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P J Barter

Publications and source records attributed to P J Barter.

At least 19 recordsLinked to original sources
PubMed2007

The impact of glycation on apolipoprotein A-I structure and its ability to activate lecithin:cholesterol acyltransferase.

AIMS/HYPOTHESIS: Hyperglycaemia, one of the main features of diabetes, results in non-enzymatic glycation of plasma proteins, including apolipoprotein A-I (apoA-I), the most abundant apolipoprotein in HDL. The aim of this study was to determine how glycation affects the structure of apoA-I and its ability to activate lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport. MATERIALS AND METHODS: Discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and apoA-I ([A-I]rHDL) were prepared by the cholate dialysis method and glycated by incubation with methylglyoxal. Glycation of apoA-I was quantified as the reduction in detectable arginine, lysine and tryptophan residues. Methylglyoxal-AGE adduct formation in apoA-I was assessed by immunoblotting. (A-I)rHDL size and surface charge were determined by non-denaturing gradient gel electrophoresis and agarose gel electrophoresis, respectively. The kinetics of the LCAT reaction was investigated by incubating varying concentrations of discoidal (A-I)rHDL with a constant amount of purified enzyme. The conformation of apoA-I was assessed by surface plasmon resonance. RESULTS: Methylglyoxal-mediated modifications of the arginine, lysine and tryptophan residues in lipid-free and lipid-associated apoA-I were time- and concentration-dependent. These modifications altered the conformation of apoA-I in regions critical for LCAT activation and lipid binding. They also decreased (A-I)rHDL size and surface charge. The rate of LCAT-mediated cholesterol esterification in (A-I)rHDL varied according to the level of apoA-I glycation and progressively decreased as the extent of apoA-I glycation increased. CONCLUSIONS/INTERPRETATION: It is concluded that glycation of apoA-I may adversely affect reverse cholesterol transport in subjects with diabetes.

Apolipoprotein A-I↗
PubMed2006

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Apolipoproteins B↗
PubMed2006

The rationale for using apoA-I as a clinical marker of cardiovascular risk.

An inverse relationship between the concentration of high-density lipoprotein (HDL) cholesterol and the risk of developing cardiovascular is well established. There are several documented functions of HDLs that may contribute to a protective role of these lipoproteins. These include the ability of HDLs to promote the efflux of cholesterol from macrophages and foam cells in the artery wall and to anti-inflammatory/antioxidant properties of these lipoproteins. The fact that the main apolipoprotein of HDLs, apoA-I, plays a prominent role in each of these functions adds support to the view that apoA-I should be measured as a component of the assessment of cardiovascular risk in humans.

Anti-Inflammatory Agents↗
PubMed2005

Effect of inhibiting cholesteryl ester transfer protein on the kinetics of high-density lipoprotein cholesteryl ester transport in plasma: in vivo studies in rabbits.

OBJECTIVE: Inhibitors of cholesteryl ester transfer protein (CETP) have been developed as potential anti-atherogenic agents. Theoretically, however, they may be pro-atherogenic by blocking one of the pathways for removing high-density lipoprotein (HDL) cholesteryl esters (CE) from plasma in the final step of reverse cholesterol transport. Here we describe how CETP inhibition in rabbits impacts on the kinetics of HDL CE transport in plasma. METHODS AND RESULTS: Administration of a CETP inhibitor reduced CETP activity by 80% to 90% and doubled the HDL cholesteryl ester concentration. Multi-compartmental analysis was used to determine HDL CE kinetics in CETP-inhibited and control rabbits after injection of tracer amounts of both native and reconstituted HDL labeled with 3H in the CE moiety. In control rabbits, HDL CE was removed from plasma by both a direct pathway and an indirect pathway after transfer of HDL CE to the very-low-density lipoprotein/low-density lipoprotein fraction. In CETP-inhibited rabbits there was an almost complete block in removal via the indirect pathway. This did not compromise the overall removal of HDL CE from plasma, which was not different in control and inhibited animals. CONCLUSIONS: Inhibiting CETP in rabbits does not compromise the removal of HDL CE from plasma.

