Inflammatory processes have been increasingly recognized as a critical step in the pathogenesis of both metabolic syndrome and carotid atherosclerosis and may be important midways linking MetS to the increased arteriosclerotic events [6, 7].
Lipoprotein-associated phospholipase A2 (Lp-PLA2) was recently characterized as a novel inflammatory biomarker correlated with several components constituting the MetS and implicated in atherosclerosis, incident cardiovascular disease [8, 9]. Lp-PLA2 is preferentially secreted by monocytes and macrophages and hydrolyzes oxidatively modified low-density lipoprotein by cleaving oxidized phosphatidylcholines thereby generating lysophosphatidylcholine and oxidized free fatty acids . Such chemoattractants are thought to play pivotal role in inflammatory reactions and particularly in vascular inflammation and atherosclerosis . However, the potential role of Lp-PLA2 in atherogenesis and the anti- or proatherogenic characteristic of this enzyme in humans are less well understood . Almost all prospective and nested case cohort studies suggested that Lp-PLA2 is proatherogenic . One recent trial  demonstrated that symptomatic carotid artery plaques are characterized by increased levels of Lp-PLA2 and its product lysoPC in correlation with markers of tissue oxidative stress, inflammation, and instability. In contrast, previous investigations reported no associations observed between carotid intima-media thickness and Lp-PLA2 levels in primary hyperlipidemia patients [15, 16].
To the best of our knowledge, few studies have explored the atherosclerotic risk for carotid arteries correlated with MetS is confounded by an association with activity of Lp-PLA2. Additionally, carotid intima-media thickness (IMT) of arteries is a useful measure of clinical atherosclerosis as assessed noninvasively by ultrasonography. Alternations in carotid IMT has been validated as a vascular marker of the progression of atherosclerosis . Therefore, in the present study, we measured the plasma Lp-PLA2 activity in patients with MetS (including with and without carotid atherosclerosis) and correlated it with anthropometric parameters and carotid IMT to evaluate the possible contribution of Lp-PLA2 to carotid atherosclerosis.
A total of 118 patients with MetS (53 men and 65 women, aged from 32 to71 years), were recruited from the Second Hospital of Shandong University according to the criteria proposed by the International Diabetes Federation . Individuals were excluded if they had a clinical history of cerebrovascular disease or present neurological abnormalities, cerebral hemorrhage and severe cardio-renal or nutritional disorders, lipid and glucose metabolism. The control group consisted of 70 age- and sex-matched healthy subjects who visited our hospital for a routine physical check-up and without a history of cardiac disease, hypertension or diabetes and having normal findings on physical examination, chest roentgenography, and echocardiography. Informed consent was obtained from all participants and the study was approved by the local ethics committee.
Definition of metabolic syndrome
In our study, metabolic syndrome was defined by the presence of 3 or more of the following conditions based on the criteria of IDF : (1) visceral obesity: waist circumference was ≥ 90 cm in men and and ≥80 cm in women, (2) hypertriglycedemia: ≥ 150 mg/dl (1.7 mmol/l) or specific treatment for this lipid abnormality, (3) low HDL cholesterol: <40 mg/dl (1.03 mmol/l) in men and <50 mg/dl (1.29 mmol/l) in women or specific treatment for this lipid abnormality, (4) hypertension: systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg or treatment of previously diagnosed hypertension, and (5) impaired fasting glucose concentration ≥100 mg/dl (5.6 mmol/l) or those who had been treated for type 2 diabetes.
The baseline and clinical characteristics of all participants were determined. The details of age, gender and the weight and height were obtained, with the body mass index calculated as the body weight in kilogram divided by the height in meters squared. Waist circumference was measured at the level of the umbilicus, systolic and diastolic blood pressures were obtained with a mercury sphygmomanometer using auscultory methods.
