Showing papers on "Endothelial lipase published in 2012"

Fatty Acids Regulate Endothelial Lipase and Inflammatory Markers in Macrophages and in Mouse Aorta: A Role for PPARγ

Abstract: Objective—Macrophage endothelial lipase (EL) is associated with increased atherosclerosis and inflammation. Because of their anti-inflammatory properties we hypothesized that n-3 fatty acids, in contrast to saturated fatty acids, would lower macrophages and arterial EL and inflammatory markers. Methods and Results—Murine J774 and peritoneal macrophages were incubated with eicosapentaenoic acid or palmitic acid in the presence or absence of lipopolysaccaride (LPS). LPS increased EL mRNA and protein. Palmitic acid alone or with LPS dose-dependently increased EL mRNA and protein. In contrast, eicosapentaenoic acid dose-dependently abrogated effects of LPS or palmitic acid on increasing EL expression. EL expression closely linked to peroxisome proliferator activated receptor (PPAR)γ expression. Eicosapentaenoic acid blocked rosiglitazone (a PPARγ agonist)-mediated EL activation and GW9662 (a PPARγ antagonist)-blocked palmitic acid-mediated EL stimulation. Eicosapentaenoic acid alone or with LPS blunted LPS-me...

ELISA System for Human Endothelial Lipase

Abstract: BACKGROUND: Endothelial lipase (EL) regulates the metabolism of HDL cholesterol (HDL-C). However, the role of EL in regulating plasma HDL-C concentrations and EL's potential involvement in atherosclerosis in humans has not been fully investigated due to the lack of reliable assays for EL mass. We developed an ELISA system for serum EL mass. METHODS: Human recombinant EL proteins, purified from cultured media of human EL-transfected CHO cells, were used as antigen and calibrator. Two specific monoclonal antibodies were generated in mice against recombinant EL protein for a sandwich ELISA. We measured EL mass in human serum using EL recombinant protein as a calibration standard. RESULTS: The EL antibodies did not cross-react with lipoprotein lipase and hepatic triglyceride lipase. The detection limit of the ELISA was 20 pg/mL, which is approximately 10 times lower than that of previous ELISA systems. Recovery of spiked EL in serum was 90%–105%. Assay linearity was intact with a >4-fold dilution of serum. Intra- and interassay CVs were <5%. The serum EL mass in 645 human subjects was [mean (SE)] 344.4 (7.7) pg/mL (range 55.2–1387.7 pg/mL). Interestingly, serum EL mass was increased in patients with diagnosed cardiovascular disease and inversely correlated with serum HDL-C concentrations. There was no difference in EL mass between pre- and post-heparin plasma samples. CONCLUSIONS: This ELISA should be useful for clarifying the impact of EL on HDL metabolism and EL's potential role in atherosclerosis.

Endothelial Lipase Mediates HDL Levels in Normal and Hyperlipidemic Rabbits

Abstract: Aim: Existing evidence suggests that endothelial lipase (EL) plays an important role in high-densitylipoprotein (HDL) metabolism. Because rabbits are a useful animal model for the study of human lipid metabolism and atherosclerosis, we characterized rabbit EL (rEL) expression and investigated its relationship with plasma HDL levels in normal and hyperlipidemic rabbits.Methods: We cloned the rEL cDNA and analyzed the EL tissue expression using Northern blotting, real-time RT-PCR, Western blotting, and in situ hybridization. We evaluated the effects of rEL antisense on plasma HDL levels.Results: We found that rEL mRNA was highly expressed in cholesterol synthesis-related organs, including the liver, testis, and adrenal along with its expression in the lung, kidney, bone marrow, and small intestine. Interestingly, Watanabe heritable hyperlipidemic (WHHL) rabbits, a model of human familial hypercholesterolemia, had lower plasma levels of HDLs than normal rabbits. The plasma HDL levels in WHHL rabbits were inversely associated with high levels of plasma rEL proteins and hepatic expression of rEL mRNA. Injection of rEL-specific antisense oligonucleotides into rabbits resulted in the elevation of plasma large HDLs. Furthermore, we demonstrated that rEL mRNA was expressed by both endothelial cells and macrophages in the lesions of aortic atherosclerosis of WHHL rabbits.Conclusions: rEL is expressed in multiple tissues and may have many physiological and pathophysiological functions, such as in the regulation of cholesterol metabolism and atherosclerosis. Our results suggest that EL is an important regulator of plasma HDL levels in rabbits.