Animals↗
PubMed2003

Investigation of pond velocities using dye and small drogues: a case study of the Nelson City waste stabilisation pond.

The city of Nelson, New Zealand, has a 27 hectare oxidation pond as its primary wastewater treatment facility. Recent changes in the configuration of the pond and installation of a mixer/aerator raised concerns that pond treatment rates and effluent quality may be affected by high internal pond velocities and short retention times. This paper presents the findings of an investigation into wastewater velocity and movement within the pond using qualitative dye dispersion and tracking of small-scale "holey-sock" drogues. Simultaneous deployment of drogues and dye allowed methods to be compared, since small-scale drogues have not commonly been used in wastewater ponds. Dye dispersion was assessed using low-level aerial photography from a tethered helium blimp to track short term movement and mixing, while a datalogger and fluorometer were used to measure pond retention time. Drogue movement was tracked in conjunction with the dye study from a small boat using hand-held GPS. The dye study found that: (i) the first portion of pond influent discharged from the pond after 37.5 hours, substantially quicker than the theoretical pond retention time of 27 days. However, the measured retention time was with a mixer in place and the theoretical time was without a mixer; (ii) the position of the paddle wheel mixer/aerator was not optimally placed for mixing the influent and a quiescent region existed adjacent to the influent point; and (iii) the low-level aerial photography was an effective method of evaluating larger pond systems. The "holey-sock" drogue studies showed that: (i) the drogues accurately followed the movement and velocity of dyed influent within the pond; (ii) wastewater velocity and movement was dominated by the paddle wheel mixer/aerator; and (iii) wind direction had a minor influence on wastewater velocity and movement in areas not directly affected by the paddle wheel mixer/aerator. The study demonstrated that the combined use of dye and drogues was a relatively low-cost and effective means of determining internal pond velocities and movement. Future studies using similar methods will be useful in helping validate computer-modelled movement and velocity.

Biodegradation, Environmental↗
PubMed2002

Hugh sinclair lecture: the regulation and remodelling of HDL by plasma factors.

High density lipoproteins (HDLs) originate as lipid-free or lipid-poor apolipoproteins that acquire most of their lipid in the extracellular space. They accept phospholipids from cells in a process promoted by the ATP binding cassette A1 transporter to form prebeta-migrating discoidal HDL that are efficient acceptors of cholesterol released from cell membranes. The cholesterol in discoidal HDL is esterified by lecithin:cholesterol acyltransferase (LCAT) in a process that converts the prebeta-migrating disc into an alpha-migrating, spherical HDL. Spherical HDL are further remodelled by cholesteryl ester transfer protein (CETP) that transfers cholesteryl esters from HDL to other lipoproteins and by hepatic lipase that hydrolyses HDL triglyceride in processes that reduce HDL size and lead to the dissociation of prebeta-migrating, lipid-poor apolipoprotein (apo)A-I from the particle. Prebeta-migrating, lipid-poor apoA-I is also generated as a product of the remodelling of HDL by phospholipid transfer protein. Thus, apoA-I cycles between lipid-poor and lipid associated forms as part of a highly dynamic metabolism of HDL. The other main HDL apolipoprotein, apoA-II is incorporated into apoA-I-containing particles in a process of particle fusion mediated by LCAT. Extracellular assembly and remodelling of HDL not only plays a major role in HDL regulation but also provides potential targets for therapeutic intervention. One example of this is the development of inhibitors of CETP.

Apolipoprotein A-I↗
PubMed2001

Evidence that apolipoprotein A-I facilitates hepatic lipase-mediated phospholipid hydrolysis in reconstituted HDL containing apolipoprotein A-II.