The laboratory measurements were carried out following overnight fasting. Blood was collected at baseline for glucose, HbA1c, total cholesterol, triglycerides, high density lipoprotein (HDL)-cholesterol and low-density lipoprotein (LDL)-cholesterol. Serum insulin levels were determined by a radio-immunoassay kit (Dongya Ltd, Beijing, China). Insulin resistance was assessed by the homeostasis model assessment equation .
Lp-PLA2 activity assay
The total plasma Lp-PLA2 activity was measured using a PAF Acetylhydrolase enzyme immunoassay (EIA) kit (Catalogue No. 760901, Cayman chemical Company , USA) with a lower limit of sensitivity of 0.02-0.2 umol/min/ml. Samples were measured in duplicate in a single experiment. Lp-PLA2 activity was expressed as micromoles of platelet-activating factor hydrolyzed per minute per milliliter of plasma samples and the inter-assay coefficient of variance was < 5%.
All participants were examined in the supine position (head turned 45°) by the same trained operator with a high resolution B-mode ultrasonography equipped with a 5-10 MHz linear array transducer (iE33, Philips Ultrasound, Washington, USA). ECG leads were attached to the ultrasound recorder for on-line continuous heart rate monitoring. All the images were recorded and stored on magneto optical disk for later playback and analysis. The right and left common carotid arteries (CCAs) and internal carotid arteries (including bifurcations) were evaluated. IMT, plaque extent of the near and far walls of the common and internal carotid arteries (ICAs) and bifurcations were measured according to the ACAPS protocol. AA thickened IMT was defined as ≥1.0 mm in either carotid artery. Presence of atherosclerotic plaques, defined as localized lesions with protrusion into the arterial lumen or regional IMT≥1.1 mm , was considered when found in either or both CCAs. IMT was therefore measured at the point of maximal thickness in the walls of both CCAs. Maximal and mean IMT were defined as the greatest and mean values, respectively, of IMT measured from 3 contiguous sites at 1-cm intervals. Maximal IMT represented the highest single measurement at any site with plaque. Both thickened IMT and plaques were reconfirmed by re-examining the lesions on the printouts from the ultrasound scanner.
Data are presented as mean ± SD for continuous variables or proportions. After testing for normal distribution of variables, student's 2-tail t-test and one-way analysis of variance (anova) followed by the post hoc least significant difference test were used where appropriate. The correlations between two variables were assessed by Pearson correlation analysis. Multiple linear regression analysis was used to evaluate the contribution of independent factors. Statistical analyses were performed using SPSS v. 15.0 (SPSS, Chicago, IL) software. A two-tailed P value <0.05 was considered statistically significant.
Baseline and clinical characteristics of participants
The baseline and clinical characteristics of the metabolic syndrome patients and controls were shown in Table 1. All MetS patients were divided into subgroups according to presence or absence of plaques, carotid atherosclerotic plaques was identified in 39 patients, and no stenosis or occlusion was found. There were no statistical differences in age or gender among three groups. Patients with MetS showed increased levels of systolic blood pressure, diastolic blood pressure, BMI, waist circumference, waist-hip ratio, triglyceride, total cholesterol, fasting glucose, insulin, HbA1c, HOMA-insulin resistance and more prescription of medications, and decreased levels of HDL-cholesterol when compared with controls (all P < 0.05-0.01), but there were no significant differences in any of those parameters between patients with and without carotid plaques. LDL cholesterol was found to increase from controls to MetS patients with and without carotid plaques, moreover, with significant difference between two patient subgroups (P < 0.05). Mean IMT values were significantly higher in MetS patients with and without carotid plaques than in controls (0.74 ± 0.11 mm vs. 0.51 ± 0.15 mm, 0.86 ± 0.20 mm vs. 0.51 ± 0.15 mm, all P < 0.01, respectively), and were highest in patients with carotid plaques. Max IMT values increased significantly in MetS patients with carotid plaques, whereas no difference was found between the other two groups.
