Dysfunctional HDL as a Therapeutic Target for Atherosclerosis Prevention

2019 ◽  
Vol 26 (9) ◽  
pp. 1610-1630 ◽  
Author(s):  
Alice Ossoli ◽  
Chiara Pavanello ◽  
Eleonora Giorgio ◽  
Laura Calabresi ◽  
Monica Gomaraschi
Keyword(s):  
Reverse Cholesterol Transport ◽  
High Density Lipoproteins ◽  
Cholesterol Transport ◽  
Hdl Function ◽  
Investigational Drugs ◽  
Hdl Dysfunction ◽  
Atherosclerosis Prevention ◽  
Endothelial Homeostasis ◽  
Dysfunctional Hdl

Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Among the various lipoprotein classes, however, high density lipoproteins (HDL) are inversely associated with the incidence of atherosclerosis, since they are able to exert a series of atheroprotective functions. The central role of HDL within the reverse cholesterol transport, their antioxidant and anti-inflammatory properties and their ability to preserve endothelial homeostasis are likely responsible for HDL-mediated atheroprotection. However, drugs that effectively raise HDL-C failed to result in a decreased incidence of cardiovascular event, suggesting that plasma levels of HDL-C and HDL function are not always related. Several evidences are showing that different pathologic conditions, especially those associated with an inflammatory response, can cause dramatic alterations of HDL protein and lipid cargo resulting in HDL dysfunction. Established and investigational drugs designed to affect lipid metabolism and to increase HDL-C are only partly effective in correcting HDL dysfunction.

Abstract 29: Alpha-1-antitrypsin Protects High Density Lipoprotein From Functional Inactivation by Elastase

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Scott M Gordon ◽  
Denis Sviridov ◽  
Toshihiro Sakurai ◽  
Lita Freeman ◽  
Alan T Remaley
Keyword(s):  
Reverse Cholesterol Transport ◽  
Density Lipoprotein ◽  
High Density ◽  
Beta Particle ◽  
High Density Lipoproteins ◽  
Cholesterol Transport ◽  
Important Species ◽  
Hdl Function ◽  
Functional Inactivation ◽  
Alpha 1 Antitrypsin

High density lipoproteins (HDL) are complexes of lipid and protein with several known atheroprotective functions. These functions are driven by specific lipids and proteins contained on the HDL particle and include reverse cholesterol transport, suppression of inflammation, and modulation of endothelial function. These activities are most important within atherosclerotic plaque, a harsh environment where HDL interact with macrophage foam cells, activated neutrophils, and dysfunctional endothelial cells. Neutrophils and macrophages secrete proteases, such as elastase, which damage structural components and soluble proteins and propagate inflammatory signaling. It has been suggested that, in plaque, HDL become damaged and dysfunctional. We recently characterized a subspecies of HDL that carries the protein alpha-1-antitrypsin (A1AT), an abundant plasma serine protease inhibitor. In the current study, we tested the hypothesis that A1AT enriched HDL are protected from proteolytic damage and functional inactivation by elastase, the main protease inhibited by A1AT. Human HDL was isolated by ultracentrifugation and was enriched with A1AT by co-incubation and unbound A1AT was removed. Treatment of native HDL with elastase resulted in significant proteolytic degradation of both apoA-I and apoA-II, visualized by coomassie stained SDS-PAGE. Analysis of lipoprotein size by one dimensional native gel electrophoresis revealed that pre-beta HDL were completely degraded by elastase. Compared to native HDL, A1AT enriched HDL samples were protected from protein and pre-beta particle degradation by elastase. We next tested the effect of elastase treatment on HDL function. In native HDL, elastase had damaging effects on ABCA1 mediated cholesterol efflux (-32%; p<0.0001) and the ability to esterify free cholesterol (-14%; p<0.02). A1AT enriched HDL displayed no loss of functionality upon treatment with elastase. Both of these activities are required for HDL to perform what is thought to be its most important function, reverse cholesterol transport. In conclusion, the data presented indicate that HDL particles which contain A1AT may represent a functionally important species of HDL, which have an advantage in the protease-rich plaque environment.

scholarly journals Gasdermin D mediates inflammation-induced defects in reverse cholesterol transport and promotes atherosclerosis.

2021 ◽  
Author(s):  
Emmanuel Opoku ◽  
Cynthia Alicia Traughber ◽  
David Zhang ◽  
Amanda J Iacano ◽  
Mariam Khan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Reverse Cholesterol Transport ◽  
Foam Cell ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
Cholesterol Transport ◽  
Inflammasome Activation ◽  
Lesion Area ◽  
Direct Role

Nlrp3 inflammasome is activated in advanced human atherosclerotic plaques. Gasdermin D (GsdmD) serves as a final executor of Nlrp3 inflammasome activity, by generating membrane pores for the release of mature Interleukin-1beta (IL-b). Inflammation dampens reverse cholesterol transport (RCT) and promotes atherogenesis, while anti-IL-1b; antibodies were shown to reduce cardiovascular disease in humans. Though Nlrp3/IL-1b; nexus is an emerging atherogenic pathway, the direct role of GsdmD in atherosclerosis is not yet clear. Here, we used in-vivo Nlrp3 inflammasome activation to show that the GsdmD-/- mice release ~80% less IL-1b; vs WT mice. The GsdmD-/- macrophages were more resistant to Nlrp3 inflammasome mediated reduction in cholesterol efflux, showing ~26% decrease vs. ~60% reduction in WT macrophages. GsdmD expression in macrophages exacerbated foam cell formation in an IL-1b; dependent fashion. The GsdmD-/- mice were resistance to Nlrp3 inflammasome mediated defect in RCT, with ~32% reduction in plasma RCT vs. ~ 57% reduction in WT mice, ~ 17% reduction in RCT to liver vs. 42% in WT mice, and ~ 37% decrease in RCT to feces vs. ~ 61% in WT mice. The LDLr anti-sense oligonucleotides (ASO) induced hyperlipidemic mouse model showed role of GsdmD in promoting atherosclerosis. The GsdmD-/- mice exhibit ~42% decreased atherosclerotic lesion area in females and ~33% decreased lesion area in males vs. WT mice. The atherosclerotic plaque-bearing WT mice showed the presence of cleaved N-terminal fragment of GsdmD, indicating cleavage of GsdmD during atherosclerosis. Our data show that GsdmD mediates inflammation-induced defect in RCT and promotes atherosclerosis.

