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Showing 1401–1420 of 2058 publications.
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Mizdrak, Jasminka; Hains, Peter G.; Kalinowski, Danuta S.; Truscott, Roger John Willis; Davies, Michael J.; Jamie, Joanne F.4-(2-Aminophenyl)-4-oxobutanoic acid, 4-(2-amino-3-hydroxyphenyl)-4-oxobutanoic acid and glutathionyl-kynurenine have been identified as novel metabolites in normal and cataractous human lenses following total synthesis and comparison with authentic human lens samples. Their structures are consistent with those derived from the major human lens UV filters kynurenine and 3-hydroxykynurenine, and it is proposed that these compounds also play a role as UV filters. These metabolites were isolated in pmol/mg levels (dry mass) in lenses. 4-(2-Amino-3-hydroxyphenyl)-4-oxobutanoic acid and glutathionyl-kynurenine were found to be unstable at physiological pH. Other potential metabolites, glutathionyl-3-hydroxykynurenine, kynurenine yellow and 3-hydroxykynurenine yellow, were not detected in either normal or cataractous lenses. 2007 Elsevier Ltd. All rights reserved.
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Bradshaw, Pamela J.; Wilkes, Edward T.; Thompson, Peter LindsayIntroduction: We studied the determinants of carotid atherosclerosis in urban-dwelling Australian Aboriginals at high risk of atherosclerotic mortality and morbidity. Methods: Cross-sectional study of self-selected adult Australian Aboriginals. Participants (n = 602) aged 18-74 years had risk factor assessment and carotid ultrasound to determine carotid intima-medial thickness (IMT) and the presence of plaque. The upper quartile (>0.71 mm in males and >0.62 mm in females) was used as a measure of increased carotid IMT. Results: Over 80% of participants were overweight or obese; the prevalence of diabetes was 25%. Age was the major predictor of thick IMT, OR 3.0 (95% CI 2.0-4.5) per decade for males and OR 6.3 (3.3-12.0) for females. Waist circumference and blood glucose were independent predictors of IMT for men, with hypertension, pack-years of smoking, diabetes, and cholesterol ratio additional predictors for women. Plaque was highly prevalent (>40%) in this relatively young population and was predicted by increasing age, a history of smoking and total cholesterol/HDL ratio, but not sex. Conclusions: Urban-dwelling Aboriginal Australians are at increased risk for early atherosclerosis. In this study an excess of obesity-related cardiovascular risk factors were the important contributors to increased IMT carotid atherosclerosis, but not inflammatory markers or other novel risk factors. 2006 Elsevier Ireland Ltd. All rights reserved.
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Barter, Philip J.; Shear, Charles L.The world is confronted with an impending epidemic of premature cardiovascular disease (CVD) that is being fueled by an increase in the prevalence of central obesity.
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Zhang, Bo; Uehara, Yoshinari; Hida, Satoru; Miura, Shinichiro; Rainwater, David L.; Segawa, Masaru; Kumagai, Kouichirou; Rye, Kerry Anne; Saku, KeijiroModified LDL in human plasma including small, dense LDL (sdLDL) and oxidized LDL carries a more negative charge than unmodified LDL and is atherogenic. We examined the effects of apolipoprotein A-I (apoA-I)/POPC discs on charge-based LDL subfractions as determined by capillary isotachophoresis (cITP). Three normal healthy subjects and seven patients with metabolic disorders were included in the study. LDL in human plasma was separated into two major subfractions, fast- and slow-migrating LDL (fLDL and sLDL), by cITP. Normal LDL was characterized by low fLDL, and mildly oxidized LDL in vitro and mildly modified LDL in human plasma were characterized by increased fLDL. Moderately oxidized LDL in vitro and moderately modified LDL in a patient with hypertriglyceridemia and HDL deficiency were characterized by both increased fLDL and a new LDL subfraction with a faster mobility than fLDL [very-fast-migrating LDL as determined by cITP (vfLDL)]. cITP LDL subfractions with faster electrophoretic mobility (fLDL vs. sLDL, vfLDL vs. fLDL) were associated with an increased content of sdLDL. Incubation of a plasma fraction with d > 1.019 g/ml (depleted of triglyceride-rich lipoproteins) in the presence of apoA-I/POPC discs at 37C greatly decreased vfLDL and fLDL but increased sLDL. Incubation of whole plasma from patients with an altered distribution of cITP LDL subfractions in the presence of apoA-I/ POPC discs also greatly decreased fLDL but increased sLDL. ApoA-I/POPC discs decreased the cITP fLDL level, the free cholesterol concentration, and platelet-activating factor acetylhydrolase activity in the sdLDL subclasses (d = 1.040-1.063 g/ml) and increased the size of LDL. ApoA-I/POPC discs reduced charge-modified LDL in human plasma by remodeling cITP fLDL into sLDL subfractions. Copyright 2007 by the American Society for Biochemistry and Molecular Biology, Inc.
