Serum Angiopoietin-like Protein 2 Research Articles

Serum angiopoietin-like protein 2 level in patients who received bevacizumab-containing chemotherapy for metastatic colorectal cancer.

209 Background: Anti-angiogenic agents are important for treating patients with advanced colorectal adenocarcinoma, however, their efficacy is not long-lasting and survival benefits are modest. Reliable biomarkers and novel targets for angiogenesis are still required in this era. Angiopoietin-like protein 2 (AGLP-2) is an emerging biomarker for angiogenesis in cardiovascular disease, but its role in the oncology area is yet to be elucidated. Methods: Serum samples from patients with advanced colorectal carcinoma treated with bevacizumab-containing chemotherapy were retrospectively studied. Blood samples at baseline and at disease progression of the first line systemic therapy were selected. Serum angiopoietin-like protein 2 (AGLP-2) concentrations were measured using ELISA kit, serial changes, and the relationship with progression-free survival and overall survival on the systemic therapy were statistically analyzed. Results: 68 patients were enrolled. Their median age was 66 years old (range, 38-82), and 14 (20.6%) patients had metastatic lesions at 3 or 4 organs. The median serum AGLP-2 levels at baseline and at disease progression (PD) were 41,618 pg/ml (95% confidence interval (CI) 34,560-40,713), and 49,706 pg/ml (95% CI 39,853-49,017), respectively. There was a tendency of difference between AGLP-2 levels at baseline and at PD ( p=0.057). Patients whose baseline serum AGLP-2 levels with 40,000 pg/ml or above showed relatively shorter overall survival (median 31.4 months with 95% CI, 14.4-38.6) compared with patients with serum AGLP-2 level below 40,000 pg/ml at baseline (median 38.6 months with 95% CI, 23.6-127.3), but not statistically significant ( p=0.0946). There was no survival difference observed according to serum AGLP-2 levels at disease progression on the first line bevacizumab-containing chemotherapy. Conclusions: Serum angiopoietin-like protein-2 has potential as a new target for novel anti-angiogenic therapy in metastatic colorectal cancer.

Serum Angiopoietin-Like Protein 2 and NT-Pro BNP Levels and Their Associated Factors in Patients with Chronic Heart Failure Participating in a Phase III Cardiac Rehabilitation Program.

Angiopoietin-like protein 2 (ANGPTL2) promotes chronic inflammation and plays a key role in the pathogenesis of heart failure. Cardiac rehabilitation (CR) is an integral component of heart failure management and has been shown to have anti-inflammatory effects. However, ANGPTL2 concentration in chronic heart failure patients undergoing CR has not been evaluated. This study aimed to investigate serum ANGPTL2 levels and their associated factors and compare the results with those of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with chronic heart failure undergoing phase III CR.A total of 56 patients were enrolled. Clinical characteristics including body composition, grip strength, exercise tolerance, duration of CR, blood counts and biochemistry, and echocardiographic parameters were evaluated for their association with serum ANGPTL2 and NT-proBNP levels.The median (first and third quartiles) value of ANGPTL2 was 4.05 (2.70-5.57) ng/mL. Clinical parameters that correlated with serum ANGPTL2 levels were body weight, body mass index, body fat mass, body fat percentage, anaerobic threshold (AT), C-reactive protein, and total protein (TP), which were mostly distinct from those that correlated with serum NT-proBNP levels. A multivariate analysis revealed that AT and TP were independent factors related to ANGPTL2 levels, whereas age, left ventricular ejection fraction, and left atrial dimension were independently related to NT-proBNP levels.These observations suggest that CR increases the exercise tolerance and exhibits anti-inflammatory effects simultaneously, and this situation is reflected by decreased serum ANGPLT2 and TP levels. ANGPTL2 may be a useful marker of inflammation and impaired exercise tolerance in patients with chronic heart failure.

Angiopoietin-Like Proteins 2 and 3 in Children and Adolescents with Obesity and Their Relationship with Hypertension and Metabolic Syndrome.