Distribution of Lp-PLA2 activity approximates a normal distribution. Lp-PLA2 activity was significantly increased in MetS subgroups when compared with controls (all P < 0.01), and was higher in patients with carotid plaques than those without plaques (34.10 ± 9.51 umol/min/mL vs. 29.62 ± 8.98 umol/min/mL, P < 0.05) (Table 1, Figure 1). There were no age (<65 vs. ≥65 years) and gender differences of Lp-PLA2 activity in patients (Data not shown). To assess the association of metabolic syndrome components with Lp-PLA2 activity, we further found that significant difference in Lp-PLA2 was obtained between patients with three (n = 89) and four (n = 28) disorders of metabolic syndrome (38.79 ± 9.22 umol/min/mL vs. 30.60 ± 9.58 umol/min/mL, P < 0.01).
Relationship of Lp-PLA2 activity and determinant factors
In simple regression analyses, Lp-PLA2 activity correlated positively with age (r = 0.250, P = 0.006), total cholesterol (r = 0.371, P = 0.000), LDL-cholesterol (r = 0.402, P = 0.000), glucose (r = 0.188, P = 0.042) and HbA1c (r = 0.188, P = 0.042) in the patients with MetS. We also found Lp-PLA2 activity correlated with waist-hip ratio weakly but not significantly (r = 0.174, P = 0.061). However, in multivariable stepwise regression analyses, age (β = 0.183, P = 0.029), LDL-cholesterol (β = 0.401, P = 0.000) and waist-hip ratio (β = 0.410, P = 0.000) emerged as significant and independent determinants of Lp-PLA2 activity (Table 2).
Relationship of max IMT and risk factors
Pearson's correlation coefficient and multiple regression analysis were performed to examine the relationship of max IMT to Lp-PLA2 activity and other biomarkers in overall MetS patients in order to identify a parameter that reflects carotid atherosclerosis. As shown in Table 3, Lp-PLA2 activity (r = 0.199, P = 0.023), LDL-cholesterol (r = 0.333, P = 0.000), age (r = 0.325, P = 0.000) and systolic blood pressure (r = 0.225, P = 0.015) were significantly correlated with max carotid IMT. Unexpectedly, in multiple stepwise regression analysis, Lp-PLA2 activity correlated with the presence of atherosclerosis weakly but not significantly (β = 0.146, P = 0.097). Our results revealed that only LDL-cholesterol (β = 0.309, P = 0.000), systolic blood pressure (β = 0.322, P = 0.002) and age (β = 0.235, P = 0.007) were the significant predictors of max IMT. Moreover, after adjustment for age and lipid variables, the associations between Lp-PLA2 activity and carotid IMT did not reach statistical significance.
The present study identified elevated total plasma Lp-PLA2 activity in patients with the MetS, especially in those with carotid atherosclerosis when compared to the control subjects. We demonstrated that the Lp-PLA2 activity correlated with age, LDL-cholesterol and waist-hip ratio in patients with metabolic syndrome. Unfortunately, our data provided no evidence that Lp-PLA2 activity independently influence carotid IMT in MetS patients. The associations of Lp-PLA2 activity with carotid atherosclerosis may be mediated through age and LDL-cholesterol level.
