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Showing 1241–1260 of 2058 publications.
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Lane, Amanda E.; Tan, Joanne Tsui Ming; Hawkins, Clare L.; Heather, Alison Kay; Davies, Michael J.MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by hydrogen peroxide to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid) respectively. Specificity constants indicate that SCN- is amajor substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. While HOCl and HOBr are powerful oxidizing agents, HOSCN is a less reactive, but more specific, oxidant which targets thiols and especially low pK<inf>a</inf> species. In the present study we showthatHOSCNtargets cysteine residues present in PTPs (protein tyrosine phosphatases) with this resulting in a loss of PTP activity for the isolated enzyme, in cell lysates and intact J774A.1 macrophage-like cells. Inhibition also occurs with MPO-generated HOCl and HOBr, but ismoremarked with MPO-generated HOSCN, particularly at longer incubation times. This inhibition is reversed by dithiothreitol, particularly at early time points, consistent with the reversible oxidation of the active site cysteine residue to give either a cysteine-SCN adduct or a sulfenic acid. Inhibition of PTP activity is associated with increased phosphorylation of p38a and ERK2 (extracellular-signal-regulated kinase 2) as detected byWestern blot analysis and phosphoprotein arrays, and results in altered MAPK (mitogen-activated protein kinase) signalling. These data indicate that the highly selective targeting of some protein thiols by HOSCN can result in perturbation of cellular phosphorylation and altered cell signalling. These changes occur with (patho)physiological concentrations of SCN- ions, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage, particularly in smokers who have elevated plasma levels of SCN-. The Authors.
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Sieveking, Daniel P.; Chow, Renee W.Y.; Ng, Martin K.C.Purpose of Review: Striking sex differences exist not only in the incidence of cardiovascular disease, but also in the clinical outcomes. Although cardiovascular events occur earlier in men, in women, it appears they have poorer short-term and long-term outcomes following these events compared to men. Thus, intrinsic sex differences may exist not only in atherogenesis, but also with respect to cardiovascular adaptation/repair in response to ischemia and/or infarction. Angiogenesis, the growth of new blood vessels, is essential for organ development and is critical to cardiovascular repair/regeneration. Although the effect of estrogen on angiogenesis has been studied extensively, the role of androgens has remained largely unexplored. Recent Findings: Multiple lines of evidence now suggest an important role for androgens in cardiovascular repair and regeneration. Studies suggest that androgens stimulate angiogenesis via vascular endothelial growth factor-related mechanisms and by the stimulation of erythropoietin production. Furthermore, endothelial progenitor cells, important in angiogenesis, appear to be hormonally regulated and an important target of androgen action. Summary: Given the age-related decline in androgens, the findings discussed here have implications for therapeutic angiogenesis and androgen replacement therapies in aging and hypogonadal men. 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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Moheimani, Fatemeh; Morgan, Philip E.; Van Reyk, David M.; Davies, Michael J.People with diabetes experience chronic hyperglycemia and are at a high risk of developing atherosclerosis and microvascular disease. Reactions of glucose, or aldehydes derived from glucose (e.g. methylglyoxal, glyoxal, or glycolaldehyde), with proteins result in glycation that ultimately yield advanced glycation end products (AGE). AGE are present at elevated levels in plasma and atherosclerotic lesions from people with diabetes, and previous in vitro studies have postulated that the presence of these materials is deleterious to cell function. This accumulation of AGE and glycated proteins within cells may arise from either increased formation and/or ineffective removal by cellular proteolytic systems, such as the proteasomes, the major multi-enzyme complex that removes proteins within cells. In this study it is shown that whilst high glucose concentrations fail to modify proteasome enzyme activities in J774A.1 macrophage-like cell extracts, reactive aldehydes enhanced proteasomal enzyme activities. In contrast BSA, pre-treated with high glucose for 8. weeks, inhibited both the chymotrypsin-like and caspase-like activities. BSA glycated using methylglyoxal or glycolaldehyde, also inhibited proteasomal activity though to differing extents. This suppression of proteasome activity by glycated proteins may result in further intracellular accumulation of glycated proteins with subsequent deleterious effects on cellular function. 2010 Elsevier B.V.