Background Angiopoietin-like protein 2 (ANGPTL2) is one of the adipocyte-derived inflammatory factors which connects obesity to insulin resistance. ANGPTL3 has a direct role in regulation of lipid metabolism. The objective of this study was to evaluate ANGPTL2 and ANGPTL3 in childhood obesity and their relationship with metabolic syndrome. Methods 70 children and adolescents, 35 obese and 35 normal-weight subjects, were enrolled in this research after complete clinical examination and anthropometric evaluations. Serum ANGPTL2 and ANGPTL3 and insulin were measured by enzyme-linked immunosorbent assay (ELISA). Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated and used to estimate insulin resistance (IR). Colorimetric methods were used for the assessment of fasting plasma glucose (FPG), LDL-C, HDL-C, total cholesterol (TC), and triglyceride (TG). Results The levels of ANGPTL2 and ANGPTL3 were significantly higher in obese subjects than those in controls, but they did not differ significantly in subjects with or without IR. ANGPTL3 was found to be significantly elevated in obese children with metabolic syndrome (MetS) in comparison with those without MetS. Both of the studied ANGPTLs were positively correlated with BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, and LDL-C. The correlation between ANGPTL3 and either TC or LDL-C remained significant after adjusting for BMI. Conclusion Serum ANGPTL2 and ANGPTL3 were elevated in obesity and associated with blood pressure and indices of metabolic syndrome, suggesting that they might be involved in the advancement of obesity-related hypertension and metabolic syndrome.

Evaluation of serum Angiopoietin-like protein 2 (ANGPTL-2), Angiopoietin-like protein 8 (ANGPTL-8), and high-sensitivity C-reactive protein (hs-CRP) levels in patients with gestational diabetes mellitus and normoglycemic pregnant women

Objective In the present study, we aimed to investigate the role of the fasting serum levels of Anjiopoetın 2 - like protein (ANGPTL2), Anjiopoetın 8-like protein (ANGPTL8), and high-sensitivity C-reactive protein (hs-CRP) in the etiopathogenesis of gestational diabetes mellitus (GDM), and analyze the relationships between insulin resistance parameters. Material and method The 90 individuals admitted to İzmir Katip Celebi University Hospital Internal Medicine, Endocrinology and Obstetrics, and gynecology outpatient clinic were included in the study of similar ages and similar demographic characteristics. Forty-five women with diet-controlled GDM and 45 women with normoglycemic pregnancy were enrolled. ANGPTL-2, ANGPTL-8, hs-CRP, creatinine, ALT, GGT, lipid profile, HBA1c(%), and serum insülin, c-peptide levels were studied in the fasting serum samples of research groups. All individuals had 75-g OGTT testing. GDM screening was performed at 24–28 weeks’ gestation. Exclusion criteria were as follows: Age <18 years or >40 years, pregestational diabetes (type 1 or 2), drug or alcohol abuse, thyroid dysfunction, Hepatitis B, and other infectious diseases (Herpes virus, Streptococcus B carriers, Chlamydia and Candida), Thalassemia carriers or other significant medical conditions, the use of any medication that interferes with lipid or glucose metabolism that would affect glucose regulation. Result Forty-five women with GDM and for the control group, 45 women with normoglycemic pregnant women were identified. The mean gestational age was 30.7 (18–38) for GDM and 29.6 (24–39) for the control group. Serum ANGPTL-8 (GDM =19.5 ± 93 Control = 0.73 ± 3.78 p = <.001). There was a statistically significant difference between the case and control groups for serum ANGPTL-8 levels. Serum ANGPTL-2 (GDM =19.9 ± 23.1 Control = 26.0 ± 23.4 p = .105) and serum hs-CRP(GDM =106 ± 65.1 Control =98.2 ± 87.3 p = .768). There was no statistically significant difference between the case and control groups for serum ANGPTL-2 and hsCRP levels. Serum ANGPTL8 levels were positively correlated with FPG (r = 0.391, p = <.001), FPI (r = 0.212, p = .045), 1-h PPG (r = 0.514, p = <.001), 2-h PPG (r = 0.502, p = <.001), HOMA-IR) score (r = 0.310, p = .003), TG (r = 0.245, p = .020); they were not except for BMI, hs-CRP levels and ANGPTL2 levels. Conclusions ANGPTL8 levels were significantly higher in GDM than in healthy control group. ANGPTL2 levels and hs-CRP levels were similar to the healthy control group. Elevated serum ANGPTL8 levels were correlated significantly with insulin resistance parameters, the main component of GDM pathophysiology. Our data showed that ANGPTL8 could be a new biomarker for diagnosing GDM.

Higher levels of circulating ANGPTL2 are associated with macular edema in patients with type 2 diabetes.