This study examines hepatic lipase (HL) mediated phospholipid hydrolysis in mixtures of apolipoprotein-specific, spherical reconstituted high-density lipoproteins (rHDL). We have shown previously that apolipoprotein A-I (apoA-I) and apoA-II have a major influence on the kinetics of HL-mediated phospholipid and triacylglycerol hydrolysis in well-characterized, homogeneous preparations of spherical rHDL [Hime, N. J., Barter, P. J., and Rye, K.-A. (1998) J. Biol. Chem. 273, 27191-27198]. In the present study, phospholipid hydrolysis was assessed in mixtures of rHDL containing either apoA-I only, (A-I)rHDL, apoA-II only, (A-II)rHDL, or both apoA-I and apoA-II, (A-I/A-II)rHDL. The rHDL contained trace amounts of radiolabeled phospholipid, and hydrolysis was measured as the formation of radiolabeled nonesterified fatty acids (NEFA). As predicted from our previous kinetic studies, the (A-II)rHDL acted as competitive inhibitors of HL-mediated phospholipid hydrolysis in (A-I)rHDL. Less expected was the observation that the rate of phospholipid hydrolysis in (A-II)rHDL was enhanced when (A-I)rHDL were also present in the incubation mixture. The rate of phospholipid hydrolysis in (A-I/A-II)rHDL was also greater than in (A-II)rHDL, indicating that apoA-I enhances phospholipid hydrolysis when it is present as a component of (A-I/A-II)rHDL. It is concluded that apoA-I enhances HL-mediated phospholipid hydrolysis in apoA-II containing rHDL, irrespective of whether the apoA-I is present in the same particle as the apoA-II [as in (A-I/A-II)rHDL] or whether it is present as a component of a different particle, such as when (A-I)rHDL are added to incubations of (A-II)rHDL.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

Lack of effect of serum amyloid A (SAA) on the ability of high-density lipoproteins to inhibit endothelial cell adhesion molecule expression.

Studies have been conducted to determine whether the ability of high density lipoproteins (HDL) to inhibit the cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells is altered by the presence in HDL of the acute phase reactant, serum amyloid-A (SAA). Preparations of HDL(3) were isolated on two separate occasions from the plasma of each of 19 patients: the first was collected before and the second 3 days after undergoing coronary artery bypass graft surgery. Whereas the preoperative HDL(3) sample contained no SAA, in the postoperative sample SAA accounted for an average of 42% of the HDL(3) protein. The preoperative HDL(3) and postoperative, SAA-enriched HDL(3) were identical in terms of their ability to inhibit the tumour necrosis factor-alpha (TNF-alpha)-induced expression of VCAM-1 in human umbilical vein endothelial cells (HUVECs). To assess the effect of having an even greater SAA enrichment of HDL(3), samples of HDL(3) were incubated with purified SAA, which displaced almost all of the apoAI and about 40% of the apoAII from the HDL(3). This in vitro SAA-enriched HDL(3) inhibited the TNF-alpha-induced expression of VCAM-1 in HUVECs in a concentration dependent manner, which was identical to that of the unmodified HDL(3). The presence of SAA did not alter the cell-surface binding of HDL(3) to endothelial cells. It has been concluded that the presence of SAA in HDL has no effect on the ability of these lipoproteins either to inhibit the expression of VCAM-1 in endothelial cells or to bind to proteins on the endothelial cell surface.

Apolipoprotein A-I↗
PubMed2001

Time sequence of the inhibition of endothelial adhesion molecule expression by reconstituted high density lipoproteins.

We have used discoidal reconstituted high density lipoproteins (rHDL) containing apolipoprotein (apo) A-I and dimyristoyl phosphatidylcholine (DMPC) as a tool to investigate the time sequence of the HDL-mediated inhibition of vascular cell adhesion molecule (VCAM)-1 and E-selectin expression in cytokine-activated human umbilical vein endothelial cells (HUVECs). Specifically, we have asked a few questions - (i) how long do the cells need to be exposed to the rHDL before adhesion molecule expression is inhibited and (ii) how long does the inhibition persist after removing the rHDL from the cells. When the cells were not pre-incubated with the rHDL, there was no inhibition. The magnitude of the inhibition increased progressively with increasing duration of pre-incubation up to 16 h. Inhibition did not require the rHDL to be physically present during the activation of adhesion molecule expression by tumour necrosis factor(TNF)-alpha, excluding the possibility that the rHDL was merely interfering with the interaction between TNF-alpha and the cells. When HUVECs were pre-incubated for 16 h with rHDL, the inhibition remained substantial even if the rHDL were removed from the medium up to 8 h prior to addition of TNF-alpha. The HDL-mediated inhibition of VCAM-1 in HUVECs was unaffected by the presence of puromycin, an inhibitor of protein synthesis, excluding the possibility that HDL may have acted by stimulating the synthesis of a cell protein that itself inhibits adhesion molecule expression. These results have important implications in terms of understanding the mechanism(s) of the HDL-mediated inhibition of endothelial adhesion molecule expression.

