Abstract
Objectives
We previously observed an association between ovarian cancer outcome and statin use and hypothesized lipoproteins have direct effects on ovarian cancer proliferation. Here we investigate the direct effects of low density lipoprotein (LDL) and oxidized LDL (oxLDL) on proliferation and the inhibitory effects of fluvastatin and a liver X receptor (LXR) agonist.
Methods
The effects of LDL, oxLDL, the LXR agonist TO901317, fluvastatin and cisplatin on cellular proliferation were determined using MTT assays. LXR pathway proteins were assayed by immunoblotting. Cytokine expression was determined by antibody array.
Results
Concentrations of oxLDL as small as 0.1 μg/ml stimulated CAOV3 and SKOV3 proliferation, while LDL had no effect. TO901317 inhibited the proliferation of CAOV3, OVCAR3 and SKOV3 cells stimulated by oxLDL. Fluvastatin inhibited oxLDL mediated proliferation of CAOV3 and SKOV3. Cardiotrophin 1 (CT-1) was mitogenic to CAOV3 and SKOV3, was induced by oxLDL, and was reversed by TO901317. OxLDL increased cisplatin IC50s by 3.8 μM and > 60 μM for CAOV3 and SKOV3 cells, respectively. The LXR pathway proteins CD36, LXR, and ABCA1 were expressed in eight ovarian carcinoma cell lines (A2780, CAOV3, CP70, CSOC882, ES2, OVCAR3, SKOV3).
Conclusions
OxLDL reduced ovarian carcinoma cell chemosensitivity and stimulated proliferation. These effects were reversed by LXR agonist or fluvastatin. The LXR agonist also inhibited expression of the ovarian cancer mitogen CT-1. These observations suggest a biologic mechanism for our clinical finding that ovarian cancer survival is associated with statin use. Targeting LXR and statin use may have a therapeutic role in ovarian cancer.
Daniel R. Scolesa, b, , , Xuan Xua, Haimei Wangc, Hang Trana, Barbie Taylor-Hardingb, Andrew Lia, b and Beth Y. Karlana, b
aWomen's Cancer Research Institute and Division of Gynecologic Oncology, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, USA
bDepartment of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
cDivision of Cardiothoracic Surgery, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, USA
Received 17 April 2009. Available online 24 October 2009.
Thursday
Liver X receptor agonist inhibits proliferation of ovarian carcinoma cells stimulated by oxidized low density lipoprotein
Tuesday
Reconstituted High-Density Lipoprotein Increases Plasma High-Density Lipoprotein Anti-Inflammatory Properties and Cholesterol Efflux Capacity in Patie
Abstract
Objectives: Our aim was to investigate the effects of reconstituted high-density lipoprotein (rHDL) infusions on plasma high-density lipoprotein (HDL) anti-inflammatory properties and ex vivo cholesterol efflux in patients with type 2 diabetes.
Background: The anti-inflammatory effects of HDL contribute to protection from cardiovascular events. Individuals with type 2 diabetes are at elevated risk for cardiovascular disease, and typically have low HDL with reduced anti-inflammatory properties.
Methods: Thirteen fasting male patients (mean age 52 years) with type 2 diabetes mellitus received both rHDL (80 mg/kg of apolipoprotein A-I) and a saline placebo on separate occasions in a randomized cross-over design study. Changes in the ability of isolated HDL to influence the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human coronary artery endothelial cells was the main outcome measure. Other outcome measures included expression of the key integrin, CD11b on patient monocytes, adhesiveness of patient neutrophils to fibrinogen, and the ability of plasma to promote cholesterol efflux to THP-1 macrophages.
Results: Four and 72 h post-rHDL infusion, the anti-inflammatory properties of isolated HDL increased in parallel to their concentration in plasma (by up to 25%, p < 0.01). Participants' peripheral blood monocyte CD11b expression and neutrophil adhesion to a fibrinogen matrix was also reduced 72 h post-rHDL, compared with that seen in placebo (p = 0.02). rHDL increased the capacity of plasma to receive cholesterol from THP-1 macrophages by 1 h up to 72 h post-infusion (by 40% to 60%, p < 0.05).
Conclusions: rHDL infusions have significant, potentially atheroprotective effects in individuals with diabetes, including suppression of inflammation and enhancement of cholesterol efflux.