Macular edema (ME) is an inflammatory disease characterized by increased microvascular permeability. Here, we proposed that plasma angiopoietin-like protein 2 (ANGPTL2) level may be related to the severity of ME patients with type 2 diabetes mellitus (T2DM). In this cross-sectional study, 172 T2DM patients were recruited and divided into clinically significant macular edema (CSME), non-CSME (nCSME), and control groups. Serum ANGPTL2 level was quantified by ELISA and best corrected vision acuity (BCVA) was detected. After adjust age, sex, body mass index (BMI), and duration of diabetes variables, ANGPTL2 performed statistics difference among CSME-, nCSME-groups, and control group (4.46 [3.97, 4.96, 95%CI] ng/mL in CSME group, 3.80 [3.42, 4.18, 95%CI] ng/mL in nCSME-group, 3.33 [3.03, 3.63, 95%CI] ng/mL in control, P < .01). After adjustment of confounding factors, high levels of circulating ANGPTL2 were related with the diagnosis of ME, BCVA, and C reactive protein (CRP) through univariate regression analysis (P < .05). Meanwhile, in the multiple regression model, ANGPTL2 took the mainly effect proportion for the diagnosis of diabetic macular edema (DME), with a LogWorth value 3.559 (P < .001). Our study suggested that elevated circulating ANGPTL2 may be associated with the development of DME and the severity of visual impairment in patients with type 2 diabetes.

Effects of aerobic exercise training on circulating angiopoietin-like protein 2 in overweight and obese men: a pilot study

Background and objective: Angiopoietin-like protein 2 (ANGPTL2) is a pro-inflammatory adipokine that is upregulated in obesity and plays a role in the progression of cardiometabolic diseases, including diabetes and atherosclerosis. Aerobic exercise is one of the effective strategies for reducing the levels of various pro-inflammatory biomolecules in obese individuals. However, the effects of aerobic exercise training on circulating ANGPTL2 levels in obese individuals remain unclear. The objective of this study was to investigate the effect of aerobic exercise training on serum ANGPTL2 levels in overweight and obese men.Material and methods: Twenty overweight and obese men (age, 49 ± 10 years; body mass index, 27.4± 2.2 kg/m2) completed a 12-week aerobic exercise training program (60–85% Heart ratemax, 40–60 min/day, 3 days/week). Before and after the exercise program, serum ANGPTL2 levels were measured using the enzyme-linked immunosorbent assay. Daily step counts and the different physical activities based on the intensity were assessed using a triaxial accelerometer.Results: Serum ANGPTL2 levels were significantly decreased after the 12-week aerobic exercise training program ((3.0 ± 0.6) vs. (2.7 ± 0.7) ng/mL, P < 0.05). Daily step counts ((8362 ± 4551) vs.(10357 ± 3168) steps/day, P < 0.05) and moderate- to vigorous-intensity physical activity (MVPA) time ((58 ± 45) vs. (76 ± 37) min/day, P < 0.001) were significantly increased after the exercise intervention. The changes in serum ANGPTL2 levels were negatively correlated with corresponding changes in daily step counts (partial r = –0.49, P < 0.05) and MVPA time (partial r = –0.47, P < 0.05) after adjustment for age and accelerometer wear time.Conlcusion: These findings collectively suggest that aerobic exercise training, in particular an increase in MVPA, can be associated with decreased circulating levels of ANGPTL2 in overweight and obese men.

Angiopoietin-like protein 2 in psoriasis: a new linkage with metabolic syndrome.

IntroductionPsoriasis is a chronic disease of inflammatory nature which can be considered as a systemic disorder. Metabolic syndrome is prevalent in psoriatic patients, with a negative impact on disease severity. Angiopoietin-like protein 2 (ANGPTL2) role has been investigated in several chronic inflammatory conditions, but not in psoriasis.AimTo evaluate the serum level of ANGPTL2 and its possible role in the occurrence of metabolic syndrome in psoriatic patients.Material and methodsThis study enrolled 180 participants divided into two groups: psoriatic group (120 patients with chronic plaque psoriasis) and control group (60 normal subjects). Psoriasis severity was determined by the psoriasis area severity index. Anthropometric measurements, lipid profile, fasting blood sugar and ANGPTL2 have been evaluated in both groups.ResultsPsoriatic patients had a higher body mass index (p = 0.014), waist circumference (p < 0.001), and blood pressure than controls (p Ł 0.001). Fasting blood sugar and the serum level of ANGPTL2 were also higher in psoriatic patients than in controls (p < 0.001, 0.025, respectively). In addition, the serum level of ANGPTL2 was significantly correlated with both disease severity (p < 0.001) and occurrence of metabolic syndrome (p < 0.001).ConclusionsSerum ANGPTL2 is elevated in psoriasis patients compared to normal subjects. Serum ANGPTL2 elevation may have a role in chronic inflammatory status in psoriasis and occurrence of metabolic syndrome.

Dietary modification reduces serum angiopoietin-like protein 2 levels and arterial stiffness in overweight and obese men.