Cells, Cultured↗
PubMed2001

Cholesteryl ester transfer protein, high density lipoprotein and arterial disease.

The reported relationships between cholesteryl ester transfer protein, high density lipoproteins and arterial disease are confusing and conflicting. Several papers published during the review period add substantially to the evidence base regarding the atherogenicity (or anti-atherogenicity) of cholesteryl ester transfer protein, although none clearly resolves the continuing conflict. These new papers are presented against the backdrop of the previous state of knowledge.

Animals↗
PubMed2001

Threshold level or not for low-density lipoprotein cholesterol.

As drugs, such as the statins, and other therapies demonstrate the ability to significantly lower levels of low-density lipoprotein cholesterol (LDL-C), one issue is whether there is a lower threshold below which no further decline in coronary heart disease occurs. Those who evaluate the data from multiple trials and conclude that no significant decrease in coronary event rates occurs at or below 125 mg/dL suggest using this level as a guideline for clinical application of cholesterol-lowering therapy. On the other hand, analysis of the results of the same population and primary prevention studies concludes that no such threshold exists. The issues affected by the decision of whether to use a threshold include costs to the healthcare system for additional physician time, tests, and medication; unknown clinical events and safety related to very low LDL-C; and resource prioritization to an unestablished therapeutic approach.

Anticholesteremic Agents↗
PubMed2000

Formation of spherical, reconstituted high density lipoproteins containing both apolipoproteins A-I and A-II is mediated by lecithin:cholesterol acyltransferase.

Previous studies have provided detailed information on the formation of spherical high density lipoproteins (HDL) containing apolipoprotein (apo) A-I but no apoA-II (A-I HDL) by an lecithin:cholesterol acyltransferase (LCAT)-mediated process. In this study we have investigated the formation of spherical HDL containing both apoA-I and apoA-II (A-I/A-II HDL). Incubations were carried out containing discoidal A-I reconstituted HDL (rHDL), discoidal A-II rHDL, and low density lipoproteins in the absence or presence of LCAT. After the incubation, the rHDL were reisolated and subjected to immunoaffinity chromatography to determine whether A-I/A-II rHDL were formed. In the absence of LCAT, the majority of the rHDL remained as either A-I rHDL or A-II rHDL, with only a small amount of A-I/A-II rHDL present. By contrast, when LCAT was present, a substantial proportion of the reisolated rHDL were A-I/A-II rHDL. The identity of the particles was confirmed using apoA-I rocket electrophoresis. The formation of the A-I/A-II rHDL was influenced by the relative concentrations of the precursor discoidal A-I and A-II rHDL. The A-I/A-II rHDL included several populations of HDL-sized particles; the predominant population having a Stokes' diameter of 9.9 nm. The particles were spherical in shape and had an electrophoretic mobility slightly slower than that of the alpha-migrating HDL in human plasma. The apoA-I:apoA-II molar ratio of the A-I/A-II rHDL was 0.7:1. Their major lipid constituents were phospholipids, unesterified cholesterol, and cholesteryl esters. The results presented are consistent with LCAT promoting fusion of the A-I rHDL and A-II rHDL to form spherical A-I/A-II rHDL. We suggest that this process may be an important source of A-I/A-II HDL in human plasma.

Apolipoprotein A-I↗
PubMed2000

Treating to target with statins.