Journal of the American College of Cardiology, Volume 53, Issue 11, Pages 962-971
S. Patel, B. Drew, S. Nakhla, S. Duffy, A. Murphy, P. Barter, K. Rye, J. Chin-Dusting, A. Hoang, D. Sviridov
Objectives: Our aim was to investigate the effects of reconstituted high-density lipoprotein (rHDL) infusions on plasma high-density lipoprotein (HDL) anti-inflammatory properties and ex vivo cholesterol efflux in patients with type 2 diabetes.
Background: The anti-inflammatory effects of HDL contribute to protection from cardiovascular events. Individuals with type 2 diabetes are at elevated risk for cardiovascular disease, and typically have low HDL with reduced anti-inflammatory properties.
Methods: Thirteen fasting male patients (mean age 52 years) with type 2 diabetes mellitus received both rHDL (80 mg/kg of apolipoprotein A-I) and a saline placebo on separate occasions in a randomized cross-over design study. Changes in the ability of isolated HDL to influence the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in human coronary artery endothelial cells was the main outcome measure. Other outcome measures included expression of the key integrin, CD11b on patient monocytes, adhesiveness of patient neutrophils to fibrinogen, and the ability of plasma to promote cholesterol efflux to THP-1 macrophages.
Results: Four and 72 h post-rHDL infusion, the anti-inflammatory properties of isolated HDL increased in parallel to their concentration in plasma (by up to 25%, p < 0.01). Participants' peripheral blood monocyte CD11b expression and neutrophil adhesion to a fibrinogen matrix was also reduced 72 h post-rHDL, compared with that seen in placebo (p = 0.02). rHDL increased the capacity of plasma to receive cholesterol from THP-1 macrophages by 1 h up to 72 h post-infusion (by 40% to 60%, p < 0.05).
Conclusions: rHDL infusions have significant, potentially atheroprotective effects in individuals with diabetes, including suppression of inflammation and enhancement of cholesterol efflux.
Journal of the American College of Cardiology, Volume 53, Issue 11, Pages 962-971
S. Patel, B. Drew, S. Nakhla, S. Duffy, A. Murphy, P. Barter, K. Rye, J. Chin-Dusting, A. Hoang, D. Sviridov
Thursday
Effects of sour tea on lipid profile and lipoproteins in patients with type II diabetes
OBJECTIVES: There is increasing evidence that intake of sour tea (Hibiscus sabdariffa) has hypoglycemic and hypolipidemic effects and may benefit patients suffering from metabolic disorders such as diabetes. The objective of the present study was to investigate the hypolipidemic effects of sour tea in patients with diabetes and compare them with those of black tea. DESIGN: In this sequential randomized controlled clinical trial, 60 patients with diabetes were recruited and randomly assigned into two groups: sour tea (ST) and black tea (BT). They were instructed to consume sour tea or black tea two times a day for 1 month. OUTCOME MEASURES: Fasting blood samples were taken at the beginning and at the end of the study for evaluation of lipids, lipoproteins, and apoproteins. RESULTS: Fifty-three (53) patients concluded the study. In the ST group, mean of high-density lipoprotein-cholesterol (HDLc) increased significantly (p = 0.002) at the end of the study, whereas changes in apolipoprotein-A1, and lipoprotein (a) were not significant. Also, a significant decrease in the mean of total cholesterol, low density lipoprotein-cholesterol, triglycerides, and Apo-B100 were seen in this group. In the BT group, only HDLc showed significant change (p = 0.002) at the end of the study and changes in the other measures were not statistically significant. CONCLUSIONS: The results of the present study showed that ST has a significant effect on blood lipid profile in patients with diabetes.
Mozaffari-Khosravi H, Jalali-Khanabadi BA, Afkhami-Ardekani M, Fatehi F.
Department of Nutrition, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Mozaffari-Khosravi H, Jalali-Khanabadi BA, Afkhami-Ardekani M, Fatehi F.
Department of Nutrition, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
Wednesday
Lipid treatment guidelines and cardiovascular risk for Aboriginal people in Central Australia
OBJECTIVE: To evaluate the extent to which the current Pharmaceutical Benefits Scheme (PBS) guidelines for patient eligibility for lipid-lowering medication are applicable to Aboriginal people in Central Australia.