Weight loss can reduce obesity-induced arterial stiffening that is attributed to decreased inflammation. Angiopoietin-like protein 2 (ANGPTL2) is a pro-inflammatory adipokine that is upregulated in obesity and is important in the progression of atherosclerosis and cardiovascular disease. The purpose of this study is to investigate the effects of dietary modification on circulating ANGPTL2 levels and arterial stiffness in overweight and obese men. Twenty-two overweight and obese men (with mean age of 56 ± 2 years and body mass index of 28.6 ± 2.6 kg/m2) completed a 12-week dietary modification program. We measured the arterial compliance and β-stiffness index (as the indices of arterial stiffness) and serum ANGPTL2 levels before and after the program. After the 12-week dietary modification, body mass and daily energy intake were significantly reduced. Arterial compliance was significantly increased and β-stiffness index was significantly decreased after the 12-week dietary modification program. Serum ANGPTL2 levels were significantly decreased. Also, the changes in arterial compliance were negatively correlated with the changes in serum ANGPTL2 levels, whereas the changes in β-stiffness index were positively correlated with the changes in serum ANGPTL2 levels. These results suggest that the decrease in circulating ANGPTL2 levels can be attributed to the dietary modification-induced reduction of arterial stiffness in overweight and obese men.

Diagnostic value of angiopoietin-like protein 2 for CHB-related hepatocellular carcinoma.

PurposeAngiopoietin-like protein 2 (ANGPTL2) is a secretory glycoprotein with various functions in vascular biology, inflammation and tumor development. As shown in our previous studies, ANGPTL2 expression positively correlates with liver fibrosis stages in chronic hepatitis B (CHB) patients. The aim of this study was further to assess whether ANGPTL2 represents a potential biomarker for detecting hepatocellular carcinoma (HCC).Patients and methodsThis study enrolled 361 participants including healthy controls (HCs) and patients with CHB, liver cirrhosis (LC) and HCC. A discovery cohort consisted of 35 HCs and 55 patients with HCC. A total of 271 participants, including 45 HCs, 125 patients with CHB, 38 patients with LC, and 63 patients with HCC were enrolled in a validation cohort. Serum ANGPTL2 levels were detected using a human ANGPTL2 assay kit, and hepatic expression of ANGPTL2 was analyzed using immunohistochemistry.ResultsIn the discovery cohort, a significantly higher serum ANGPTL2 level was detected in HCC than in HCs (73.49±33.87 vs 30.54±9.86; p<0.001). The results of the receiver operating characteristic curve indicated a significantly higher area under the curve for the ability of the ANGPTL2 to predict HCC than alpha fetoprotein (AFP). In the validation cohort, serum ANGPTL2 level gradually increased with the progression of chronic hepatitis B virus infection and reached the highest level in HCC. Immunohistochemical staining also confirmed these findings. The serum ANGPTL2 displayed better diagnostic efficiency not only for differentiating HCC from HC but also for differentiating HCC from high-risk controls (CHB+LC). Furthermore, the combination of ANGPTL2 and AFP may increase the diagnostic accuracy for HCC compared to ANGPTL2 or AFP alone. Importantly, ANGPTL2 levels also correlated with the detection of AFP-negative HCC.ConclusionsANGPTL2 may be used as a promising biomarker for the diagnosis of CHB-related HCC.

Angiopoietin-Like Protein 2 Promotes the Progression of Diabetic Kidney Disease

Angiopoietin-like protein 2 (ANGPTL2) is a circulating, proinflammatory protein. To examine the role of ANGPTL2 in the pathogenesis of diabetic kidney disease (DKD), we studied the epigenetic regulation of angptl2 expression in patients with diabetes. We determined the relationship between serum ANGPTL2 levels and the progression of DKD in cross-sectional (220 patients) and cohort (145 patients, 7-year follow-up) studies. Furthermore, we investigated the direct effect of ANGPTL2 on podocyte function. The main outcome was progression of DKD. We found that the expression of angptl2 was decreased by the methylation of its promoter region. Multivariate logistic regression analyses revealed that the baseline level of serum ANGPTL2 was an independent risk factor for the progression of DKD during follow-up periods. In cultured podocytes, ANGPTL2 directly increased albumin permeability through the translocation of zonula occludens-1 from the membrane to the cytosol via activation of focal adhesion kinase. ANGPTL2 might be directly involved in podocyte dysfunction and independently associated with the progression of DKD stages.

Angiopoietin-like Protein 2 is a Useful Biomarker for Pancreatic Cancer that is Associated with Type 2 Diabetes Mellitus and Inflammation.