Endothelial Lipase Activity Predicts High-Density Lipoprotein Catabolism in Hemodialysis Novel Phospholipase Assay in Postheparin Human Plasma

Abstract: Objective— A novel phospholipase assay was used to measure for the first time the behavior of endothelial and hepatic phospholipase activities in postheparin human plasma of hemodialyzed patients and its relationship with atherogenic and antiatherogenic lipoprotein levels. Methods and Results— Endothelial and hepatic phospholipase activity was assessed in a total SN1-specific phospholipase assay, using (1-decanoylthio-1-deoxy-2-decanoyl-sn-glycero-3-phosphoryl) ethylene glycol as the substrate. Hemodialyzed patients presented lower values of total and hepatic phospholipase activity than controls: 4.4 (1.9–9.0) versus 7.5 (3.6–18.0) and 2.6 (0.7–6.2) versus 6.6 (1.3–15.2) μmol of fatty acid released per milliliter of postheparin plasma per hour, respectively ( P P =0.008). EL was negatively associated with high-density lipoprotein (HDL)-cholesterol ( r =–0.427; P =0.001), and apolipoprotein A-I levels, total phospholipase, and hepatic lipase activity were directly associated with low-density lipoprotein-cholesterol and apolipoprotein B. The association of EL and HDL-cholesterol remained significant when adjusting for waist circumference (β=–0.26; P =0.05), and the effect of hepatic lipase on low-density lipoprotein-cholesterol continued after adjusting for age (β=0.46; P = 0.001). Conclusion— Our results support the hypothesis that EL is the predominant enzyme responsible for lipolytic catabolism of HDLs in hemodialyzed patients and resolve the apparent paradox observed between low hepatic lipase activity and decreased HDL-cholesterol levels observed in these patients. In addition, the ability to assess total hepatic lipase and EL phospholipase activity in plasma will increase our knowledge of the mechanisms involved in controlling HDL levels and cardiovascular risk in hemodialyzed patients, as well as other populations with low levels of HDL-cholesterol.

Several Lipid-Related Gene Polymorphisms Interact with Overweight/Obesity to Modulate Blood Pressure Levels

Abstract: Little is known about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on blood pressure levels. The present study was undertaken to detect 10 lipid-related gene SNPs and their interactions with overweight/obesity on blood pressure levels. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII hepatic lipase gene (LIPC) −250G > A, endothelial lipase gene (LIPG) 584C > T, methylenetetrahydrofolate reductase (MTHFR) 677C > T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T > C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed in 978 normal weight and 751 overweight/obese subjects. The interactions were detected by factorial regression analysis. The genotypes of ACAT-1 AC, LIPC GA and AA, and SCARB1 TT; LDL-R A-A- and LIPC GA; and SCARB1 TT were interacted with overweight/obesity to increase systolic, diastolic blood pressure (SBP, DBP) and pulse pressure (PP) levels; respectively. The genotypes of ACAT-1 CC; ACAT-1 AA and CC were interacted with overweight/obesity to decrease SBP, PP levels (p < 0.01–0.001); respectively. The differences in blood pressure levels between normal weight and overweight/obese subjects might partly result from different interactions of several SNPs and overweight/obesity.

The association between endothelial lipase -384A/C gene polymorphism and acute coronary syndrome in a Chinese population.