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Makris, Angela; Thornton, Charlene Eliza; Thompson, John F.; Thomson, Sally E.; Martin, Richard C.W.; Ogle, Robert F.; Waugh, Richard C.; McKenzie, Paul R.; Kirwan, Paul D.; Hennessy, AnnemariePreeclampsia is a complication of pregnancy with significant morbidity and mortality for the mother and the fetus. Presumptions are made that placental hypoxia has a causative role in the clinical syndrome. Furthermore, soluble fms-like tyrosine kinase 1 (sFLT-1) has been shown to have a role in the maternal syndrome of preeclampsia. We investigated the relationship between uteroplacental ischemia (UPI), the maternal clinical syndrome of preeclampsia and sFLT-1 in non-human primates. The induction of UPI in a pregnant non-human primate resulted in the development of a clinical entity analogous to human preeclampsia. This was illustrated by the increase in blood pressure, development of proteinuria, and renal histological changes identical to human preeclampsia. A significant elevation in the placental and peripheral blood mononuclear cell sFLT-1 mRNA expression was noted, translating to a significant elevation in circulating sFLT-1. Thus, this sequence suggests that a pathogenic reduction in placental perfusion results in the development of the maternal syndrome of preeclampsia and an increase in circulating sFLT-1, which is derived both from placental and extra-placental sources. 2007 International Society of Nephrology.
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Gracanin, Michelle; Davies, Michael J.Reaction of radicals in the presence of O<inf>2</inf>, or singlet oxygen, with some amino acids, peptides, and proteins yields hydroperoxides. These species are key intermediates in chain reactions and protein damage. They can be detected in cells and are poorly removed by enzymatic defenses. Previously we have shown that peptide and protein hydroperoxides react rapidly with thiols, with this resulting in inactivation of some thiol-dependent enzymes. In light of these data, we hypothesized that inactivation of protein tyrosine phosphatases (PTPs), by hydroperoxides present on oxidized proteins, may contribute to cellular and tissue dysfunction by modulation of phosphorylation-dependent cell signaling. We show here that PTPs in cell lysates, and purified PTP-1B, are inactivated by amino acid, peptide, and protein hydroperoxides in a concentration- and structure-dependent manner. Protein hydroperoxides are particularly effective, with inhibition occurring with greater efficacy than with H<inf>2</inf>O<inf>2</inf>. Inactivation involves reaction of the hydroperoxide with the conserved active-site Cys residue of the PTPs, as evidenced by hydroperoxide consumption measurements and a diminution of this effect on blocking the Cys residue. This inhibition of PTPs, by oxidized proteins containing hydroperoxide groups, may contribute to cellular dysfunction and altered redox signaling in systems subject to oxidative stress. 2007 Elsevier Inc. All rights reserved.
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Nunn, Alistair Victor William; Bell, Jimmy David; Barter, Philip J.The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle. 2007 Nunn et al; licensee BioMed Central Ltd.
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Lambert, GillesPURPOSE OF REVIEW: Proprotein convertase subtilisin kexin type 9 (PCSK9) has emerged as a potential target for lowering plasma LDL cholesterol levels. This review summarizes recent studies published in print or online before January 2007 which have investigated the functional significance of this intriguing protease. RECENT FINDINGS: Increasing interest in PCSK9 has given rise to landmark epidemiological studies, the generation of animal models, the discovery of new human mutations, as well as numerous in-vitro studies. These studies have helped to unravel the molecular functions of PCSK9. SUMMARY: Mutations of PCSK9 are associated either with hypercholesterolemia or with hypocholesterolemia. In the latter case, the incidence of coronary heart disease is reduced, thereby demonstrating that low LDL cholesterol levels from birth are highly beneficial. PCSK9 promotes the degradation of the LDL receptor in hepatocytes apparently both intracellularly and by being a secreted protein that can bind the LDL receptor and be internalized. By virtue of its role as a major inhibitor of the LDL receptor, PCSK9 is a promising therapeutic target. Specific PCSK9 pharmacological inhibitors may prove to be useful in amplifying the well documented benefits of statins. 2007 Lippincott Williams & Wilkins, Inc.