Pancreatic cancer is one of the tumors with the worst prognosis, with the 5-year survival rate reported to be 6%. The number of patients suffering from pancreatic cancer in recent years has continued to increase dramatically. Carbohydrate antigen 19-9 is an established biomarker of pancreatic cancer, but it does not have sufficient ability to detect pancreatic cancer at an early stage. We focused on angiopoietin-like protein 2 (ANGPTL2), which has been reported to be related to chronic inflammation and Type 2 diabetes mellitus. In this study, whether ANGPTL2 can detect early pancreatic cancer was evaluated. It was found that the concentration of serum ANGPTL2 was significantly higher in pancreatic cancer patients and tumor stage 0-I patients than in healthy individuals (5.84 ± 1.82 ng/mL vs 3.61 ± 0.64 ng/mL; P < 0.001) (5.68 ± 0.79 ng/mL vs 3.61 ± 0.64 ng/mL; P = 0.010). In addition, the diagnostic capability of serum ANGPTL2 levels for pancreatic cancer was evaluated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) for ANGPTL2 was 0.906 (95% confidence interval (CI): 0.815-0.997; P < 0.001). To identify the risk factors for pancreatic cancer, multivariate regression models were used. Ten factors were included, and increasing age (odds ratio (OR), 1.318, 95% CI, 1.058-1.642; P = 0.014) and high ANGPTL2 levels (OR, 22.219, 95% CI, 1.962-251.659, P = 0.012) were found to be independent risk factors for pancreatic cancer, with ANGPTL2 having the strongest relationship. In addition, serum ANGPTL2 levels were strongly correlated with inflammatory markers, with blood sugar levels showing the strongest correlation with serum ANGPTL2 levels. In conclusion, this study suggested that an elevated serum ANGPTL2 level has the potential to be a biomarker capable of early detection of pancreatic cancer, and it was correlated with inflammation of the pancreas and the risk of developing diabetes mellitus.

Diagnostic and Prognostic Value of Serum Angiopoietin-Like Protein 2 in Patients with Non-Small Cell Lung Cancer.

Elevated serum angiopoietin-like protein 2 (ANGPTL2) level has been observed in several different types of cancer, but it remains unclear in non-small cell lung cancer (NSCLC). The present study aimed to explore serum ANGPTL2 in sera from NSCLC patients and analyze the association of serum ANGPTL2 with patient diagnosis and prognosis. Enzyme Linked Immunosorbent Assay (ELISA) was used to measure serum ANGPTL2 concentration. The associations of serum ANGPTL2 level with clinicopathological characteristics of NSCLC patients were further analyzed. ROC/AUC analysis and Kaplan-Meier analysis were performed to evaluate its diagnostic and prognostic value in NSCLC patients. Serum ANGPTL2 was significantly higher in NSCLC patients (8.38 ± 1.73 vs. 4.87 ± 0.96 ng/mL; p < 0.01). Higher serum ANGPTL2 could be observed in NSCLC patients with late TNM stage, lymph node metastases, distant metastases, and poor differentiation compared to those with early TNM stage, without metastases, and well/moderate differentiation. The ROC/AUC analysis yielded an AUC of 0.86 (0.83 - 0.90) (sensitivity of 0.83, specificity of 0.82) to distinguish NSCLC patients from normal controls, while serum ANGPTL2 was also an efficient indicator to distinguish NSCLC patients with late clinical stage from early stages with an AUC of 0.92 (95% CI 0.89 - 0.95) with sensitivity of 0.91, specificity of 0.86. Prognostic analysis showed that NSCLC patients with high serum ANGPTL2 levels had lower survival rates than those with low levels (p < 0.01 for log-rank test). Serum ANGPTL2 levels were significantly increased in NSCLC patients, which could serve as a novel potential diagnostic and prognostic biomarker for NSCLC.

Association between Maternal Serum Concentrations of Angiopoietin-like Protein 2 in Early Pregnancy and Subsequent Risk of Gestational Diabetes Mellitus.

