Comparison of Lipoprotein-Associated Phospholipase A2 and High Sensitive C-Reactive Protein as Determinants of Metabolic Syndrome in Subjects without Coronary Heart Disease: In Search of the Best Predictor.

High sensitivity C-reactive protein (hsCRP) is a marker of metabolic syndrome (MS) and cardiovascular (CV) disease. Lipoprotein-associated phospholipase A2 (Lp-PLA2) also predicts CV disease. There are no reports comparing these markers as predictors of MS. Methods. Cross-sectional study comparing Lp-PLA2 and hsCRP as predictors of MS in asymptomatic subjects was carried out; 152 subjects without known atherosclerosis participated. Data were collected on demographics, cardiovascular risk factors, anthropometric and biochemical measurements, and hsCRP and Lp-PLA2 activity levels. A logistic regression analysis was performed with each biomarker and receiver operating characteristic (ROC) curves were constructed for MS. Results. Mean age was 46 ± 11 years, and 38% of the subjects had MS. Mean Lp-PLA2 activity was 185 ± 48 nmol/mL/min, and mean hsCRP was 2.1 ± 2.2 mg/L. Subjects with MS had significantly higher levels of Lp-PLA2 (P = 0.03) and hsCRP (P < 0.0001) than those without MS. ROC curves showed that both markers predicted MS. Conclusion. Lp-PLA2 and hsCRP are elevated in subjects with MS. Both biomarkers were independent and significant predictors for MS, emphasizing the role of inflammation in MS. Further research is necessary to determine if inflammation predicts a higher risk for CV events in MS subjects.

Receptor activator for nuclear factor-κB ligand signaling promotes progesterone-mediated estrogen-induced mammary carcinogenesis.

Breast cancer is a leading cause of cancer-related death in women. Prolonged exposure to the ovarian hormones estrogen and progesterone increases the risk of breast cancer. Although estrogen is known as a primary factor in mammary carcinogenesis, very few studies have investigated the role of progesterone. Receptor activator for nuclear factor-κB (NF-κB) ligand (RANKL) plays an important role in progesterone-induced mammary carcinogenesis. However, the molecular mechanism underlying RANKL-induced mammary carcinogenesis remains unknown. In our current study, we show that RANKL induces glioma-associated oncogene homolog 1 (GLI-1) in estrogen-induced progesterone-mediated mammary carcinogenesis. In vivo experiments were carried out using ACI rats and in vitro experiments were carried out in MCF-7 cells. In ACI rats, mifepristone significantly reduced the incidence of mammary tumors. Likewise, mifepristone also inhibited the proliferation of MCF-7 cells. Hormone treatments induced RANKL, receptor activator of NF-κB (RANK), and NF-κB in a protein kinase B-dependent manner and inhibited apoptosis by activation of anti-apoptotic protein Bcl2 in mammary tumors and MCF-7 cells. Mechanistic studies in MCF-7 cells reveal that RANKL induced upstream stimulatory factor-1 and NF-κB, resulting in subsequent activation of their downstream target GLI-1. We have identified that progesterone mediates estrogen-induced mammary carcinogenesis through activation of GLI-1 in a RANKL-dependent manner.

Niveles de fosfolipasa A2 asociada a lipoproteína en sujetos sin enfermedad coronaria con riesgo cardiovascular variable / Association of lipoprotein-associated phospholipase activity A2 with cardiovascular risk factors

Background:Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker involved in atherosclerosis and directly associated with cardiovascular events. Aim: To determine Lp-PLA2 levels in asymptomatic subjects with differing cardiovascular risk. Material and Methods: We studied 152 subjects aged 46 ± 11 years (69 women). We recorded traditional cardiovascular risk factors, creatinine, ultrasensitive C-reactive protein, fibrinogen, fasting lipids, blood sugar and activity levels of Lp-PLA2. Cardiovascular risk was classified according to the number of risk factors of each subject (0,1-2 or ≥ 3 risk factors). Besides, we calculated global Framingham risk score. Results: The average Framingham score of participants was 6%. Twenty percent of participants had no risk factors, 46% had 1 or 2 and 34% had ≥ 3. Mean Lp-PLA2 levels were 185 ± 48 nmol/ml/min (201 ± 49 in men and 166 ± 38 in women). Lp-PLA2 correlated significantly (p < 0,05 for all) with non-HDL cholesterol, LDL, HDL, creatinine, waist circumference, body mass index and Framingham risk score. There was no correlation with blood sugar, C-reactive protein, fibrinogen or smoking status. Lp-PLA2 levels were significantly higher according to the number of risk factors: 0 factors: 163 ± 43, 1-2 factors: 185 ± 45 and ≥ 3 factors: 201 ± 47 nmol/ml/min, respectively. Linear regression analysis showed that the best predictor of Lp-PLA2 was non-HDL cholesterol (β= 0,74; p < 0,0001). Conclusions: Lp-PLA2 activity increased along with the number of cardiovascular risk factors and was correlated mainly with non -HDL cholesterol.

