Production and Characterization of
a Reconstituted High Density
Lipoprotein for Therapeutic
Applications

Lerch, P.; Förtsch, Vreni; Hodler, G.; Bolli, Reinhard

doi:10.1159/000462047

Cited by 84 publications

(86 citation statements)

References 47 publications

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“…The homogeneity and size of the reconstituted lipoprotein complexes were assessed by size exclusion chromatography and native-PAGE, as described below, and by negative staining electron microscopy (25). Electron microscopy analysis of our rHDL preparation revealed characteristic disc shaped structures (average diameter: 15 nm), similar to those found in the literature for rHDL (22,(26)(27)(28).…”

Section: Making Of Liposomessupporting

confidence: 68%

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

2007

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Because phospholipid composition of HDL plays a vital role in its reverse cholesterol transport (RCT) function, we studied RCT in vitro (uptake and efflux) with reconstituted HDLs (rHDLs) containing phosphatidylcholine with fatty acids of increasing saturation levels (stearic, oleic, linoleic, linolenic), and without or with sphingomyelin. Uptake significantly increased from basal value when phosphatidylcholine component included up to 50% (%mol) of oleic or linolenic acid, but did not change with linoleic acid. Increasing oleic and linoleic acids to 100% (%mol) significantly decreased uptake, but increasing linolenic acid to the same value did not affect it. Sphingomyelin in rHDL significantly decreased uptake, but only with phosphatidylcholine containing unsaturated fatty acids, and not with saturated fatty acid. Efflux was not affected in a dose-dependent manner when oleic or linoleic acid content was increased, but was significantly increased with levels of linolenic acid up to 25% (%mol) in phosphatidylcholine, and was dramatically lowered with higher levels. Sphingomyelin in rHDL (phosphatidylcholine:sphingomyelin, 20:80, mol:mol) significantly increased efflux only with oleic or linoleic acid-containing rHDLs, compared to efflux without sphingomyelin. In conclusion, enrichment of phosphatidylcholine component up to 25% (%mol) as linolenic acid has a beneficial effect on RCT, while a higher percentage of it or other unsaturated fatty acids seems to be detrimental. Also, high sphingomyelin content decreases uptake with rHDL containing unsaturated fatty acids, whereas it increases efflux for rHDL containing oleic or linoleic acid. These results show for the first time the importance of sphingomyelin in RCT in a well-defined in vitro system.

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Section: Making Of Liposomessupporting

confidence: 68%

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

2007

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“…2,3 Then, infusions of ACh and SNP were repeated. In further 5 hypercholesterolemic patients, the effects of intravenous rHDL infusion on ACh-and SNP-induced vasodilation were assessed during intraarterial coinfusion of N G -monomethyl-L-arginine (L-NMMA, 4 mol/min; Clinalfa), an inhibitor of NO synthase.…”

Section: · Minmentioning

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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“…Then, a venous catheter was inserted in the contralateral arm for systemic administration of apoA-I/PC disks at a dose of 80 mg/kg body weight over a period of 4 hours (ZLB Bioplasma AG). 19,20 Subsequently, all 3 infusion blocks were repeated.…”

Section: Study Protocolmentioning

confidence: 99%

Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein

et al. 2003

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Background-Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for familial hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these familial hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results-In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase N G -monomethyl-Larginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4Ϯ0.2 mmol/L; PϽ0.05), and their forearm blood flow responses to both 5HT (maximum, 49.0Ϯ10.4%) and L-NMMA (maximum, Ϫ22.8Ϯ22.9%) were blunted compared with control subjects (both PՅ0.005). Infusion of apoA-I/PC disks increased plasma HDL to 1.3Ϯ0.4 mmol/L in ABCA1 heterozygotes, which resulted in complete restoration of vasomotor responses to both 5HT and L-NMMA (both PՅ0.001). Endothelium-independent vasodilation remained unaltered throughout the protocol. Conclusions-In ABCA1 heterozygotes, isolated low HDL is associated with endothelial dysfunction, attested to by impaired basal and stimulated NO bioactivity. Strikingly, both parameters were completely restored after a single, rapid infusion of apoA-I/PC. These findings indicate that in addition to its long-term role within reverse cholesterol transport, HDL per se also exerts direct beneficial effects on the arterial wall. (Circulation. 2003;107:2944-2948.)

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Production and Characterization of a Reconstituted High Density Lipoprotein for Therapeutic Applications

Cited by 84 publications

References 47 publications

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

High-Density Lipoprotein Restores Endothelial Function in Hypercholesterolemic Men

Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein

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