The biological mechanisms involving plasma Lp-PLA2 in the pathogenesis of the MetS and atherosclerosis are not well-characterized. Recent evidence suggests inflammation is an important pathogenic factor in atherosclerosis and coronary heart disease, particularly in the context of insulin resistance, obesity , and the metabolic syndrome . Furthermore, atherosclerosis is now recognized as manifestations of vascular inflammation . Inflammatory factors such as adhesion molecules (ICAM-1 and VCAM-1), CD40 ligands, C-reactive protein (CRP) and myeloperoxidase (MPO) participate in induction of insulin resistance and atherosclerotic disease [21, 22]. Lp-PLA2, originally named platelet-activating factor acetylhydrolase (PAF-AH), is an enzyme involved in lipoprotein metabolism and inflammatory pathways . In human, 80% of Lp-PLA2 circulates bound to LDL- cholesterol, 10-15% circulates with HDL-cholesterol, and the remaining 5-10% circulates with VLDL-cholesterol . Lp-PLA2 enzymatic activity results in generation of lysophosphotidylcholine (lysoPC) and oxidized non-esterified fatty acids, two pro-inflammatory mediators . The lysoPC stimulates macrophage proliferation, up-regulates cytokines and CD40 ligands, and increases the expression of vascular adhesion molecules, implying a complex interaction between Lp-PLA2 and other inflammatory mediators [23, 24]. Based on that, Lp-PLA2 has been implicated in inflammation and considered as an inflammatory marker in the MetS. Recently, several epidemiological studies demonstrate that an elevated activity of Lp-PLA2 is associated with MetS and number of the metabolic syndrome components as well as incident fatal and non-fatal CVD regarding MetS [25, 26]. In the current study, we observed that plasma Lp-PLA2 activity was higher in patients with the MetS than in controls, suggesting that Lp-PLA2 activity may increase significantly when metabolic syndrome was present. Furthermore, our findings showed that there was a linear rise in Lp-PLA2 activity with an increment of number of metabolic syndrome components. These data were in line with previous research  and enlarged our scope for potential role of Lp-PLA2 in patients with MetS.
Results for studies of the associations of components of MetS with Lp-PLA2 activity have shown that abdominal obesity may have been independently responsible for the changes of Lp-PLA2 observed in this study. Additionally, we found Lp-PLA2 correlated with glucose and HbA1c weakly but significantly only in simple regression. Our findings were in accordance with the previous studies, in which Lp-PLA2 correlated with abdominal adiposity [27, 28] but differed from the results of Noto et al  and Rana et al , who found that plasma Lp-PLA2 activity did not appear to be associated with waist circumference. It was possible that obesity was associated with decreases in local and peripheral insulin resistance . Adipose tissue located in intra- abdominal or visceral cavities is likely to be infiltrated by macrophage, which is an important cause of the inflammatory state associated with abdominal obesity and the metabolic syndrome . Lp-PLA2, as an inflammatory marker, is mainly secreted by macrophages. Thus, our results suggested that central obesity may contribute to the Lp-PLA2 activity changes in patients with MetS. Out results also indicated that there was parallel increase in Lp-PLA2 activity with an increment of components of metabolic syndrome, which was consistent with the findings of Noto at al. .
In the present study, our results have shown that Lp-PLA2 activity was elevated among MetS patients with carotid plaques. However, we further found independent determinants for thickened IMT as being LDL-cholesterol and age in multiple regression models. The Lp-PLA2 activity was not independently facilitates the morbidity of carotid atherosclerosis. Previous studies have revealed the plasma Lp-PLA2 activity in atherosclerotic disease, but consensus is still lacking [8, 9, 31]. Biologically, Lp-PLA2 is a vascular-specific proinflammatory enzyme that operates physiologically in the arterial intima . Evidence has shown that Lp-PLA2 is expressed in human and rabbit atherosclerotic plaques . Vickers et al  revealed that carotid tissue concentrations of Lp-PLA2 was notably very high in the rupture-prone shoulder region of thin fibrous cap atheromas, and Lp-PLA2 colocalized with macrophages and oxidized LDL in atherosclerotic carotid plaques. However, several clinical studies suggested that premature coronary atherosclerosis  as well as carotid intima-media thickness plasma was not influenced by Lp-PLA2 activity and gene polymorphisms in hypercholesterolemic individuals [15, 16]. Thus, consistent with results of previous study , role of this enzyme in predicting independently the thicken IMT attenuated in our study, especially after adjustment for age and lipid variables.