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Cohn, Jeffrey S.[No abstract available]
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Ng, Martin K.C.There are substantial gender differences in the pattern, severity and clinical outcomes of coronary heart disease independent of environmental risk factor exposure. As a consequence, there has been considerable interest in the potential role of sex hormones in atherogenesis, particularly the potential protective effects of oestrogen. However, the failure of the recent clinical randomised trials to show a cardioprotective effect for oestrogen coupled with a growing interest in androgen replacement therapy in elderly men has refocused interest on the role of androgens in cardiovascular biology and disease. Over the last decade, compelling evidence has emerged that sex differences in vascular biology are not only determined by gender-related differences in sex steroid levels but also by gender-specific tissue and cellular characteristics which mediate sex-specific responses to a variety of stimuli. In the vasculature, androgens often act in a gender-specific manner, with differential effects in male and female cells. This gender-dependent regulation may have important implications for understanding the basis of the gender gap in atherosclerosis and may eventually lead to the development of sex-specific treatments for cardiovascular disease. This review will summarise the current data for the role of androgens in gender differences in coronary heart disease and cardiovascular biology. 2007 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New Zealand.
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Erectile dysfunction predicts generalised cardiovascular disease: Evidence from a case-control studyStuckey, Bronwyn G.A.; Walsh, John P.; Ching, Helena L.I.; Stuckey, Alexander W.; Palmer, Neil R.; Thompson, Peter Lindsay; Watts, Gerald F.Aims: To determine whether idiopathic erectile dysfunction, in the absence of overt cardiovascular disease or cardiovascular risk factors, is associated with vascular or autonomic dysfunction. Methods: We studied 49 men with ED (without known cardiovascular risk factors or disease) and 50 age-matched controls, aged 40-70 years. Macrovascular endothelial function was examined by brachial artery ultrasonography and microvascular function by venous occlusion plethysmography. Blood pressure measurement and electrocardiography were performed lying and standing, and the 30:15 RR ratio calculated. Results: Body mass index, testosterone, fasting lipids and glucose did not differ significantly between groups. Standing pulse pressure was higher (50 1 mm Hg versus 43 2 mm Hg, p < 0.004) and 30:15 RR ratio lower (0.97 0.01 versus 1.01 0.01, p < 0.02) in the ED group. Flow-mediated dilatation of the brachial artery was not significantly different between groups. Flow debt repayment during forearm reactive hyperaemia was lower in the ED group (7.2 0.7 ml versus 9.5 0.8 ml per 100 ml, p < 0.02) than in controls. Conclusions: Men with idiopathic ED have evidence of endothelial dysfunction in forearm resistance vessels, increased pulse pressure and impaired heart rate variability. This supports the concept that erectile dysfunction is a predictor of cardiovascular dysfunction and a precursor of clinical cardiovascular disease. 2006 Elsevier Ireland Ltd. All rights reserved.
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Bursill, C. A.; Roach, Paul D.Green tea extracts have hypocholesterolaemic properties in epidemiological and animal intervention studies. Upregulation of the low-density lipoprotein (LDL) receptor may be one mechanism to explain this as it is the main way cholesterol is removed from the circulation. This study aimed to determine if a green tea extract could upregulate the hepatic LDL receptor in vivo in the rat. A green tea extract (GTE) enriched in its anti-oxidant constituents, the catechins, was fed to rats (n = 6) at concentrations of either 0, 0.5, 1.0 or 2.0% (w/w) mixed in with their normal chow along with 0.25% (w/w) cholesterol for 12 days. Administration of the GTE had no effect on plasma total or LDL cholesterol concentrations but high-density lipoprotein significantly increased (41%; p < 0.05). Interestingly, there was a significant increase in LDL receptor binding activity (2.7-fold) and LDL receptor protein (3.4-fold) in the 2% (w/w) treatment group compared to controls. There were also significant reductions in liver total and unesterified cholesterol (40%). Administration of the GTE significantly reduced cholesterol absorption (24%) but did not affect cholesterol synthesis. These results show that, despite no effect on plasma cholesterol, the GTE upregulated the LDL receptor in vivo. This appears to be via a reduction in liver cholesterol concentration and suggests that the green tea extract was able to increase the efflux of cholesterol from liver cells. AOCS 2007.