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Barter, Philip J.; Brandrup-Wognsen, Gunnar; Palmer, Mike K.; Nicholls, Stephen J.The relationship between statin-induced increases in HDL cholesterol (HDL-C) concentration and statin-induced decreases in LDL cholesterol (LDL-C) is unknown. The effects of different statins on HDL-C levels, relationships between changes in HDL-C and changes in LDL-C, and predictors of statin-induced increases in HDL-C have been investigated in an individual patient meta-analysis of 32,258 dyslipidemic patients included in 37 randomized studies using rosuvastatin, atorvastatin, and simvastatin. The HDL-C raising ability of rosuvastatin, and simvastatin was comparable, with both being superior to atorvastatin. Increases in HDL-C were positively related to statin dose with rosuvastatin and simvastatin but inversely related to dose with atorvastatin. There was no apparent relationship between reduction in LDL-C and increase in HDL-C, whether analyzed overall for all statins (correlation coeffi-cient = 0.005) or for each statin individually. Percentage increase in apolipoprotein A-I was virtually identical to that of HDL-C at all doses of the three statins. Baseline concentrations of HDL-C and triglyceride (TG) and presence of diabetes were strong, independent predictors of statin-induced elevations of HDL-C. Statins vary in their HDL-C raising ability. The HDL-C increase achieved by all three statins was independent of LDL-C decrease. However, baseline HDL-C and TGs and the presence of diabetes were predictors of statin-induced increases in HDL-C. Copyright 2010 by the American Society for Biochemistry and Molecular Biology, Inc.
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Chow, Renee W.Y.; Handelsman, David J.; Ng, Martin K.C.The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days.Andyet,someeffects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades. Copyright 2010 by The Endocrine Society.
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Kennett, Eleanor C.; Rees, Martin D.; Malle, Ernst; Hammer, Astrid; Whitelock, John; Davies, Michael J.The heparan sulfate (HS) proteoglycan perlecan is a major component of basement membranes, plays a key role in extracellular matrix (ECM) structure, interacts with growth factors and adhesion molecules, and regulates the adhesion, differentiation and proliferation of vascular cells. Atherosclerosis is characterized by chronic inflammation and the presence of oxidized materials within lesions, with the majority of protein damage present on ECM, rather than cell, proteins. Weakening of ECM structure plays a key role in lesion rupture, the major cause of heart attacks and strokes. In this study peroxynitrite, a putative lesion oxidant, is shown to damage perlecan structurally and functionally. Exposure of human perlecan to peroxynitrite decreases recognition by antibodies raised against both the core protein and heparan sulfate chains; dose-dependent formation of 3-nitrotyrosine was also detected. These effects were modulated by bicarbonate and reaction pH. Oxidant exposure resulted in aggregate formation, consistent with oxidative protein crosslinking. Peroxynitrite treatment modified functional properties of perlecan that are dependent on both the protein core (decreased binding of human coronary artery endothelial cells), and the HS chains (diminished fibroblast growth factor-2 (FGF-2) receptor-mediated proliferation of Baf-32 cells). The latter is consistent with a decrease in FGF-2 binding to the HS chains of modified perlecan. Immunofluorescence of advanced human atherosclerotic lesions provided evidence for the presence of perlecan and extensive formation of 3-nitrotyrosine epitopes within the intimal region; these materials showing marked co-localization. These data indicate that peroxynitrite induces major structural and functional changes to perlecan and that damage to this material occurs within human atherosclerotic lesions. 2010 Elsevier Inc.
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Byrom, Michael John; Bannon, Paul Gerard; White, Geoffrey H.; Ng, Martin K.C.The development of an ideal small-diameter conduit for use in vascular bypass surgery has yet to be achieved. The ongoing innovation in biomaterial design generates novel conduits that require preclinical assessment in vivo, and a number of animal models have been used for this purpose. This article examines the rationale behind animal models used in the assessment of small-diameter vascular conduits encompassing the commonly used species: baboons, sheep, pigs, dogs, rabbits, and rodents. Studies on the comparative hematology for these species relative to humans are summarized, and the hydrodynamic values for common implant locations are also compared. The large- and small-animal models are then explored, highlighting the characteristics of each that determine their relative utility in the assessment of vascular conduits. Where possible, the performance of expanded polytetrafluoroethylene is given in each animal and in each location to allow direct comparisons between species. New challenges in animal modeling are outlined for the assessment of tissue-engineered graft designs. Finally, recommendations are given for the selection of animal models for the assessment of future vascular conduits. 2010 Society for Vascular Surgery.
