Acute Effects of Intravenous Infusion of ApoA1/Phosphatidylcholine Discs on Plasma Lipoproteins in Humans

Nanjee, M. Nazeem; Je, Doran; Lerch, P.; Miller, N. E.

doi:10.1161/01.atv.19.4.979

Cited by 137 publications

(123 citation statements)

References 56 publications

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“…LDL cholesterol tended to decrease while other lipid parameters remained stable, as previously demonstrated. 5 Reverse cholesterol transport by the infused rHDL particles may therefore account for the observed improvement in endothelial function, as exogenous HDL administration enhances fecal cholesterol excretion. 6,7 Indeed, HDL experimentally reduces established atherosclerotic lesions.…”

Section: Discussionmentioning

confidence: 99%

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

et al. 2002

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Background-Hypercholesterolemia is a risk factor for atherosclerosis-causing endothelial dysfunction, an early event in the disease process. In contrast, high-density lipoprotein (HDL) cholesterol inversely correlates with morbidity and mortality representing a protective effect. Therefore, we investigated the effects of reconstituted HDL on endothelial function in hypercholesterolemic men. Methods and Results-Endothelium-dependent and -independent vasodilation to intraarterial acetylcholine and sodium nitroprusside (SNP), respectively, was measured by forearm venous occlusion plethysmography in healthy normo-and hypercholesterolemic men. In hypercholesterolemics, the effects of reconstituted HDL (rHDL; 80 mg/kg IV over 4 hours) on acetylcholine-and SNP-induced changes in forearm blood flow were assessed in the presence or absence of the nitric oxide (NO) synthase inhibitor L-NMMA. Hypercholesterolemics showed reduced vasodilation to acetylcholine but not to SNP compared with normocholesterolemics (PϽ0.0001). rHDL infusion increased plasma HDL cholesterol from 1.3Ϯ0.1 to 2.2Ϯ0.1 mmol/L (PϽ0.0001, nϭ18) and significantly enhanced the acetylcholine-induced increase in forearm blood flow without affecting that induced by SNP. rHDL infusion also improved flow-mediated dilation of the brachial artery (to 4.5Ϯ0.9% from 2.7Ϯ0.6%, Pϭ0.02). NO synthase inhibition prevented the improvement in acetylcholine-induced vasodilation while leaving the response to SNP unchanged. Albumin infusion in an equivalent protein dose had no effect on vasomotion or lipid levels. Conclusions-In hypercholesterolemic patients, intravenous rHDL infusion rapidly normalizes endotheliumdependent vasodilation by increasing NO bioavailability. This may in part explain the protective effect of HDL from coronary heart disease and illustrates the potential therapeutic benefit of increasing HDL in patients at risk from atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

et al. 2002

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“…41 The use of phospholipid liposomes as a control would have been valid only if this had had no effect on the number and types of HDLs in plasma. However, we know that this would not have been the case.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Plasma High-Density Lipoprotein Concentration Reduces Interleukin-1–Induced Expression of E-Selectin in an In Vivo Model of Acute Inflammation

et al. 2001

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Background-Although there is strong evidence that plasma HDL levels correlate inversely with the incidence of coronary artery disease, the precise mechanism(s) for the protective effect of HDLs remains unclear. We recently showed that HDLs inhibit endothelial cell expression of cytokine-induced leukocyte adhesion molecules in vitro. Our study therefore sought to test the hypothesis that elevating the level of circulating HDLs would inhibit endothelial cell activation in vivo. Methods and Results-We used a porcine model of inflammation previously established in our laboratory, in which the level of vascular endothelial cell expression of E-selectin in interleukin (IL)-1␣-induced skin lesions was measured by the uptake of a radiolabeled anti-E-selectin antibody (1.2B6). Porcine plasma HDL levels were elevated by use of a bolus injection of reconstituted discoidal HDL (recHDL). These particles resemble nascent HDL particles in shape and contain apolipoprotein A-I as the sole protein and soybean phosphatidylcholine as the sole phospholipid. We found that recHDLs inhibited the expression of IL-1␣-induced E-selectin by porcine aortic endothelial cells in vitro, confirming that the inhibitory effect is conserved with synthetic HDLs and demonstrating that the phenomenon is not restricted to human endothelial cells. In vivo, elevating the circulating level of HDLs Ϸ2-fold led to significant inhibition of basal and IL-1␣-induced E-selectin expression by porcine microvascular endothelial cells. Conclusions-These observations demonstrate the potential anti-inflammatory action of HDLs and provide support for the further investigation of the mechanisms underlying the inhibitory effects of HDLs on endothelial cell activation.