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Xu, Bei; Thornton, Charlene Eliza; Makris, Angela; Ogle, Robert F.; Hennessy, AnnemarieObjective: Antihypertensive drugs are administered to women with preeclampsia to control blood pressure and fluid overload. Whether they modulate placental or circulating cytokine production in women with preeclampsia is unknown. This study examines the effect of pharmacological doses of antihypertensive drugs on the production of IL-10, tumor necrosis factor ? (TNF-?), and IL-6 in placental tissue and peripheral blood mononuclear cells (PBMCs) from women with preeclampsia. Methods: Term placenta samples (n = 6) and PBMCs from whole blood (n = 6) were obtained from women with preeclampsia. Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs (clonidine, diazoxide, hydralazine, and furosemide). The dose effect of drugs on the production of placental and circulating cytokines IL-10, TNF-?, and IL-6 was examined by enzyme-linked immunosorbent assay (ELISA). Results: Our data suggest that clonidine can stimulate anti-inflammatory IL-10 production from PBMC while decreasing pro-inflammatory TNF-?, whereas low doses of hydralazine increased the production of IL-10, TNF-?, and IL-6 from preeclamptic PBMCs. There was a reduction in IL-10, TNF-?, and IL-6 production with increasing doses of clonidine and hydralazine by placentas in preeclampsia. IL-10, TNF-?, and IL-6 production from preeclamptic placenta and PBMCs were inhibited by diazoxide and furosemide. Conclusions: Antihypertensive drugs may alter Th1/Th2 cytokine balance in preeclamptic tissues in vitro. Copyright Informa Healthcare.
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Hennessy, Annemarie; Thornton, Charlene Eliza; Makris, Angela; Ogle, Robert F.; Henderson-Smart, David John; Gillin, Adrian G.; Child, Andrew G.Aims: Diazoxide is one of few available agents for treatment of hypertensive emergencies in pregnancy. From previous studies, there is a question concerning safety after moderate-dose administration caused episodes of hypotension. Rapid control of severe hypertension is necessary to reduce maternal morbidity, for example, stroke and placental abruption. This study was designed to compare the efficacy of mini-bolus diazoxide with intravenous (i.v.) hydralazine. Design: A randomised controlled trial. Setting: Tertiary referral maternity hospital, Royal Prince Alfred Women and Babies, Sydney Australia. Population: Antenatal and postnatal women with severe hypertension. Methods: One hundred and twenty-four hypertensive women were randomised to either i.v. hydralazine (5.mg doses) or mini-bolus diazoxide (15.mg doses). Primary outcome measure: Achievement of target blood pressure reduction; secondary measures included requirement for Caesarean section because of fetal deterioration as determined by non-reassuring cardiotocograph (CTG). Results: Reduction in systolic and diastolic blood pressure was 34.min for hydralazine and 19.min for diazoxide (P<0.001). There were no episodes of hypotension after diazoxide and one after hydralazine (after epidural). Episodes of persistent severe hypertension were more common with hydralazine (38%) than with diazoxide (16%), P<0.01. The Caesarean section rate for no-reassuring CTG was no different between the two groups. Neonatal outcomes were similar. Conclusion: Diazoxide and hydralazine are safe and effective antihypertensives, showing a controlled and comparable blood pressure reduction in women with hypertensive emergencies in pregnancy. The mini-bolus doses of 15.mg of diazoxide did not precipitate maternal hypotension as previously described and reduces episodes of persistent severe hypertension. 2007 The Authors Journal compilation 2007 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.