Background:A recent study reported a positive association between elevated serum levels of angiopoietin-like protein 2 (ANGPTL2) and the development of type 2 diabetes in a general population. However, the relationship of serum ANGPTL2 levels with the risk of developing gestational diabetes mellitus (GDM) has not been reported to date. The aim of this study was to investigate the change of maternal serum ANGPTL2 concentrations in the first trimester of pregnancy and to determine whether ANGPTL2 is a biomarker for subsequent GDM development.Methods:We conducted a prospective, nested case-control study in a pregnancy cohort. First-trimester ANGPTL2 levels were measured using a high-resolution assay in 89 women who subsequently developed GDM and in a random sample of 177 women who remained euglycemic throughout the pregnancy. Median ANGPTL2 levels were compared using Mann-Whitney U-test. Logistic regression was used to compute unadjusted and multivariable-adjusted odds ratios for developing GDM among ANGPTL2 quartiles.Results:The serum levels of ANGPTL2 was higher in women with GDM than that in women without GDM (3.06 [2.59, 3.65] ng/ml vs. 2.46 [2.05, 2.96] ng/ml, P = 0.003). Fasting blood glucose was higher in women with GDM than that in women without GDM (5.0 ± 0.9 mmol/L vs. 4.4 ± 0.6 mmol/L, P < 0.001). Glucose challenge test showed that the blood glucose was higher in women with GDM than that in women without GDM (9.1 ± 3.5 mmol/L vs. 6.2 ± 1.2 mmol/L, P < 0.001). A multivariate model adjusted for baseline characteristics, medical complications, and gestational characteristics revealed that the risk of developing GDM among women in Q4 compared with Q1 was 2.90-fold more likely to develop GDM later in pregnancy.Conclusions:At 11–13 weeks in pregnancies that develop GDM, the serum concentration of ANGPTL2 is increased, and it can be combined with maternal factors to provide effective early screening for GDM.

Serum Angiopoietin-Like Protein 2 Is a Novel Risk Factor for Cardiovascular Disease in the Community: The Hisayama Study.

Angiopoietin-like protein 2 (ANGPTL2), a proinflammatory mediator, has been reported to accelerate the development of insulin resistance, endothelial dysfunction, and atherosclerosis in mice. However, no cohort studies have examined the relationship between serum ANGPTL2 levels and the development of cardiovascular disease (CVD) in a general population. A total of 3005 community-dwelling Japanese aged ≥40 years without a history of CVD were divided into 4 groups according to the quartiles of serum ANGPTL2 concentrations (Q1, lowest and Q4, highest) and followed up for 10 years. The hazards ratios and their 95% confidence intervals for the development of CVD (coronary heart disease or stroke) were estimated using a Cox proportional hazards model. During the follow-up, 219 first-ever CVD events were observed. The risk of CVD increased significantly with elevating ANGPTL2 levels after adjustment for age, sex, serum total cholesterol, use of lipid-lowering agents, ECG abnormalities, smoking habits, alcohol intake, and regular exercise (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.27 [0.80-2.04]; Q3, 1.48 [0.95-2.32]; and Q4, 1.85 [1.20-2.85]; P=0.003 for trend). After additional adjustment for metabolic syndrome components and serum high-sensitivity C-reactive protein levels as an inflammatory marker, the association was attenuated but remained significant (hazards ratios [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.21 [0.76-1.94]; Q3, 1.38 [0.87-2.17]; and Q4, 1.66 [1.05-2.60]; P=0.02 for trend). Our findings suggest that elevated serum ANGPTL2 levels are a novel risk factor for the development of CVD in the general population. This association is partially mediated by metabolic disorders and inflammation.

Relationship between serum angiopoietin-like protein 2 and plaque vulnerability in patients with coronary artery disease and diabetes.

Obesity is characterized by low-grade inflammation state and excessive inflammatory cytokine production of adipose tissue. Angiopoietin-like protein 2 (ANGPTL2), a novel proinflammatory adipokine, has recently been suggested to be involved in the pathogenesis of atherosclerosis in animal studies. However, no data regarding the relationship between ANGPTL2 and morphologic characteristics of coronary plaques in humans are available. The aim of the current study was to investigate the in vivo association between serum ANGPTL2 level and plaque vulnerability in patients with coronary artery disease (CAD) and diabetes. 72 consecutive patients with clinically proven CAD and diabetes were enrolled between October 2013 and December 2014. Circulating ANGPTL2 concentration was measured using a human ANGPTL2 sandwich enzyme-linked immunosorbent assay (ELISA) kit. The morphologic characteristics of non-culprit lipid-rich plaques were assessed by optical coherence tomography. Fibrous cap thickness was significantly and negatively correlated with serum ANGPTL2 levels (r = -0.29, P = 0.005). A significant and positive correlation was observed between mean lipid core arc and serum ANGPTL2 concentration (r = 0.32, P = 0.01). In addition, levels of serum ANGPTL2 were significantly higher in patients with thin-cap fibroatheroma (TCFA) than those without TCFA (P < 0.001). Multivariate logistic regression analysis showed that a higher serum ANGPTL2 concentration was a powerful predictor of TCFA (odds ratio: 3.18, P = 0.002). Serum ANGPTL2 level is significantly associated with plaque vulnerability in patients with CAD and diabetes. Systemic ANGPTL2 comprises an inflammatory adipokine that links the adipose tissue and coronary plaque.

Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients.

Chronic inflammation of gastric mucosa by Helicobacter pylori infection can initiate gastric carcinogenesis. As angiopoietin-like protein 2 (ANGPTL2) mediates inflammation and inflammation-associated carcinogenesis, we investigated the functional and clinical significance of ANGPTL2 in human gastric cancer (GC). SiRNA knockdown studies were performed for the functional assessment of ANGPTL2 in GC cell lines. ANGPTL2 expression was evaluated immunohistochemically in 192 tissue specimens from GC patients. In addition, we screened serum ANGPTL2 levels from 32 GC patients and 23 healthy controls; and validated these results in 194 serum samples from GC patients and 45 healthy controls by ELISA. ANGPTL2 knockdown caused anoikis and inhibited proliferation, invasion and migration in GC cells. ANGPTL2 expression was upregulated in GC tissues compared to normal gastric mucosa; and high ANGPTL2 expression was significantly associated with tumor progression, early recurrence (P = 0.003) and poor prognosis (P = 0.007). Serum ANGPTL2 in GC patients was significantly higher than for healthy controls (P < 0.05), and accurately distinguished GC patients from healthy control (AUC = 0.865). The validation step confirmed significantly higher serum ANGPTL2 levels in GC patients than healthy controls (P < 0.0001). Receiver operating characteristic curves yielded robust AUC value (0.831) accompanied by high sensitivity (73.0%) and specificity (82.2%) in distinguishing GC patients from healthy controls. High serum ANGPTL2, rather than its expression in matched tissues, was significantly associated with tumor progression, and emerged as an independent marker for recurrence (HR: 5.05, P = 0.0004) and prognosis (HR: 3.6, P = 0.01). Serum ANGPTL2 expression is a potential noninvasive biomarker for diagnosis, early recurrence and prognosis of GC patients.

Serum Angiopoietin-Like Protein 2 Concentrations Are Independently Associated with Heart Failure.

ObjectiveAngiopoietin-like protein 2 (ANGPTL2), which is mainly expressed from adipose tissue, is demonstrated to be involved in obesity, metabolic syndrome, and atherosclerosis. Because several adipocytokines are known to be associated with heart failure (HF), here we investigated the association of ANGPTL2 and HF in Taiwanese subjects.Methods and ResultsA total of 170 symptomatic HF patients and 130 age- and sex-matched controls were enrolled from clinic. The echocardiography was analyzed in each patient, and stress myocardial perfusion study was performed for clinical suspicion of coronary artery disease. Detailed demographic information, medications, and biochemical data were recorded. Circulating adipocytokines, including tumor necrosis factor-alpha (TNF-α), adiponectin, adipocyte fatty acid-binding protein (A-FABP) and ANGPTL2, were analyzed. Compared with the control group subjects, serum ANGPTL2 concentrations were significantly higher in HF group patients. In correlation analyses, ANGPTL2 level was positively correlated to creatinine, fasting glucose, triglyceride, hsCRP, TNF-α, NT-proBNP and A-FABP levels, and negatively correlated with HDL-C and left ventricular ejection fraction. In multiple regression analysis, A-FABP, hsCRP, and HDL-C levels remained as independent predictors for ANGPTL2 level. To determine the association between serum ANGPTL2 concentrations and HF, multivariate logistic regression analyses were performed with subjects divided into tertiles by ANGPTL2 levels. For the subjects with ANGPTL2 levels in the highest tertile, their risk of HF was about 2.97 fold (95% CI = 1.24–7.08, P = 0.01) higher than those in the lowest tertile.ConclusionOur results demonstrate a higher circulating ANGPTL2 level in patients with HF, and the upregulating ANGPTL2 levels might be associated with metabolic derangements and inflammation.

Association of serum angiopoietin-like protein 2 with carotid intima-media thickness in subjects with type 2 diabetes