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“…These profiles were very similar to those observed in normal humans. 28,29 Analysis of the lipid profile of the Tg mice showed gross hypertriglyceridemia and a moderate increase in plasma cholesterol, mainly in the non-HDL fraction. This lipid profile and the changes in apoB 48 and apoB 100 concentrations in lipoprotein subclasses show that the major increases in plasma lipids in the Tg mice reflect an accumulation of apoB 48 -rich particles.…”

Section: Vergnes Et Al Human Apoa-i/c-iii/a-iv Cluster Tg Micementioning

confidence: 99%

Expression of Human Apolipoprotein A-I/C-III/A-IV Gene Cluster in Mice Induces Hyperlipidemia but Reduces Atherogenesis

Vergnes

Baroukh

Ostos

et al. 2000

ATVB

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Abstract-The apolipoprotein (apo)A-I/C-III/A-IV gene cluster is involved in lipid metabolism and atherosclerosis.Overexpression of apoC-III in mice causes hypertriglyceridemia and induces atherogenesis, whereas overexpression of apoA-I or apoA-IV increases cholesterol in plasma high density lipoprotein (HDL) and protects against atherosclerosis. Each gene has been studied alone in transgenic mice but not in combination as the entire cluster. To determine which phenotype is produced by the expression of the entire gene cluster, transgenic mice were generated with a 33-kb human DNA fragment. The results showed that the transgene contained the necessary elements to direct hepatic and intestinal expression of the 3 genes. In the pooled data, plasma concentrations were 257Ϯ9, 7.1Ϯ0.5, and 1.0Ϯ0.2 mg/dL for human apoA-I, apoC-III, and apoA-IV, respectively (meanϮSEM). Concentrations of these apolipoproteins were higher in males than in females. Human apoA-I and apoC-III concentrations were positively correlated, suggesting that they are coregulated. Transgenic mice exhibited gross hypertriglyceridemia and accumulation of apoB 48 -containing triglyceride-rich lipoproteins. Plasma triglyceride and cholesterol concentrations were correlated positively with human apoC-III concentration, and HDL cholesterol was correlated with apoA-I concentration. In an apoE-deficient background, despite being markedly hypertriglyceridemic, cluster transgenic animals compared with nontransgenic animals showed a 61% reduction in atherosclerosis. This suggests that apoA-I and/or apoA-IV can protect against atherosclerosis even in the presence of severe hyperlipidemia. These mice provide a new model for studies of the regulation of the 3 human genes in combination. Key Words: transgenic mice Ⅲ hypertriglyceridemia Ⅲ cholesterol Ⅲ lipoproteins Ⅲ atherosclerosis P lasma lipoproteins influence the development of atherosclerosis, and their concentrations are associated with the risk of coronary heart disease. 1 The genes for 3 apolipoproteins, apoA-I, apoC-III, and apoA-IV, are grouped together in a cluster on 17 kb of human chromosome 11. 2 ApoA-I is the major protein component of HDL. Through its ability to promote cholesterol efflux from cultured cells and to activate lecithin:cholesterol acyltransferase (LCAT), it is involved in reverse cholesterol transport (RCT). 1 Expression of the human apoA-I ( h apoA-I) gene decreases the development of fatty lesions in cholesterol-fed transgenic (Tg) mice 3 and in apoE-deficient (apoE Ϫ/Ϫ ) mice. 4 ApoA-I deficiency in mice did not increase atherogenesis in a normal background 5 but did so in hypercholesterolemic mice expressing human apoB. 6 ApoC-III is a component of HDL and triglyceride-rich lipoproteins (TGRLs). Plasma apoC-III concentration is positively correlated with triglyceride concentration. By inhibiting TGRL catabolism, apoC-III induces hypertriglyceridemia in Tg mice. 7 Expression of the gene was not atherogenic in apoE Ϫ/Ϫ mice. 8 In contrast, h apoC-III expression, in normal or in LDL ...

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Acute Effects of Intravenous Infusion of ApoA1/Phosphatidylcholine Discs on Plasma Lipoproteins in Humans

Cited by 137 publications

References 56 publications

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

Elevation of Plasma High-Density Lipoprotein Concentration Reduces Interleukin-1–Induced Expression of E-Selectin in an In Vivo Model of Acute Inflammation

Expression of Human Apolipoprotein A-I/C-III/A-IV Gene Cluster in Mice Induces Hyperlipidemia but Reduces Atherogenesis

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