HDL-replacement therapy: mechanism of action, types of agents and potential clinical indications

Remaley, Alan T.; Amar, Marcelo; Sviridov, Dmitri

doi:10.1586/14779072.6.9.1203

Cited by 67 publications

(71 citation statements)

References 142 publications

(127 reference statements)

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“…HDL lipid composition may be altered in atherogenic dyslipidemia and associated with inflammatotry state. An increase in HDL-TG content is frequently found in an acute phase reactant setting and as consequence of increase CETP activity [6].Elevated plasma TG levels represent another important factor that lowers HDL particles stability and plasma residence time, leading to functionally defective HDL [21].Thus, it is clear that HDL particles can vary in their atheroprotective capacity, and functionally deficient HDL may be involved with other atherogenic factors in the development of atherosclerosis. In support of this, we observed an association between dysfunctionalilty in HDL and higher levels of serum TG, phospholipids, enhanced systemic oxidative stress and inflammatory response in few healthy subjects as well as in subjects with established CHD.…”

Section: Discussionmentioning

confidence: 99%

“…HDL appears to inhibit inflammation associated with atherosclerotic plaque development and regress atherosclerosis. HDL-replacement therapy is a promising new treatment strategy involving the acute administration of HDL to rapidly stabilize patients at imminent risk for developing a myocardial infarction, such as those with acute coronary syndrome [21].…”

Section: Introductionmentioning

confidence: 99%

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Functionally Defective High Density Lipoprotein is Pro-Oxidant: a Deviation from Normal Atheroprotective Character

Sini¹,

Jayakumari

2013

IJNFS

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High-density lipoprotein is a potential life saving antiatherogenic molecule. However, not all HDL is functionally similar, it can become dysfunctional and may increase atherosclerotic risk. At present, it is unknown, which structural alterations of HDL are essential accounting for its defective functionality and the precise pro-atherogenic mechanisms of action. This study is aimed at identification of the possible prevalence of dysfunctional HDL in subjects and its compositional and functional characterization in comparison to that of functional HDL. HDL was isolated from serum by ultracentrifugation and subjected to functional assays. HDL from majority of healthy subjects showed remarkable antioxidant property by inhibiting LDL oxidation. However, in those healthy subjects with systemic oxidative stress and inflammatory response as well as in those with known coronary heart disease, HDL was dysfunctional and promoted LDL oxidation. Dysfunctional HDL was truly pro-oxidant as it induced intracellular reactive oxygen species formation in cultured monocytes/macrophages. Functional deficiency in HDL did not show any association with HDL-cholesterol content. However, its characterization showed an enrichment of triglycerides, phospholipids, lipid peroxides, and diminished activity of paraoxonase-1, compared to functional HDL, which might render the particle dysfunctional and pro-oxidant.This study demonstrates the prevalence of dysfunctional HDL even among healthy subjects, despite normal HDL-C level, and in majority of subjects with known CHD, which is pro-oxidant in nature that might promote vascular inflammation and atherogenesis. The functional assay of HDL could lead to improved predictive accuracy of cardiovascular disease risk associated with circulating HDL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functionally Defective High Density Lipoprotein is Pro-Oxidant: a Deviation from Normal Atheroprotective Character

Sini¹,

Jayakumari

2013

IJNFS

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“…This finding led to the first positive clinical trial of HDL replacement therapy (Remaley et al 2008). However, the production of therapeutic quantities of recombinant HDL and the Milano variant is costly.…”

Section: Introductionmentioning

confidence: 99%

A Short Synthetic Peptide Mimetic of Apolipoprotein A1 Mediates Cholesterol and Globotriaosylceramide Efflux from Fabry Fibroblasts

et al. 2015

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Fabry disease is an X-linked sphingolipid storage disorder caused by a deficiency of the lysosomal enzyme agalactosidase A (AGA, EC 3.2.1.22) resulting in the intracellular accumulation of globotriaosylceramide (Gb3). We found that Gb3 storage also correlates with accumulation of endosomal-lysosomal cholesterol in Fabry fibroblasts. This cholesterol accumulation may contribute to the phenotypic pathology of Fabry disease by slowing endosomal-lysosomal trafficking. We found that LDL receptor expression is not downregulated in Fabry fibroblasts resulting in accumulation of both cholesterol and Gb3. 5A-Palmitoyl oleoyl-phosphatidylcholine (5AP) is a phospholipid complex containing a short synthetic peptide that mimics apolipoprotein A1, the main protein component of high-density lipoprotein (HDL) that mediates the efflux of cholesterol from cells via the ATP-binding cassette transporter. We used 5AP and HDL to remove cholesterol from Fabry fibroblasts to examine the fate of accumulated cellular Gb3. Using immunostaining techniques, we found that 5AP is highly effective for depleting cholesterol and Gb3 in these cells. 5AP restores the ApoA-1-mediated cholesterol efflux leading to mobilization of cholesterol and reduction of Gb3 in Fabry fibroblasts.

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“…1,[7][8][9]13 Even when synthetic ApoA-I mimic peptide was used to assemble HDL drug delivery carriers, chromatographic purification of nanoparticles was required postassembly. 10,14 In this study, we used a different amphipathic helix peptide, 5A, which is designed to bind lipids with high affinity and form stable sHDL particles.…”

mentioning

confidence: 99%

“…Several formulation strategies have utilized preferential partitioning of the lactone into the hydrophobic lipid phase to improve lactone stability and CPT efficacy including liposomes, emulsions, nanoparticles, and microspheres. 13,[19][20][21][22] It is also reported that HDL reconstituted with ApoA-I cysteine mutants was used as delivery vehicles for HCPT. 7 The goal of this study was to develop a novel 5A-peptidebased sHDL delivery system for treatment of colon carcinoma.…”

mentioning

confidence: 99%

Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin

Yuan

Wen

Tang

et al. 2016

IJN

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HDL-replacement therapy: mechanism of action, types of agents and potential clinical indications

Cited by 67 publications

References 142 publications

Functionally Defective High Density Lipoprotein is Pro-Oxidant: a Deviation from Normal Atheroprotective Character

Functionally Defective High Density Lipoprotein is Pro-Oxidant: a Deviation from Normal Atheroprotective Character

A Short Synthetic Peptide Mimetic of Apolipoprotein A1 Mediates Cholesterol and Globotriaosylceramide Efflux from Fabry Fibroblasts

Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin

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