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Akram, Omar N.; Bernier, Adeline; Petrides, Francine; Wong, Gida; Lambert, Gilles[No abstract available]
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Stanley, Naomi R.; Pattison, David I.; Hawkins, Clare L.Myeloperoxidase is a heme enzyme released by activated phagocytes that is responsible for the generation of the strong oxidant hypochlorous acid (HOCl). Although HOCl has potent bactericidal properties and plays an important role in the human immune system, this oxidant also causes damage to tissues, particularly under inflammatory conditions. There is a strong link between chronic inflammation and the incidence of many cancers, which may be associated with the ability of HOCl and related oxidants such as N-chloramines to damage DNA. However, in contrast to HOCl, little is known about the reactivity of N-chloramines with DNA and its constituents. In this study, we examine the ability of HOCl and various N-chloramines to form chlorinated base products on nucleosides, nucleotides, DNA, and in cellular systems. Experiments were performed with N-chloramines formed on N?-acetyl-histidine (His-C), N?-acetyl-lysine (Lys-C), glycine (Gly-C), taurine (Tau-C), and ammonia (Mono-C). Treatment of DNA and related materials with HOCl and His-C resulted in the formation of 5-chloro-2'-deoxycytidine (5CldC), 8-chloro-2'-deoxyadenosine (8CldA) and 8-chloro-2'-deoxyguanosine (8CldG). With the nucleosides, 8CldG was the favored product in each case, and HOCl was the most efficient chlorinating agent. 5Cl(d)C was the most abundant product on exposure of the nucleotides and DNA to HOCl and His-C, with only low levels of chlorinated products observed with Lys-C, Gly-C, Tau-C, and Mono-C. 5CldC was also formed on exposure of smooth muscle cells to either HOCl or His-C. Cellular RNA was also a target for HOCl and His-C, with evidence for the formation of 5-chloro-cytidine (5ClC). This study shows that HOCl and the model N-chloramine, His-C, are able to chlorinate cellular genetic material, which may play a role in the development of various inflammatory cancers. 2010 American Chemical Society.
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Fryirs, Michelle A.; Barter, Philip J.; Appavoo, Mathiyalagan; Tuch, Bernard Edward; Tabet, Fatiha; Heather, Alison Kay; Rye, Kerry AnneObjective: Type 2 diabetes is characterized by impaired ?-cell secretory function, insulin resistance, reduced high-density lipoprotein (HDL) levels, and increased cardiovascular risk. Given the current interest in therapeutic interventions that raise HDLs levels, this study investigates the effects of HDLs on insulin secretion from ?-cells. Methods and results: Incubation of Min6 cells and primary islets under basal or high-glucose conditions with either apolipoprotein (apo) A-I or apoA-II in the lipid-free form, as a constituent of discoidal reconstituted HDLs (rHDLs), or with HDLs isolated from human plasma increased insulin secretion up to 5-fold in a calcium-dependent manner. The increase was time and concentration dependent. It was also K<inf>ATP</inf> channel and glucose metabolism dependent under high-glucose, but not low-glucose, conditions. The lipid-free apolipoprotein-mediated increase in insulin secretion was ATP binding cassette (ABC) transporter A1 and scavenger receptor-B1 dependent. The rHDL-mediated increase in insulin secretion was ABCG1 dependent. Exposure of ?-cells to lipid-free apolipoproteins also increased insulin mRNA expression and insulin secretion without significantly depleting intracellular insulin or cholesterol levels. Conclusion: These results establish that lipid-free and lipid-associated apoA-I and apoA-II increase ?-cell insulin secretion and indicate that interventions that raise HDLs levels may be beneficial in type 2 diabetes. 2010 American Heart Association, Inc.