Abstract: Endothelial lipase (EL) is a novel member of the triglyceride (TG) lipase family. A growing body of evidence has indicated that EL gene polymorphism might contribute to the process of cardiovascular diseases. This study was aimed to reveal the potential relationship between EL −384A/C gene polymorphism and acute coronary syndrome (ACS) in a Chinese Han population. The subjects were composed of 320 ACS patients and 315 age- and gender- matched controls. We detected the EL −384A/C genotypes and allele frequencies by using polymerase chain reaction-restriction fragment length polymorphism analysis. There was significant difference in AA genotype and AC+CC genotype between ACS and control groups (P = 0.014). The A allele frequency was significantly higher in ACS group than in control group (87.8 vs 83.8 %, P = 0.041). The relationship between the variant and ACS remained significant after adjusting for current smoker, hypertension, diabetes mellitus, total cholesterol and TG (OR = 0.682, 95 % CI = 0.472–0.986). The levels of HDL and ApoA-I were significantly higher in AC+CC genotype than in AA genotype (HDL: 1.20 ± 0.35 vs 1.11 ± 0.29 mmol/L, P = 0.001; ApoA-I: 1.14 ± 0.25 vs 1.08 ± 0.21 g/L, P = 0.009). We found that the EL −384A/C gene polymorphism might be associated with ACS in Chinese Han population, suggesting that the variant might be involved in the pathogenesis of ACS.

Pyrrolinone carboxamide compounds useful as endothelial lipase inhibitors

Abstract: The present invention provides compounds of Formula (I) or Formula (III): [INSERT CHEMICAL STRUCTURE HERE] (I) [INSERT CHEMICAL STRUCTURE HERE] (III) as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.

Pyridinedione carboxamide inhibitors of endothelial lipase

Abstract: The present invention provides compounds of Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.

Expression of endothelial lipase correlates with the size of neointima in a murine model of vascular remodeling.

Abstract: Aim Endothelial lipase (EL) regulates plasma high-density lipoprotein-cholesterol (HDL-C) levels by promoting HDL catabolism. However, it remains unknown whether the inhibition of EL has beneficial effects on the genesis of vascular diseases. Here, we investigated the role of EL on vascular remodeling in mice. Methods Vascular remodeling was developed by ligation of the left common carotid artery and neointimal lesions were histologically compared between EL-knockout (ELKO), EL-transgenic (ELTg), and wild-type (WT) mice. HDL was isolated from these mice, and effects of the HDL on cell growth and Erk activation were evaluated in vitro using cultured vascular smooth muscle cells. Results Plasma HDL-C levels were 62% higher in ELKO and 13% lower in ELTg than in WT mice, after the carotid ligation. The size of neointimal lesion was significantly larger in ELTg and smaller in ELKO than in WT mice. Vascular expression of adhesion molecules was lower in ELKO and higher in ELTg compared with WT mice. Moreover, oxidative stress was attenuated in ELKO mice. HDL isolated from ELKO, ELTg, and WT mice inhibited expression of intercellular adhesion molecule-1, angiotensin II-induced activation of Erk, and growth of cultured vascular smooth muscle cells, whereas EL expression itself did not affect cell migration or growth. Conclusion EL expression modulates vascular remodeling as well as plasma HDL-C levels. EL inactivation may increase HDL particles that can inhibit smooth muscle cell growth and migration.

Resorufin Butyrate as a Soluble and Monomeric High-Throughput Substrate for a Triglyceride Lipase

Abstract: Triglyceride lipases such as lipoprotein lipase, endothelial lipase, and hepatic lipase play key roles in controlling the levels of plasma lipoprotein. Accordingly, small-molecule modulation of these species could alter patient lipid profiles with corresponding health effects. Screening of these enzymes for small-molecule therapeutics has historically involved the use of lipid-based particles to mimic native substrates. However, particle-based artifacts can complicate the discovery of therapeutic molecules. As a simplifying solution, the authors sought to develop an approach involving a soluble and monomeric lipase substrate. Using purified bovine lipoprotein lipase as a model system, they show that the hydrolysis of resorufin butyrate can be fluorescently monitored to give a robust assay (Z' > 0.8). Critically, using parallel approaches, they show that resorufin butyrate is soluble and monomeric under assay conditions. The presented assay should be useful as a simple and inexpensive primary or secondary screen for the discovery of therapeutic lipase modulators.

Endothelial Lipase Plasma Levels are Increased in Patients With Significant Carotid Artery Stenosis and History of Neurological Impairment.