Although the exact mechanisms underlying contribution of Lp-PLA2 to carotid atherosclerosis in MetS patients remain to be elucidated, there are several possible explanations. Firstly, our study demonstrated that lipid parameters may contribute to Lp-PLA2 activity changes. An increase in plasma Lp-PLA2 activity, reflecting LDL-cholesterol values, has been established in several investigations [9, 36]. Stafforini et al investigated that Lp-PLA2 participated in the key oxidative steps of atherogenesis due to the association of Lp-PLA2 and LDL-cholesterol via an interaction with apolipoprotein B (apoB) . Kawamoto et al  reported that LDL-cholesterol was independently associated with carotid atherosclerosis in addition to clustering of cardiovascular risk factors regarding MetS. Several studies [39–41] suggested that the components of metabolic and LDL-cholesterol played a role to synergistically influence vascular thickness. Our results revealed that levels of LDL-cholesterol were significantly increased in MetS patients with carotid plaques than those without. Secondly, in present study, multivariate linear regression showed that age had a similar positive association with Lp-PLA2 activity and contributed strongly to the variation in IMT. Thus, taken together previous important results [38–41] and our intriguing findings implied that Lp-PLA2 activity was intimately associated with carotid thicken IMT and atherosclerosis via correlation with age and LDL-cholesterol in our study. Lp-PLA2 may be a modulating factor in the process of carotid atherosclerosis. Lastly, owing to the prominent biological activities, the opposing proinflammatory and antiatherogenic properties of Lp-PLA2 have been demonstrated both in human and animal models. In rabbit models, administration of Lp-PLA2 inhibited myocardial ischemia/reperfusion injury , and local expression of Lp-PLA2 reduced accumulation of oxidized LDL-cholesterol in balloon-injured arteries . However, previous findings did not ascertain a causal relationship between Lp-PLA2 and the clinical consequences of atherosclerotic disease in patients with primary hyperlipidemia [15, 16] and diabetes mellitus . Interestingly, elevated Lp-PLA2 has been identified in human symptomatic carotid atherosclerotic plaque and its product lysophosphatidylcholine (lysoPC) correlated with markers of tissue oxidative stress, inflammation, and instability . These paradoxical results may partly be explained by the relatively small study populations and selected inclusion criteria. Further studies are required to clarify whether Lp-PLA2 is a risk marker that participates in the pathogenesis of carotid atherosclerosis in patients with MetS.
Despite of interesting findings, potential limitations of this study merit consideration. Our results are based on single measurements of circulating Lp-PLA2, which may not reflect the true activity of Lp-PLA2 over time or true expression in carotid atherosclerotic plaques. For this reason, further outcome-directed prospective studies would give insight into the significance of Lp-PLA2 activity versus expression in atherosclerotic plaques. Several studies have shown that activity of Lp-PLA2 was impacted by lipid-lowering drugs such as statins and fibric acid derivatives (fibrates)[25, 45]. Thus, we could not eliminate the possible effect of medications for Lp-PLA2 activity on the present findings. Finally, even though intriguing, results obtained in further confirmatory studies need to be considered to clarify the validity of Lp-PLA2 in large series of patients.
In conclusion, our results of increased plasma Lp-PLA2 activity in patients with the metabolic syndrome, especially in those with carotid atherosclerosis, suggest that Lp-PLA2 may be an inflammatory marker of metabolic syndrome. However, multiple stepwise regression analysis suggested that Lp-PLA2 may be a modulating factor, not independent risk predictor in the pathophysiological process of carotid atherosclerosis in MetS patients. Because Lp-PLA2 activity may represent a novel pathway associated with thicken IMT, further research using large samples and general population need to be done to clarify the exact role of Lp-PLA2 on carotid atherosclerosis in metabolic syndrome subjects.