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Dunn, Louise L.; Buckle, Andrew M.; Cooke, John P.; Ng, Martin K.C.Although there have been a multitude of studies, the mechanisms of angiogenesis remain incompletely understood. Increasing evidence suggests that cellular redox homeostasis is an important regulator of angiogenesis. The thioredoxin (TRX) system functions as an endogenous antioxidant that can exert influence over endothelial cell function via modulation of cellular redox status. It has become apparent that the cytosolic TRX1 isoform participates in both canonical and novel angiogenic signaling pathways and may represent an avenue for therapeutic exploitation. Recent studies have further identified a role for the mitochondrial isoform TRX2 in ischemia-induced angiogenesis. TRX-interacting protein (TXNIP) is the endogenous inhibitor of TRX redox activity that has been implicated in growth factor-mediated angiogenesis. As TXNIP is strongly induced by glucose, this molecule could be of consequence to disordered angiogenesis manifest in diabetes mellitus. This review will focus on data implicating the TRX system in endothelial cell homeostasis and angiogenesis. 2010 American Heart Association, Inc.
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Taskinen, Marja Riitta; Barter, Philip J.; Ehnholm, Christian P.; Sullivan, David R.; Robledo, Kristy P.; Simes, Robert John; Best, James D.; Hamwood, S. M.; Keech, Anthony C.Aims/hypothesis: The apolipoprotein B (ApoB):apolipoprotein A (ApoA)-I ratio may be a better indicator of cardiovascular disease (CVD) risk in people with type 2 diabetes than traditional lipid risk markers (LDL-cholesterol, HDL-cholesterol and triacylglycerol), but whether the ApoB:ApoA-I ratio should be used to indicate lipid-lowering therapy is still debated. Methods: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomised 9,795 patients with type 2 diabetes to fenofibrate (200 mg daily) or placebo and followed them up for a median of 5 years. We compared ApoB, ApoA-I, ApoAII and the ApoB:ApoA-I ratio with traditional lipid variables as predictors of CVD risk. We estimated the HR of the effect of 1 SD difference in baseline concentrations of lipids, apolipoproteins and respective ratios on the risk of CVD events and also used receiver operating characteristic curve analysis. Results: In the placebo group, the variables best predicting CVD events were non-HDL-cholesterol:HDL-cholesterol, total cholesterol:HDL-cholesterol (HR 1.21, p?<?0.001 for both), ApoB:ApoA-I (HR 1.20, p?<?0.001) , LDL-cholesterol:HDL-cholesterol (HR 1.17, p?<?0.001), HDL-cholesterol (HR 0.84, p?<?0.001) and ApoA-I (HR 0.85, p?<?0.001). In the fenofibrate group, the first four predictors were very similar (but ApoB:ApoA-I was fourth), followed by non-HDL-cholesterol and ApoB. Lipid ratios and ApoB:ApoA-I performed better than any single lipid or apolipoprotein in predicting CVD risk. Conclusions/interpretation: In patients with type 2 diabetes in the FIELD study, traditional lipid ratios were as strong as the ApoB:ApoA-I ratio in predicting CVD risk. The data provide little evidence for replacement of traditional lipids and their ratios with measures of ApoB, ApoA-I and their ratio. 2010 Springer-Verlag.
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Bursill, C. A.; Castro, Maria L.; Beattie, Douglas T.; Nakhla, Shirley; van der Vorst, Emiel P.C.; Heather, Alison Kay; Barter, Philip J.; Rye, Kerry AnneObjective: To investigate whether high-density lipoproteins (HDLs) suppress chemokine (CCL2, CCL5, and CX<inf>3</inf>CL1) and chemokine receptor (CCR2 and CX<inf>3</inf>CR1) expression, a mechanism for the atheroprotective properties of HDLs. Methods and Results: Apolipoprotein (apo) E-/- mice were fed a high-fat diet for 12 weeks. Before being euthanized, the mice received 5 consecutive daily injections of lipid-free apoA-I, 40 mg/kg, or saline (control). The injection of apoA-I reduced CCR2 and CX<inf>3</inf>CR1 expression in plaques compared with controls (P<0.05). ApoA-I-injected mice had lower plasma CCL2 and CCL5 levels. Hepatic CCL2, CCL5, and CX<inf>3</inf>CL1 levels were also reduced (P<0.05). In vitro studies found that reconstituted HDL (rHDL) reduced monocyte CCR2 and CX<inf>3</inf>CR1 expression and inhibited their migration toward CCL2 and CX<inf>3</inf>CL1 (P<0.05). Preincubation with rHDL reduced CCL2, CCL5, and CX<inf>3</inf>CL1 expression in monocytes and human coronary artery endothelial cells. The stimulation of CX<inf>3</inf>CR1 with peroxisome proliferator-activated receptor ? agonist CAY10410 was suppressed by preincubation with rHDL but did not affect the peroxisome proliferator-activated receptor ? antagonist (GW9664)-mediated increase in CCR2. In monocytes and human coronary artery endothelial cells, rHDL reduced the expression of the nuclear p65 subunit, I?B kinase activity, and the phosphorylation of I?B? (P<0.05). Conclusion: Lipid-free apoA-I and rHDL reduce the expression of chemokines and chemokine receptors in vivo and in vitro via modulation of nuclear factor ?B and peroxisome proliferator-activated receptor ?. 2010 American Heart Association, Inc.