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Ooi, Esther M.; Chan, Dick C.F.; Rye, Kerry Anne; Watts, Gerald F.[No abstract available]
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Parker, Nicole Renee; Korlimbinis, Anastasia; Jamie, Joanne F.; Davies, Michael J.; Truscott, Roger John WillisPURPOSE. Human ultraviolet light (UV) filters, such as kynurenine (Kyn), readily deaminate to reactive unsaturated ketones that covalently modify proteins in older human lenses. The aim of this study was to examine in vitro rates of formation and decomposition of the three major Kyn-amino acid adducts and possible consequences for the lens. METHODS. The t-Boc-protected Kyn-His, Kyn-Lys, and Kyn-Cys adducts and Kyn-Cys were synthesized from the corresponding amino acids and Kyn. Calf lens proteins were modified with Kyn by incubation at pH 7. Stability and competition studies of the adducts were conducted under physiological conditions. Kyn-amino acids and their decomposition products were quantified using HPLC. RESULTS. At physiological pH, Kyn-Cys adducts formed more rapidly than either Lys or His adducts, but they also decomposed readily. By contrast, His adducts were stable. Cysteine (Cys) residues in ?-crystallins were major sites of modification. The Kyn moiety, initially bound to Cys residues, was found to transfer to other amino acids. Glutathione promoted the breakdown of Kyn-Cys. CONCLUSIONS. These data may help explain why proteins in young lenses are not modified by UV filters in situ. The initial phase of the modification of proteins in the human lens by UV filters may be a dynamic process. In lenses, Cys residues of crystalline modify preferentially, but these adducts also decompose to release deaminated Kyn. This can then potentially react with other amino acids. Glutathione, which is present in high concentrations in the lenses of young people, may play a vital role in keeping proteins free from modification by intercepting reactive deaminated kynurenines formed by the spontaneous breakdown of free UV filters, promoting the decomposition of Kyn-Cys residues, and sequestering the unsaturated ketones once they are released from modified proteins. Copyright Association for Research in Vision and Ophthalmology.
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Pattison, David I.; Hawkins, Clare L.; Davies, Michael J.Hypochlorous acid (HOCl) is a powerful oxidant generated from H <inf>2</inf>O<inf>2</inf> and Cl- by the heme enzyme myeloperoxidase, which is released from activated leukocytes. HOCl possesses potent antibacterial properties, but excessive production can lead to host tissue damage that occurs in numerous human pathologies. As proteins and amino acids are highly abundant in vivo and react rapidly with HOCl, they are likely to be major targets for HOCl. In this study, two small globular proteins, lysozyme and insulin, have been oxidized with increasing excesses of HOCl to determine whether the pattern of HOCl-mediated amino acid consumption is consistent with reported kinetic data for isolated amino acids and model compounds. Identical experiments have been carried out with mixtures of N-acetyl amino acids (to prevent reaction at the ?-amino groups) that mimic the protein composition to examine the role of protein structure on reactivity. The results indicate that tertiary structure facilitates secondary chlorine transfer reactions of chloramines formed on His and Lys side chains. In light of these data, second-order rate constants for reactions of Lys side chain and Gly chloramines with Trp side chains and disulfide bonds have been determined, together with those for further oxidation of Met sulfoxide by HOCl and His side chain chloramines. Computational kinetic models incorporating these additional rate constants closely predict the experimentally observed amino acid consumption. These studies provide insight into the roles of chloramine formation and three-dimensional structure on the reactions of HOCl with isolated proteins and demonstrate that kinetic models can predict the outcome of HOCl-mediated protein oxidation. 2007 American Chemical Society.
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Matsuo, Yoshino; Miura, Shinichiro; Kawamura, Akira; Uehara, Yoshinari; Rye, Kerry Anne; Saku, KeijiroReconstituted high-density lipoprotein (rHDL) has been shown to produce a rapid regression of atherosclerosis in animal models and humans. Sphingosine-1-phosphate (S1P), which is a bioactive lipid in HDL, plays a role in mitogenesis, endothelial cell motility, and cell survival, as well as organization and differentiation into a vessel. In this study, we examined the direct role of a newly developed rHDL, [POPC(1-palmitoyl-2-oleoyl phosphatidylcholine)/S1P/apolipoproteinA-I(A-I)]rHDL containing S1P in tube formation in endothelial cells (ECs) as well as cholesterol efflux in macrophage. The effect of (POPC/S1P/A-I)rHDL on cholesterol efflux in macrophage was similar to that of conventional rHDL, (POPC/A-I)rHDL. In addition, (POPC/S1P/A-I)rHDL induced EC proliferation through the activation of phospho-Akt and phospho-extracellular-signal-regulated kinases (p-ERK) 1/2 and EC tube formation, and this effect was blocked by inhibitors of Akt, ERK and endothelial nitric-oxide synthase (eNOS). In addition, (POPC/S1P/A-I)rHDL-induced p-ERK1/2 activation and EC tube formation can be mainly attributed to S1P-stimutated signaling through S1P<inf>2</inf> and S1P<inf>3</inf> as determined by an anti-sense strategy. In conclusion, (POPC/S1P/A-I)rHDL induces cholesterol efflux independently of S1P but has additional S1P-mediated effects on EC tube formation mediated by Akt/ERK/NO through S1P<inf>2</inf> and S1P<inf>3</inf>. In the future, these new discs may be useful for the treatment of atherosclerotic and ischemic cardiovascular disease, such as acute coronary syndrome and atherosclerosis obliterans. 2006 Elsevier Ireland Ltd. All rights reserved.