Grundy SM, Brewer HB, Cleeman JI, Smith SC, Lenfant C, , : Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004, 109: 433-438. 10.1161/01.CIR.0000111245.75752.C6
Ford ES: The metabolic syndrome and mortality from cardiovascular disease and all-causes: findings from the national health and nutrition examination survey ii mortality study. Atherosclerosis. 2004, 173: 309-314. 10.1016/j.atherosclerosis.2003.12.022
Kullo IJ, Cassidy AE, Peyser PA, Turner ST, Sheedy PF, Bielak LF: Association between metabolic syndrome and subclinical coronary atherosclerosis in asymptomatic adults. Am J Cardiol. 2004, 94: 1554-1558. 10.1016/j.amjcard.2004.08.038
Tzou WS, Douglas PS, Srinivasan SR, Bond MG, Tang R, Chen W, Berenson GS, Stein JH: Increased subclinical atherosclerosis in young adults with metabolic syndrome: the bogalusa heart study. J Am Coll Cardiol. 2005, 46: 457-463. 10.1016/j.jacc.2005.04.046
Wallenfeldt K, Hulthe J, Fagerberg B: The metabolic syndrome in middle-aged men according to different definitions and related changes in carotid artery intima-media thickness (IMT) during 3 years of follow-up. J Intern Med. 2005, 258: 28-37. 10.1111/j.1365-2796.2005.01511.x
Koh KK, Han SH, Quon MJ: Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol. 2005, 46: 1978-1985. 10.1016/j.jacc.2005.06.082
Ross R: Atherosclerosis-an inflammatory disease. N Engl J Med. 1999, 340: 115-126. 10.1056/NEJM199901143400207
Persson M, Hedblad B, Nelson JJ, Berglund G: Elevated Lp-PLA2 Levels Add Prognostic Information to the Metabolic Syndrome on Incidence of Cardiovascular Events Among Middle-Aged Nondiabetic Subjects. Arterioscler Thromb Vasc Biol. 2007, 27: 1411-1416. 10.1161/ATVBAHA.107.142679
Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, Sharrett AR: Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2004, 109: 837-842. 10.1161/01.CIR.0000116763.91992.F1
Karasawa K, Harada A, Satoh N, Inoue K, Setaka M: Plasma platelet activating factor-acetylhydrolase (PAF-AH). Prog Lipid Res. 2003, 42: 93-114. Review., 10.1016/S0163-7827(02)00049-8
Tsimikas S, Tsironis LD, Tselepis AD: New Insights Into the Role of Lipoprotein(a)- Associated Lipoprotein-Associated Phospholipase A2 in Atherosclerosis and Cardiovascular Disease. Arterioscler Thromb Vasc Biol. 2007, 27: 2094-2099. 10.1161/01.ATV.0000280571.28102.d4
McConnell JP, Hoefner DM: Lipoprotein-associated phospholipase A2. Clin Lab Med. 2006, 26: 679-697. vii. Review., 10.1016/j.cll.2006.06.003
Sudhir K: Clinical review: Lipoprotein-associated phospholipase A2, a novel inflammatory biomarker and independent risk predictor for cardiovascular disease. J Clin Endocrinol Metab. 2005, 90: 3100-3105. 10.1210/jc.2004-2027
Mannheim D, Herrmann J, Versari D, Gössl M, Meyer FB, McConnell JP, Lerman LO, Lerman A: Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques. Stroke. 2008, 39: 1448-1455. 10.1161/STROKEAHA.107.503193
Kiortsis DN, Tsouli S, Lourida ES, Xydis V, Argyropoulou MI, Elisaf M, Tselepis AD: Lack of association between carotid intima-media thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia. Angiology. 2005, 56: 451-458. 10.1177/000331970505600413
Campo S, Sardo MA, Bitto A, Bonaiuto A, Trimarchi G, Bonaiuto M, Castaldo M, Saitta C, Cristadoro S, Saitta A: Platelet-Activating Factor Acetylhydrolase Is Not Associated with Carotid Intima-Media Thickness in Hypercholesterolemic Sicilian Individuals. Clin Chem. 2004, 50: 2077-2082. 10.1373/clinchem.2004.036863
Bots ML, Grobbee DE: Intima media thickness as a surrogate marker for generalised atherosclerosis. Cardiovasc Drugs Ther. 2002, 16: 341-351. 10.1023/A:1021738111273
Alberti KG, Zimmet P, Shaw J, : The metabolic syndrome-a new worldwide definition. Lancet. 2005, 366: 1059-1062. 10.1016/S0140-6736(05)67402-8
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985, 28: 412-419. 10.1007/BF00280883
Sidhu PS, Desai SR: A simple and reproducible method for assessing intimal-medial thickness of the common carotid artery. Br J Radiol. 1997, 70: 85-89.