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Napier, Christine E.; Veas, Laura A.; Kan, Chinyi; Taylor, Lisa M.; Yuan, Jun; Wen, Victoria W.; James, Alexander C.; O'Brien, Tracey A.; Lock, Richard B.; Mackenzie, Karen L.Reactivation of telomerase in endothelial cells (ECs) may be an effective approach to the treatment of vascular disorders associated with telomere attrition and EC senescence. However, overexpression of human telomerase reverse transcriptase (hTERT) does not prevent net telomere loss in ECs grown in standard culture medium with exposure to atmospheric oxygen (21% O<inf>2</inf>). Since these culture conditions are hyperoxic relative to normal tissue in vivo, where oxygen tension is estimated to be 1%-6%, we examined the effects of reduced exposure to oxidative stress (OS) on telomere length maintenance in hTERT-transduced bone marrow endothelial (BMhTERT) cells. Propagation of BMhTERT cells in the free radical scavenger, tert-butylhydroxylamine (tBN), and/or in 5% O<inf>2</inf> increased telomerase enzyme activity and facilitated telomere length maintenance. The enhancement of telomerase activity correlated with higher levels of the telomerase RNA component (hTR). We also investigated the role of the telomere binding protein, TRF1, in telomere length regulation under alternate OS conditions. Inhibition of TRF1 function had no effect on telomere length in BMhTERT cells grown under standard culture conditions. However, alleviation of OS by growth in tBN plus 5% O<inf>2</inf>, elevated hTR levels, enhanced telomerase enzyme activity, and enabled progressive telomere lengthening. The direct impact of hTR levels on telomerase-mediated telomere lengthening was demonstrated by overexpression of hTR. BMhTERT cells transduced with hTR exhibited very high telomerase enzyme activity and underwent dramatic telomere lengthening under standard culture conditions. Overall, these results demonstrate that hTR levels are reduced by mild hyperoxia and limit telomerase-mediated telomere lengthening in hTERT-transduced ECs. 2010 Elsevier B.V.
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Patel, Sanjay; Di Bartolo, Belinda Ann; Nakhla, Shirley; Heather, Alison Kay; Mitchell, Todd W.; Jessup, Wendy K.; Celermajer, David S.; Barter, Philip J.; Rye, Kerry AnneObjective: Infusions of apoA-I in the lipid-free form or as a constituent of discoidal reconstituted high-density lipoproteins, (A-I)rHDL, markedly inhibit acute vascular inflammation in normocholesterolemic New Zealand White (NZW) rabbits. This effect is apparent even when apoA-I is administered 24 h prior to the inflammatory insult. The present study asks if this benefit is related to an improved anti-inflammatory capacity of the high-density lipoprotein (HDL) fraction, or to increased arterial expression of genes that inhibit inflammation. Methods and results: The ability of apoA-I to increase the anti-inflammatory capacity of HDL was assessed by infusing normocholesterolemic NZW rabbits with saline, lipid-free apoA-I or (A-I)rHDL. The infused apoA-I incorporated rapidly into the rabbit HDL fraction. The animals were sacrificed at 5 or 360 min post-infusion and plasma was collected. HDL were isolated by ultracentrifugation and incubated with cytokine-activated cultured human coronary artery endothelial cells. HDL from animals sacrificed at 5 min post-apoA-I infusion had a slightly enhanced anti-inflammatory capacity relative to HDL from the saline-infused animals. The anti-inflammatory capacity of HDL from the animals sacrificed at 360 min post-apoA-I infusion was comparable to that of HDL from the saline-infused animals. The effect of (A-I)rHDL infusions on arterial 3?-hydroxysteroid-?24 reductase (DHCR24) and endothelial adhesion molecule expression was investigated in cholesterol-fed NZW rabbits. Relative to animals infused with saline, (A-I)rHDL infusions decreased aortic VCAM-1 and ICAM-1 protein expression by 73 and 54%, respectively (p< 0.05), and increased DHCR24 mRNA levels by 56% (p< 0.0001). Conclusion: ApoA-I inhibits vascular inflammation in NZW rabbits, at least in part, by increasing DHCR24 expression. 2010 Elsevier Ireland Ltd.