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Skropeta, Danielle; Settasatian, Chatri; McMahon, Monica R.; Shearston, Kate D.; Caiazza, Daniela; McGrath, Kristine C.Y.; Jin, Weijun; Rader, Daniel J.; Barter, Philip J.; Rye, Kerry AnneEndothelial lipase (EL) is a member of the triglyceride lipase gene family with high phospholipase and low triacylglycerol lipase activities and a distinct preference for hydrolyzing phospholipids in HDL. EL has five potential N-glycosylation sites, four of which are glycosylated. The aim of this study was to determine how glycosylation affects the phospholipase activity of EL in physiologically relevant substrates. Site-directed mutants of EL were generated by replacing asparagine (N) 62, 118, 375, and 473 with alanine (A). These glycan-deficient mutants were used to investigate the kinetics of phospholipid hydrolysis in fully characterized preparations of spherical reconstituted high density lipoprotein (rHDL) containing apolipoprotein E2 (apoE2) [(E2)rHDL], apoE3 [(E3)rHDL], apoE4 [(E4)rHDL], or apoA-I [(A-I)rHDL] as the sole apolipoprotein. Wild-type EL hydrolyzed the phospholipids in (A-I)rHDL, (E2)rHDL, (E3)rHDL, and (E4)rHDL to similar extents. The phospholipase activities of EL N118A, EL N375A, and EL N473A were significantly diminished relative to that of wild-type EL, with the greatest reduction being apparent for (E3)rHDL. The phospholipase activity of EL N62A was increased up to 6-fold relative to that of wild-type EL, with the greatest enhancement of activity being observed for (E2)rHDL. These data show that individual N-linked glycans have unique and important effects on the phospholipase activity and substrate specificity of EL. Copyright 2007 by the American Society for Biochemistry and Molecular Biology, Inc.
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Barter, Philip J.; Gotto, Antonio M.; LaRosa, John C.; Maroni, Jaman M.; Szarek, Michael J.; Grundy, Scott M.; Kastelein, Johannes Jacob Pieter; Bittner, Vera A.; Fruchart, Jean CharlesBACKGROUND: High-density lipoprotein (HDL) cholesterol levels are a strong inverse predictor of cardiovascular events. However, it is not clear whether this association is maintained at very low levels of low-density lipoprotein (LDL) cholesterol. METHODS: A post hoc analysis of the recently completed Treating to New Targets (TNT) study assessed the predictive value of HDL cholesterol levels in 9770 patients. The primary outcome measure was the time to a first major cardiovascular event, defined as death from coronary heart disease, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The predictive relationship between HDL cholesterol levels at the third month of treatment with statins and the time to the first major cardiovascular event was assessed in univariate and multivariate analyses and was also assessed for specific LDL cholesterol strata, including subjects with LDL cholesterol levels below 70 mg per deciliter (1.8 mmol per liter). RESULTS: The HDL cholesterol level in patients receiving statins was predictive of major cardiovascular events across the TNT study cohort, both when HDL cholesterol was considered as a continuous variable and when subjects were stratified according to quintiles of HDL cholesterol level. When the analysis was stratified according to LDL cholesterol level in patients receiving statins, the relationship between HDL cholesterol level and major cardiovascular events was of borderline significance (P = 0.05). Even among study subjects with LDL cholesterol levels below 70 mg per deciliter, those in the highest quintile of HDL cholesterol level were at less risk for major cardiovascular events than those in the lowest quintile (P = 0.03). CONCLUSIONS: In this post hoc analysis, HDL cholesterol levels were predictive of major cardiovascular events in patients treated with statins. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter. (ClinicalTrials.gov number, NCT00327691.) Copyright 2007 Massachusetts Medical Society.