Abstract: Background : Endothelial lipase (EL) is a phospholipase expressed predominantly by vascular endothelial cells. The goal of the present study was to examine whether EL plasma levels in patients with carotid artery stenosis differ between those with previous history of neurological impairment and those without neurological symptoms. Methods : EL plasma levels were measured by a competitive ELISA assay. Results: EL plasma levels were significantly higher in the symptomatic, compared with the asymptomatic group (mean 489.61 ± 145 ng / ml (n = 31) vs. 388.39 ± 133 ng / ml (n = 24), t-test, P = 0.011). Conclusion : We concluded that increased EL plasma levels reflect the patients' overall susceptibility for cerebrovascular events. doi:10.4021/jocmr734w

Quinolinone carboxamide inhibitors of endothelial lipase

Abstract: The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are endothelial lipase inhibitors which may be used as medicaments.

Endothelial Lipase Is Localized to Follicular Epithelial Cells in the Thyroid Gland and Is Moderately Expressed in Adipocytes

Abstract: Endothelial lipase (EL), a member of the triglyceride lipase gene family, has been shown to be a key player in HDL metabolism. Northern blots revealed that EL was highly expressed in endothelium, thyroid, lung, placenta, liver, and testis. In liver and adrenal gland, EL protein was localized with vascular endothelial cells but not parenchymal cells. EL was shown to be upregulated in tissues such as atherosclerotic plaque where it was located in macrophages, endothelial cells, and medial smooth muscle cells. The purpose of this study was to investigate the cellular localization of EL in thyroid and other tissues where EL is known to be expressed. Besides its presence in vascular endothelial and smooth muscle cells, EL protein was detected in the epithelial cells that line the follicles within the thyroid gland. EL-specific immunostaining was also found near the cell surface as well as in the cytoplasm of adipocytes. Using immunoblots, EL expression was confirmed in cultured human omental and subcutaneous adipocytes. EL expression, however, was not found in preadipocytes. These findings suggest that EL plays a role in thyroid and adipocyte biology in addition to its well-known role in endothelial function and HDL metabolism.

LIPG promoter polymorphism is associated with ischemic stroke in Korean population

Abstract: Endothelial lipase (LIPG) is a member of the triglyceride lipase family which includes hepatic lipase and lipoprotein lipase. Its activity is related to clinically important parameters like blood lipid levels, hypertension, and obesity. In this work, we investigated the association of a LIPG promoter polymorphism, rs9958947C>T, with susceptibility to ischemic stroke in a Korean population. A total of 1,144 subjects (656 cerebral infarction patients and 488 controls) were enrolled on a voluntary basis. The rs9958947C>T polymorphism was genotyped using the single-base extension method. The association of rs9958947C>T with disease status was evaluated by statistical analyses. The frequencies of the rs9958947 C and T alleles were significantly different between the stroke patient group and control group (OR [95% CI], 1.300 [1.000–1.691], P=0.0449). A significantly higher frequency of the CT+TT genotype was observed in the patient group compared to the control group (CC/CT+TT, OR [95% CI], 1.632 [1.094–2.435], P=0.0164). The results suggest that the T allele of the LIPG promoter polymorphism rs9958947C>T should be considered as a genetic risk factor for ischemic stroke. Further association studies in other ethnic populations would help to generalize this hypothesis.

Lipasa endotelial y su relación con la enfermedad cardiovascular y diabetes mellitus tipo 2

Abstract: Endothelial lipase (EL) is synthetized by endothelial cells and its main substrates are lipoprotein phospholipids. Over expression of EL reduces high density lipoprotein (HDL) cholesterol and phospholipids, in vivo and in vitro. Inhibition of the enzyme achieves the opposite effects. The synthesis of the enzyme is regulated by interleukin 1 and tumor necrosis factor a. These inflammatory cytokines play a role in diabetes and vascular disease. An increase in vascular mechanical forces, that play a role in atherogenesis, also increase the synthesis of EL. There is expression of EL in endothelial cells, macrophages and muscle cells of atherosclerotic lesions of coronary arteries of humans. This evidence leads to the suspicion that EL plays a role in atherogenesis. There are also higher plasma levels of EL in subjects with type 2 diabetes, who are especially susceptible to the development of vascular lesions. Therefore the inhibition of EL could play an important role in HDL metabolism and could be a new therapeutic strategy for the prevention of atherosclerosis.