DESIGN, SETTING AND PARTICIPANTS: A 10-year cohort study of 659 Aboriginal people who participated in population-based cardiovascular disease (CVD) risk factor surveys in 1995 and who were free of CVD at baseline, for the period from 1995 to 2004-2005 or until first CVD event. Evidence of atherosclerotic CVD (ischaemic heart disease, ischaemic stroke, and peripheral vascular disease) was sought from hospital, primary health care and death records. PBS eligibility was assigned according to the current PBS criteria, which were amended in 2006 to include Aboriginal-specific criteria, using participants' baseline (1995) and 10-year follow-up data.
MAIN OUTCOME MEASURES: Proportions of PBS-eligible and PBS-ineligible participants who had CVD events during the study period; sensitivity and specificity of the criteria. RESULTS: Of 42 participants who had CVD events during the study period, 35 were PBS-eligible (incidence, 1130/100 000 person-years; relative risk compared with PBS-ineligible population, 4.87 [95% CI, 2.19-10.80]) and seven were PBS-ineligible. PBS eligibility was associated with older mean age (37 v 32 years) and male sex (48% v 37%), with 50.7% of participants (334/659) meeting eligibility criteria. The mean high-density lipoprotein cholesterol level at baseline was very low in both groups (0.81 v 0.87 mmol/L). The current PBS guidelines have low specificity (52%) in this population, which was found to improve (to 71%-82%) by incorporating additional non-lipid criteria (age and multiple non-lipid risk factors).
CONCLUSION: The current PBS lipid treatment criteria, which include any Aboriginal person with diabetes and less stringent cholesterol thresholds than the previous version, identify a group at very high risk of CVD. Global risk assessment may better identify those at risk.
Onemda VicHealth Koori Health Unit, Centre for Health and Society, School of Population Health, University of Melbourne, Melbourne, VIC, Australia
DESIGN, SETTING AND PARTICIPANTS: A 10-year cohort study of 659 Aboriginal people who participated in population-based cardiovascular disease (CVD) risk factor surveys in 1995 and who were free of CVD at baseline, for the period from 1995 to 2004-2005 or until first CVD event. Evidence of atherosclerotic CVD (ischaemic heart disease, ischaemic stroke, and peripheral vascular disease) was sought from hospital, primary health care and death records. PBS eligibility was assigned according to the current PBS criteria, which were amended in 2006 to include Aboriginal-specific criteria, using participants' baseline (1995) and 10-year follow-up data.
MAIN OUTCOME MEASURES: Proportions of PBS-eligible and PBS-ineligible participants who had CVD events during the study period; sensitivity and specificity of the criteria. RESULTS: Of 42 participants who had CVD events during the study period, 35 were PBS-eligible (incidence, 1130/100 000 person-years; relative risk compared with PBS-ineligible population, 4.87 [95% CI, 2.19-10.80]) and seven were PBS-ineligible. PBS eligibility was associated with older mean age (37 v 32 years) and male sex (48% v 37%), with 50.7% of participants (334/659) meeting eligibility criteria. The mean high-density lipoprotein cholesterol level at baseline was very low in both groups (0.81 v 0.87 mmol/L). The current PBS guidelines have low specificity (52%) in this population, which was found to improve (to 71%-82%) by incorporating additional non-lipid criteria (age and multiple non-lipid risk factors).
CONCLUSION: The current PBS lipid treatment criteria, which include any Aboriginal person with diabetes and less stringent cholesterol thresholds than the previous version, identify a group at very high risk of CVD. Global risk assessment may better identify those at risk.
Onemda VicHealth Koori Health Unit, Centre for Health and Society, School of Population Health, University of Melbourne, Melbourne, VIC, Australia
Monday
Risk factors for aortic valve calcification in patients on regular hemodialysis
Urology and Nephrology Clinic, Kragujevac Clinical Center, Kragujevac - Serbia.
Introduction: Aortic valve calcification (AVC) accelerates development of aortic valve stenosis and cardiovascular complications. Hyperphosphatemia is one of the key risk factors for aortic valve calcification.
Aim: The aim of this study was to evaluate the prevalence of AVC in patients on regular hemodialysis and to assess the impact of different factors on its appearance. Method: The study investigated a total of 115 patients treated in the Hemodialysis Department of the Urology and Nephrology Clinic at the Kragujevac Clinical Center in Serbia. The variables investigated were: serum albumin, C-reactive protein (CRP), homocysteine, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG), Apolipoprotein A-I (Apo A-I), Apolipoprotein B (Apo B) and lipoprotein (a), calcium, phosphate and parathormone, and calcium-phosphorus product (Ca x P). Patients were evaluated by echocardiography for AVC. Statistical analysis included univariate and multivariate logistic regression analysis.