[Association of lipoprotein-associated phospholipase activity A2 with cardiovascular risk factors]. / Niveles de fosfolipasa A2 asociada a lipoproteína en sujetos sin enfermedad coronaria con riesgo cardiovascular variable.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker involved in atherosclerosis and directly associated with cardiovascular events. AIM: To determine Lp-PLA2 levels in asymptomatic subjects with differing cardiovascular risk. MATERIAL AND METHODS: We studied 152 subjects aged 46 ± 11 years (69 women). We recorded traditional cardiovascular risk factors, creatinine, ultrasensitive C-reactive protein, fibrinogen, fasting lipids, blood sugar and activity levels of Lp-PLA2. Cardiovascular risk was classified according to the number of risk factors of each subject (0,1-2 or ≥ 3 risk factors). Besides, we calculated global Framingham risk score. RESULTS: The average Framingham score of participants was 6%. Twenty percent of participants had no risk factors, 46% had 1 or 2 and 34% had ≥ 3. Mean Lp-PLA2 levels were 185 ± 48 nmol/ml/min (201 ± 49 in men and 166 ± 38 in women). Lp-PLA2 correlated significantly (p < 0,05 for all) with non-HDL cholesterol, LDL, HDL, creatinine, waist circumference, body mass index and Framingham risk score. There was no correlation with blood sugar, C-reactive protein, fibrinogen or smoking status. Lp-PLA2 levels were significantly higher according to the number of risk factors: 0 factors: 163 ± 43, 1-2 factors: 185 ± 45 and ≥ 3 factors: 201 ± 47 nmol/ml/min, respectively. Linear regression analysis showed that the best predictor of Lp-PLA2 was non-HDL cholesterol (ß = 0,74; p < 0,0001). CONCLUSIONS: Lp-PLA2 activity increased along with the number of cardiovascular risk factors and was correlated mainly with non -HDL cholesterol.

Mammary cancer promotion by ovarian hormones involves IGFR/AKT/mTOR signaling.

In a previous study, we observed that N-methyl-N-nitrosourea (MNU)-induced mammary lesions are promoted to overt mammary cancers by exogenous administration of estradiol (E) and progesterone (P). The purpose of the present study was to identify the early molecular events occurring during the hormonal promotion of mammary carcinogenesis and persistent activation of molecular pathways responsible for tumor growth. Seven-week-old female Copenhagen (COP) rats, which are resistant to MNU-induced mammary carcinogenesis, were intraperitoneally administered a single dose of MNU (50 mg/kg body weight). Six weeks after carcinogen administration, the rats were treated with E+P, killed at 15th week and 43rd week to obtain mammary lesions and tumor tissues and the molecular analysis were performed. Quantitative RT-PCR experiments showed increased mRNA expression of Igfr, Grb2, Sos1, and Shc1 in mammary lesions and tumors. Immunoblot data also showed increased protein levels of IGFR, GRB2 and SHC1 in mammary lesions and tumors, which is in correlation with their respective RT-PCR data. Activation of AKT and ERK1/2 were up regulated in E+P treated mammary lesions and tumors. Molecular analysis of mTOR pathway proteins revealed increased phosphorylation of p70S6K and 4EBP1 in the hormone treated tumors indicating the activation of mTOR signaling. E+P treatment reduced the protein expression of BAX and increased BCL2 expression along with down regulation of active caspase 3 and 8. Together, these data demonstrate that ovarian hormones promote the lesions to mammary tumors by enhancing IGFR and Akt/mTOR signaling along with inhibition of apoptotic stimuli.