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Barter, Philip J.[No abstract available]
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Waterhouse, Anna; Yin, Yongbai; Wise, Steven G.; Bax, Daniel V.; McKenzie, David R.; Bilek, Marcela M.M.; Weiss, Anthony Steven; Ng, Martin K.C.Current endovascular stents have sub-optimal biocompatibility reducing their clinical efficacy. We previously demonstrated a plasma-activated coating (PAC) that covalently bound recombinant human tropoelastin (TE), a major regulator of vascular cells in vivo, to enhance endothelial cell interactions. We sought to develop this coating to enhance its mechanical properties and hemocompatibility for application onto coronary stents. The plasma vapor composition was altered by incorporating argon, nitrogen, hydrogen or oxygen to modulate coating properties. Coatings were characterized for 1) surface properties, 2) mechanical durability, 3) covalent protein binding, 4) endothelial cell interactions and 5) thrombogenicity. The N<inf>2</inf>/Ar PAC had optimal mechanical properties and did not delaminate after stent expansion. The N<inf>2</inf>/Ar PAC was mildly hydrophilic and covalently bound the highest proportion of TE, which enhanced endothelial cell proliferation. Acute thrombogenicity was assessed in a modified Chandler loop using human blood. Strikingly, the N<inf>2</inf>/Ar PAC alone reduced thrombus weight by ten-fold compared to 316L SS, a finding unaltered with immobilized TE. Serum soluble P-selectin was reduced on N<inf>2</inf>/Ar PAC and N<inf>2</inf>/Ar PAC + TE (p < 0.05), consistent with reduced platelet activation. We have demonstrated a coating for metal alloys with multifaceted biocompatibility that resists delamination and is non-thrombogenic, with implications for improving coronary stent efficacy. 2010 Elsevier Ltd.
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Tandy, Sally; Chung, Rosanna W.S.; Kamili, Alvin; Wat, Elaine C.L.; Weir, Jacquelyn M.; Meikle, Peter J.; Cohn, Jeffrey S.The ability of the fatty acid composition of dietary phosphatidylcholine (PC) to affect hepatic lipid levels was investigated in C57BL/6 mice (n= 8-10 per group) by feeding: (1) a high-fat semi-purified diet (HF), (2) HF diet supplemented with 1.25 wt% soy PC (SPC), (3) HF with 1.25 wt% hydrogenated soy PC (SPCH), (4) HF with 1.25 wt% egg PC (EPC), and (5) HF with 1.25 wt% hydrogenated egg PC (EPCH). The polyunsaturated fatty acid content (C18:2. +. C18:3. +. C20:4) of soy, egg and hydrogenated PC was 70%, 20% and 0%, respectively. Total liver lipid was significantly lower in SPCH and EPCH vs. HF (8.7 0.1 and 8.5 0.5 vs. 11.8 0.6 g/100, P< 0.05), but not in SPC or EPC. SPCH and EPCH had significantly lower levels of hepatic cholesterol (-52% and -53% vs. HF, respectively). Bioactive lipids (i.e., sphingomyelin and ceramide) were also lower in the liver of SPCH and EPCH rather than in SPC or EPC. Hepatic expression of genes controlling fatty acid synthesis and catabolism were not significantly affected by dietary PC. However, hepatic expression of HMGCR, LDLR and SREBP2 was higher and that of ABCA1, ABCG5 and ABCG8 was reduced in SPCH and EPCH vs. HF. These results demonstrate that hydrogenated PC supplementation reduces hepatic lipid levels in mice fed a high-fat diet supporting the concept that the ability of dietary PC to lower hepatic lipid levels is not due to its content of polyunsaturated fatty acids. 2010 Elsevier Ireland Ltd.