BackgroundAlthough recent animal studies have suggested that angiopoietin-like protein 2 (ANGPTL2), a novel inflammatory adipokine, is likely to be involved in the pathogenesis of atherosclerosis, in rodents, little is known regarding whether serum ANGPTL2 level is also associated with atherosclerosis in humans, especially in patients with type 2 diabetes. The aim of this study was to investigate whether serum ANGPTL2 concentration is associated with atherosclerosis by measuring carotid intima-media thickness (IMT) in subjects with type 2 diabetes without previous history of cardiovascular diseases. In addition, we examined the clinical and biochemical variables associated with serum ANGPLT2 concentration.MethodsWe measured the circulating ANGPTL2 level in 166 subjects (92 men and 74 women; mean age of 60.0 years) with type 2 diabetes. Measurements of carotid IMT were performed in all subjects.ResultsSerum ANGPTL2 concentration was positively correlated with carotid IMT (r = 0.220, p = 0.004). In multiple linear regression, serum ANGPTL2 concentration was independently associated with increased carotid IMT along with older age, male gender, and higher systolic blood pressure. Higher levels of hemoglobin A1c and high-sensitivity C-reactive protein were significantly associated with elevated serum ANGPTL2 concentration in subjects with type 2 diabetes.ConclusionsSerum ANGPTL2 concentration was significantly and positively associated with carotid atherosclerosis in patients with type 2 diabetes, suggesting that ANGPTL2 may be important in the atherosclerosis in humans.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0198-z) contains supplementary material, which is available to authorized users.

Angiopoietin-like protein 2 as a novel biomarker for diagnosis and prognosis in esophageal cancer.

73 Background: Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein with homology to the angiopoietins and overexpression of ANGPTL2 is known to act as a causative mediator of chronic inflammatory carcinogenesis. Recently, expression in tumor cells which are associated with tumor progression has been recognized in lung, breast, colon and gastric cancer. However, to our knowledge, functional and clinical significance of ANGPTL2 expression has not been investigated in esophageal cancer (EC). Aim: We investigated the functional roles of ANGPTL2 in vitro assay and evaluated the clinical significance of ANGPTL2 expression in both primary tumor and matched serum in patients with EC. Materials and Methods: First, in vitro assays were performed for functional analysis of ANGPTL2 using small interfering RNA (siRNA). Next, ANGPTL2 expression in EC tissues was evaluated by immunohistochemically (IHC) in 71 EC patients. Finally, we investigated serum ANGPLT2 levels from EC patients (n=71) and healthy controls (n=35) by ELISA. Results: Knockdown of ANGPTL2 expression decreased proliferative, invasive and migrated capacity in EC cell lines. ANGPTL2 expression in EC tissues was significantly elevated in EC patients with high T stage, squamous cell carcinoma, and high TNM stage. Kaplan–Meier analysis showed that patients with high expression of ANGPTL2 had significantly poorer overall (p&lt;0.01) and disease-free survival (p&lt;0.01) than those with low expression, respectively. Furthermore, multivariate analysis revealed that high ANGPTL2 expression in EC tissues was an independent predictive marker for poor prognosis (HR: 2.30, p=0.04). On the other hands, serum ANGPTL2 levels in EC patients was significantly elevated compared to healthy controls (p&lt;0.001), and it can discriminate EC patients from healthy controls with high accuracy (AUC=0.913). However, no significant association between serum ANGPTL2 levels and clinicopathological findings were recognized in EC patients. Conclusions: We have demonstrated several novel evidences for biological and clinical significance of ANGPTL2 in EC. This study indicates ANGPTL2 had the potential to be useful as a biomarker in EC.

Angiopoietin-Like Protein 2 Acts as a Novel Biomarker for Diagnosis and Prognosis in Patients with Esophageal Cancer.

Angiopoietin-like protein 2 (ANGPTL2) mediates chronic inflammation. Tumor cell-derived ANGPTL2 promotes tumor invasion and angiogenesis. Overexpression of ANGPTL2 in tumor cells is associated with tumor progression and has been recognized in lung, breast, colon, and gastric cancer. However, to our knowledge the functional and clinical significance of ANGPTL2 expression has not been investigated in patients with esophageal cancer (EC). First, in vitro assays were performed for functional analysis of ANGPTL2 using small interfering RNA. Next, ANGPTL2 expression in EC tissues (n=71) was evaluated by immunohistochemistry (IHC in patients with EC (n=71). Finally, serum ANGPLT2 levels from patients with EC (n=71) and healthy controls (n=35) were evaluated using enzyme-linked immunosorbent assay. Knockdown of ANGPTL2 expression decreased the proliferative, invasive, and migration capacity in EC cell lines. ANGPTL2 expression in EC tissues was significantly elevated in patients with a high T stage, squamous cell carcinoma, and high TNM stage. Patients with high ANGPTL2 expression had significantly poorer overall and disease-free survival than those with low expression. Furthermore, high ANGPTL2 expression in EC tissues was an independent predictive marker for a poor prognosis. On the other hand, the serum ANGPTL2 level in patients with EC was significantly higher than that in healthy controls, and allowed for highly accurate discrimination between patients with and without EC. However, no significant association between serum ANGPTL2 levels and clinicopathological findings was observed in patients with EC. We have demonstrated novel evidence for the clinical significance of ANGPTL2 as a biomarker in patients with EC.