Large-scale drug intervention trials have proven that cholesterol-lowering therapy reduces the risk of coronary events in a wide range of at-risk patient groups. This has led to a growing consensus that plasma total and low-density lipoprotein cholesterol (LDL-C) should be reduced to target levels that have been shown in population studies to be associated with low rates of coronary heart disease (CHD). Despite this consensus, however, a substantial proportion of patients at high coronary risk still do not receive lipid-lowering therapy. Furthermore, of those patients receiving therapy, many do not achieve the recommended targets. In order to address this problem, several treatment-to-target studies have been conducted to determine whether recommended targets are attainable with the lipid-lowering drugs that are currently available. These studies have confirmed that the statins are able to achieve recommended target levels in the majority of patients at risk. The studies have also demonstrated that most patients achieve a total cholesterol target with atorvastatin.

Anticholesteremic Agents↗
PubMed2000

Achievement of target plasma cholesterol levels in hypercholesterolaemic patients being treated in general practice.

A total of 1028 hypercholesterolaemic men and women aged 18-75 participated in an open label, randomised, parallel group, 6-month treatment-to-target study conducted in 240 general practices throughout Australia. The study compared atorvastatin monotherapy with simvastatin monotherapy or, if necessary, with the combination of simvastatin and cholestyramine in terms of their abilities to achieve a plasma total cholesterol target of<5.0 mmol/l. The initial daily dose of each drug was 10 mg. If the target was not achieved, the dose was doubled at 6 week intervals to a maximum daily dose of 80 mg atorvastatin or 40 mg simvastatin, with the simvastatin supplemented if necessary with 4 g cholestyramine. The percentage of patients achieving the target at 10 and 20 mg doses of atorvastatin were comparable to 20 and 40 mg of simvastatin, respectively. Despite relatively high baseline levels of plasma total cholesterol (mean levels of 7.41 and 7.31 mmol/l in the atorvastatin and simvastatin groups, respectively) the majority of patients in each group achieved the plasma total cholesterol target of<5.0 mmol/l. Treatment with atorvastatin achieved the target in 83% of patients, while simvastatin (or simvastatin plus cholestyramine) achieved the target in 66% of the patients (P<0.005). The target was achieved with 10 mg atorvastatin in 38% of patients and with 10 mg simvastatin in 26% of cases (P<0.005). In patients whose baseline cholesterol levels were between 5.6 and 6.5 mmol/l, 95% of the atorvastatin group and 86% of the simvastatin group reached the target. Even with baseline cholesterol levels between 7.6 and 8.5 mmol/l, the target was reached in 78% of the atorvastatin group and 61% of the simvastatin group. It is thus realistic for general practitioners to expect the majority of their at risk patients to achieve target plasma cholesterol levels that have been shown in population studies to be associated with relatively low rates of coronary heart disease. These targets are achieved in significantly more patients and at lower mg doses with atorvastatin than simvastatin.

Administration, Oral↗
PubMed2000

Phospholipid composition of reconstituted high density lipoproteins influences their ability to inhibit endothelial cell adhesion molecule expression.

The ability of different phosphatidylcholine (PC) species to inhibit cytokine-induced expression of vascular cell adhesion molecule 1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) was investigated. PC species containing palmitoyl- in the sn-1 position and palmitoyl- (DPPC), arachidonyl- (PAPC), linoleoyl- (PLPC) or oleoyl- (POPC) in the sn-2 position were compared. These PC species were studied as components of reconstituted high density lipoproteins (rHDL) (containing apolipoprotein A-I [apoA-I] as the sole protein) or as small unilamellar vesicles (SUVs). The rHDL containing PLPC and PAPC inhibited VCAM-1 expression in activated HUVECs by 95 and 70%, respectively, at an apoA-I concentration of 16 micrometer. At this concentration of apoA-I, POPC rHDL inhibited by only 16% and DPPC rHDL did not inhibit at all. These differences could not be explained by differential binding of the rHDL to HUVECs. The same hierarchy of inhibitory activity was observed when these PC species were presented to the cells as SUVs but only when the SUVs also contained an antioxidant. It was concluded that rHDL PC is responsible for their inhibitory activity and that this varies widely with different PC species.

Cells, Cultured↗