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Ayer, Julian Ganesh J.; Song, Changjie; Steinbeck, Katharine S.; Celermajer, David S.; Freedman, Ben Ben1. The relationship between inflammation, obesity-related proteins and tissue factor (TF), the major initiator of the extrinsic clotting cascade, is not well understood. We examined if basal and stimulated peripheral blood mononuclear cell (PBMC) TF-procoagulant activity (PCA) was higher in obese subjects and examined the effects of leptin, resistin and serum amyloid A (SAA). 2. PBMC from 12 obese (six male, aged 29//4/years, body mass index 46.0//8.7/kg/m2) and 12 age- and sex-matched lean controls were cultured either unstimulated or stimulated by lipopolysaccharide (LPS; 10/?g/mL and 100/ng/mL, for 4-16/h) or SAA (1/ng/mL, 25/ng/mL, 250/ng/mL, for 4/h). Separately, PBMC from lean subjects were cultured unstimulated with leptin (100/?g/mL, 1/ng/mL, 10/ng/mL, 100/ng/mL, 1/?g/mL), resistin (0.1/ng/mL, 1/ng/mL, 10/ng/mL, 100/ng/mL) or leptin (100/ng/mL) plus LPS (100/?g/mL). TF-PCA was determined by a 1-stage plasma recalcification assay. 3. Four-hour unstimulated PBMC TF-PCA was greater in the obese (90.4//16.5 vs 39.9//4.7/mu TF/106 PBMC, P/=/0.01). After 4/h stimulation with SAA or LPS the TF-PCA was similar. Unstimulated TF-PCA correlated with log serum high sensitivity C- reactive protein (hs-CRP) (r/=/0.42, P/=/0.04) and insulin (r/=/0.44, P/=/0.048), but not with log serum SAA (r/=/0.192, P/=/0.55). Physiological concentrations of leptin or resistin and leptin plus LPS did not increase TF-PCA in PBMC from lean subjects. 4. Basal PBMC TF-PCA is higher in the obese and is associated with serum hs-CRP. The obesity-related proteins SAA, leptin and resistin are unlikely to play a major role in increasing PBMC TF-PCA. 2010 The Authors. Clinical and Experimental Pharmacology and Physiology 2010 Blackwell Publishing Asia Pty Ltd.
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Waterworth, Dawn M.; Ricketts, Sally L.; Song, Kjioung S.; Chen, Li; Zhao, Jinghua; Ripatti, Samuli; Aulchenko, Yurii S.; Zhang, Weihua; Yuan, Xin; Lim, Noha; Luan, Jian'fan A.; Ashford, Sofie E.; Wheeler, Eleanor; Young, Elizabeth H.; Hadley, David J.; Thompson, John R.; Braund, Peter S.; Johnson, Toby; Struchalin, Maksim V.; Surakka, Ida L.; Luben, Robert N.; Khaw, Kay Tee T.; Rodwell, Sheila A.Bingham; Loos, Ruth J.f.; Boekholdt, S. M.; Inouye, Michael T.; Deloukas, Panos; Elliott, Paul; Schlessinger, David; Sanna, Serena; Scuteri, Angelo; Jackson, Anne U.; Mohlke, Karen L.; Tuomilehto, Jaakko O.I.; Roberts, Robert K.; Stewart, Alexandre F.R.; Kesaniemi, YrjAntero; Mahley, Robert W.; Grundy, Scott M.; McArdle, Wendy L.; Cardon, Lon R.; Waeber, Gard; Vollenweider, Peter K.; Chambers, John Campbell; Boehnke, Michael L.; Abecasis, Gonlo R.; Salomaa, Veikko V.; J?arvelin, Mjo Riitta R.; Ruokonen, Aimo O.; Barroso, In E.; Epstein, Stephen E.; Honarson, Hon H.; Rader, Daniel J.; Reilly, Muredach P.; Witteman, Jacqueline C.M.; Hall, Alistair Scott; Samani, Nilesh J.; Strachan, David Peter; Barter, Philip J.; van Duijn, Cornelia M.; Kooner, Jaspal Singh; Peltonen-Palotie, Leena Johanna; Wareham, Nicholas J.; McPherson, Ruth M.; Mooser, Vincent E.; Sandhu, Manjinder SinghOBJECTIVE-: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS-: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.60-8 to 3.10-10). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.10-3 to 1.20-9). CONCLUSION-: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk. 2010 American Heart Association, Inc.