Shoelson SE, Herrero L, Naaz A: Obesity, Inflammation, and Insulin Resistance. Gastroenterology. 2007, 132: 2169-2180. 10.1053/j.gastro.2007.03.059
Brennan ML, Hazen SL: Emerging role of myeloperoxidase and oxidant stress markers in cardiovascular risk assessment. Curr Opin Lipidol. 2003, 14: 353-359. 10.1097/00041433-200308000-00003
Kume N, Gimbrone MA: Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest. 1994, 93: 907-911. 10.1172/JCI117047
Tselepis AD, John Chapman M: Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. Atheroscler Suppl. 2002, 3: 57-68. 10.1016/S1567-5688(02)00045-4
Noto H, Chitkara P, Raskin P: The role of lipoprotein-associated phospholipase A2 in the metabolic syndrome and diabetes. J Diabetes Complications. 2006, 20: 343-348. 10.1016/j.jdiacomp.2006.07.004
Tsimikas S, Willeit J, Knoflach M, Mayr M, Egger G, Notdurfter M, Witztum JL, Wiedermann CJ, Xu Q, Kiechl S: Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study. Eur Heart J. 2009, 30: 107-115. 10.1093/eurheartj/ehn502
Persson M, Nilsson JA, Nelson JJ, Hedblad B, Berglund G: The epidemiology of Lp-PLA(2): distribution and correlation with cardiovascular risk factors in a population-based cohort. Atherosclerosis. 2007, 190: 388-396. 10.1016/j.atherosclerosis.2006.02.016
Okada T, Miyashita M, Kuromori Y, Iwata F, Harada K, Hattori H: Platelet-activating factor acetylhydrolase concentration in children with abdominal obesity. Arterioscler Thromb Vasc Biol. 2006, 26: e40-41. 10.1161/01.ATV.0000217284.86123.2c
Rana JS, Arsenault BJ, Després JP, Côté M, Talmud PJ, Ninio E, Jukema JW, Wareham NJ, Kastelein JJ, Khaw KT, Boekholdt SM: Inflammatory biomarkers, physical activity, waist circumference, and risk of future coronary heart disease in healthy men and women. Eur Heart J. 2009.
Alpert MA, Lambert CR, Panayiotou H, Terry BE, Cohen MV, Massey CV, Hashimi MW, Mukerji V: Relation of duration of morbid obesity to left ventricular mass, systolic function, and diastolic filling, and effect of weight loss. Am J Cardiol. 1995, 76: 1194-1197. 10.1016/S0002-9149(99)80338-5
Shohet RV, Anwar A, Johnston JM, Cohen JC: Plasma plateletactivating factor acetylhydrolase activity is not associated with premature coronary atherosclerosis. Am J Cardiol. 1999, 83: 109-111. A8-9, 10.1016/S0002-9149(98)00791-7
Toth PP, McCullough PA, Wegner MS, Colley KJ: Lipoprotein-associated phospholipase A2: role in atherosclerosis and utility as a cardiovascular biomarker. Expert Rev Cardiovasc Ther. 2010, 8: 425-438. 10.1586/erc.10.18
Häkkinen T, Luoma JS, Hiltunen MO, Macphee CH, Milliner KJ, Patel L, Rice SQ, Tew DG, Karkola K, Ylä-Herttuala S: Lipoprotein-associated phospholipase A(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 1999, 19: 2909-2917.