Results: Univariate regression analysis showed that serum phosphate levels and Ca x P are the most important risk factors for AVC (p<0.001). Multivariate logistic regression analysis revealed that hyperphosphatemia is an independent risk factor for AVC (p<0.001).
Conclusion: Hyperphosphatemia is an independent risk factor for aortic valve calcification.
Introduction: Aortic valve calcification (AVC) accelerates development of aortic valve stenosis and cardiovascular complications. Hyperphosphatemia is one of the key risk factors for aortic valve calcification.
Aim: The aim of this study was to evaluate the prevalence of AVC in patients on regular hemodialysis and to assess the impact of different factors on its appearance. Method: The study investigated a total of 115 patients treated in the Hemodialysis Department of the Urology and Nephrology Clinic at the Kragujevac Clinical Center in Serbia. The variables investigated were: serum albumin, C-reactive protein (CRP), homocysteine, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG), Apolipoprotein A-I (Apo A-I), Apolipoprotein B (Apo B) and lipoprotein (a), calcium, phosphate and parathormone, and calcium-phosphorus product (Ca x P). Patients were evaluated by echocardiography for AVC. Statistical analysis included univariate and multivariate logistic regression analysis.
Results: Univariate regression analysis showed that serum phosphate levels and Ca x P are the most important risk factors for AVC (p<0.001). Multivariate logistic regression analysis revealed that hyperphosphatemia is an independent risk factor for AVC (p<0.001).
Conclusion: Hyperphosphatemia is an independent risk factor for aortic valve calcification.
Tuesday
Risk Stratification of Apolipoprotein B, Apolipoprotein A1, and Apolipoprotein B/AI Ratio on the Prevalence of the Metabolic Syndrome: the ATTICA Stud
First Cardiology Clinic, School of Medicine, University of Athens, Greece
We investigated the association of apolipoproteins AI and B in relation to the prevalence of metabolic syndrome in a random sample of cardiovascular disease— free adults from the ATTICA study (1,514 men, aged 18-87 y; 1,528 women, aged 18-89 y). Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence of metabolic syndrome was 25% in men and 15% in women (P < .001). Using the area under the Receiver Operation Characteristic curve, apolipoprotein B/AI was the best diagnostic marker of metabolic syndrome, the optimal discriminating cut-off value of this ratio was 0.72 (sensitivity 74%, specificity 67%), and individuals with apolipoprotein B/AI ratio greater than 0.74 had 3.29 times higher odds of having metabolic syndrome (95% confidence interval: 2.56-4.21) after adjusting for potential confounders.
We investigated the association of apolipoproteins AI and B in relation to the prevalence of metabolic syndrome in a random sample of cardiovascular disease— free adults from the ATTICA study (1,514 men, aged 18-87 y; 1,528 women, aged 18-89 y). Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence of metabolic syndrome was 25% in men and 15% in women (P < .001). Using the area under the Receiver Operation Characteristic curve, apolipoprotein B/AI was the best diagnostic marker of metabolic syndrome, the optimal discriminating cut-off value of this ratio was 0.72 (sensitivity 74%, specificity 67%), and individuals with apolipoprotein B/AI ratio greater than 0.74 had 3.29 times higher odds of having metabolic syndrome (95% confidence interval: 2.56-4.21) after adjusting for potential confounders.
Thursday
Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis
To evaluate the therapeutic potential of an apolipoprotein A-1 (apoA-1) mimetic peptide, D-4F, in combination with pravastatin in collagen-induced arthritis (CIA), syngeneic Louvain rats were immunized with type II collagen and randomized to vehicle control, D-4F monotherapy, pravastatin monotherapy, or D-4F + pravastatin combination therapy. Clinical arthritis activity was evaluated and radiographs, type II collagen antibody titers, cytokine/chemokine levels, and HDL function analysis were obtained. There was significant reduction in clinical severity scores in the high and medium dose D-4F + pravastatin groups compared to controls (p ≤ 0.0001). Reduction in erosive disease occurred in the medium/high dose combination groups compared to non-combination groups (p ≤ 0.01). Favorable changes in cytokines/chemokines were noted with treatment, and response to combination D-4F/pravastatin therapy was associated with improvement in HDL's anti-inflammatory properties. Combination D-4F/pravastatin significantly reduced clinical disease activity in CIA, and may have dual therapeutic potential in other autoimmune diseases with increased cardiovascular morbidity and mortality.
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