Vickers KC, Maguire CT, Wolfert R, Burns AR, Reardon M, Geis R, Holvoet P, Morrisett JD: Relationship of lipoprotein-associated phospholipase A2 and oxidized low density lipoprotein in carotid atherosclerosis. J Lipid Res. 2009, 50: 1735-1743. 10.1194/jlr.M800342-JLR200
Blake GJ, Dada N, Fox JC, Manson JE, Ridker PM: A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women. J Am Coll Cardiol. 2001, 38: 1302-1306. 10.1016/S0735-1097(01)01554-6
Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB: Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur Heart J. 2005, 26: 137-144. 10.1093/eurheartj/ehi010
Stafforini DM, Tjoelker LW, McCormick SP, Vaitkus D, McIntyre TM, Gray PW, Young SG, Prescott SM: Molecular basis of the interaction between plasma platelet-activating factor acetylhydrolase and low density lipoprotein. J Biol Chem. 1999, 274: 7018-7024. 10.1074/jbc.274.11.7018
Kawamoto R, Tomita H, Oka Y, Kodama A, Kamitani A: Metabolic syndrome amplifies the LDL-cholesterol associated increases in carotid atherosclerosis. Intern Med. 2005, 44: 1232-1238. 10.2169/internalmedicine.44.1232
Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM: Insulin resistance and hyperinsulinemia in individuals with small, dense low density lipoprotein particles. J Clin Invest. 1993, 92: 141-146. 10.1172/JCI116541
Haffner SM, Mykkänen L, Robbins D, Valdez R, Miettinen H, Howard BV, Stern MP, Bowsher R: A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects. Diabetologia. 1995, 38: 1328-1336. 10.1007/BF00401766
Howard BV, Mayer-Davis EJ, Goff D, Zaccaro DJ, Laws A, Robbins DC, Saad MF, Selby J, Hamman RF, Krauss RM, Haffner SM: Relationships between insulin resistance and lipoproteins in nondiabetic African Americans, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Metabolism. 1998, 47: 1174-1179. 10.1016/S0026-0495(98)90319-5
Morgan EN, Boyle EM, Yun W, Kovacich JC, Canty TG, Chi E, Pohlman TH, Verrier ED: Platelet-activating factor acetylhydrolase prevents myocardial ischemia- reperfusion injury. Circulation. 1999, 100: II365-II368.
Arakawa H, Qian JY, Baatar D, Karasawa K, Asada Y, Sasaguri Y, Miller ER, Witztum JL, Ueno H: Local expression of platelet-activating factor-acetylhydrolase reduces accumulation of oxidized lipoproteins and inhibits inflammation, shear stress-induced thrombosis, and neointima formation in balloon-injured carotid arteries in nonhyperlipidemic rabbits. Circulation. 2005, 111: 3302-3309. 10.1161/CIRCULATIONAHA.104.476242
Wootton PT, Stephens JW, Hurel SJ, Durand H, Cooper J, Ninio E, Humphries SE, Talmud PJ: Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. Atherosclerosis. 2006, 189: 149-156. 10.1016/j.atherosclerosis.2005.12.009
Filippatos TD, Gazi IF, Liberopoulos EN, Athyros VG, Elisaf MS, Tselepis AD, Kiortsis DN: The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. 2007, 193: 428-437. 10.1016/j.atherosclerosis.2006.07.010
This work was supported by the key science and technology program of Shandong Province of China (Grant No.:2009GG20002034) and the Foundation of Science and Technology Commission of Shandong Province of China (Y2005C12).
The authors declare that they have no competing interests.
HPG and YMD participated in the design of the study and drafted the manuscript; ZQD and LNZ performed research; HPG and XW analyzed data; YJM and QHL were responsible for the study design and the funding. All authors read and approved the final manuscript.
Hui-ping Gong, Yi-meng Du contributed equally to this work.