Abstract 631: Lipid Composition of Gold Nanoparticle-Templated High-Density Lipoprotein Analogs Dictates Cholesterol Efflux Function

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
R Kannan Mutharasan ◽  
Amritha T Singh ◽  
Kaylin M McMahon ◽  
C Shad Thaxton
Keyword(s):  
Fatty Acid ◽  
Lipid Content ◽  
Lipid Composition ◽  
Reverse Cholesterol Transport ◽  
Cholesterol Efflux ◽  
Lipid Membrane ◽  
Density Lipoprotein ◽  
High Density ◽  
High Density Lipoproteins ◽  
Cholesterol Transport

Background: Reverse cholesterol transport, the process by which cholesterol is effluxed from cells to high-density lipoproteins (HDL) and is delivered to the liver for clearance, is a promising pathway to augment for treatment of atherosclerosis. Though structure-function relationships for nascent, discoidal HDL and cholesterol efflux have been well studied, how the lipid composition of spherical HDL species - which varies in pathophysiological conditions - impacts their ability to mediate cholesterol efflux has not been investigated. Methods and Results: Spherical gold nanoparticles (5 nm) were used to synthesize spherical HDL analogs (HDL-NP) by adding ApoAI protein, and various lipids. With this strategy a panel of HDL-NP varying in lipid content was generated. HDL-NP designs tested include: dipalmitylphosphatidylcholine (DPPC, saturated fatty acid), dioleoylphosphatidylcholine (DOPC, unsaturated fatty acid), sphingomyelin, lysophosphatidylcholine (LPC), and mixtures thereof. All of these species are found in natural HDL. After characterizing protein and lipid stoichiometry of the purified HDL-NP, these HDL-NP designs were tested in the cellular reverse cholesterol transport assay using J774 mouse macrophages. These studies demonstrate that all HDL-NP designs mediate more efflux than equimolar amounts of ApoAI protein control, and further demonstrate that HDL-NP designs incorporating unsaturated phospholipid (DOPC), sphingomyelin, and LPC - each of which can increase disorder in the lipid membrane and thus give rise to opportunity for cholesterol to intercalate and bind - enhance cholesterol efflux compared to saturated phospholipid (DPPC) design. Conclusion: In summary, these results demonstrate that lipid content of HDL-NP - analogs of spherical HDL - dictates cholesterol efflux function, a finding which sheds light on the functional importance of lipid content variation seen in mature, spherical HDL species.

Abstract 1728: The Defect in HDL Function and Reverse Cholesterol Transport Found in Diabetic Mice with the Haptoglobin 2–2 Genotype Can Be Corrected with High Dose Antioxidant Therapy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Rabea O Asleh ◽  
Rachel Miller-Lotan ◽  
Zaid Abassi ◽  
Andrew P Levy
Keyword(s):  
Half Life ◽  
Reverse Cholesterol Transport ◽  
Fold Increase ◽  
Oxidative Modification ◽  
Antioxidant Therapy ◽  
Cholesterol Transport ◽  
High Dose ◽  
List Type ◽  
Free Hemoglobin ◽  
Hdl Function

Background. The primary function of the haptoglobin (Hp) protein is to clear free hemoglobin (Hb). Two common alleles exist at the Hp locus (1 and 2). We recently demonstrated that reverse cholesterol transport is impaired in individuals with Diabetes Mellitus (DM) and the Hp 2–2 genotype which may explain the increased incidence of cardiovascular disease in this population. We sought to test the hypothesis that clearance of the Hp 2-Hb complex is slower in DM allowing more complex to bind to HDL thereby resulting in increased oxidative modification of HDL and inhibition of reverse cholesterol transport and determine if antioxidant therapy could restore normal HDL function in Hp 2–2 DM mice. Methods and Results. Injection of 125 I-labeled Hp 1 or Hp 2-Hb complexes into non-DM mice demonstrated that the half-life of the Hp 2-Hb complex was 2–3 fold longer than the Hp 1-Hb complex (57.8 ± 2.8 vs. 20.4 ± 1.7 min). Moreover, in DM the half-life of the Hp 2-Hb complex was doubled while the half-life of the Hp 1-Hb complex was unchanged (103 ± 3.9 vs. 18.6 ± 1.8 min). Coimmunoprecipitation studies demonstrated that over 25% of the injected Hp 2-Hb complex was associated with HDL in DM mice representing a greater than 10 fold increase compared to Hp 1-Hb complex in non-DM mice. Coimmunoprecipitation studies in Hp 0 (knockout) mice demonstrated that the Hp protein was absolutely necessary for the interaction of Hb with HDL. Reverse cholesterol transport was impaired by DM in Hp 2 mice but this impairment was prevented by high dose antioxidant supplementation to these mice. Conclusions. These data may explain why the Hp 2 genotype promotes less efficient reverse cholesterol transport in DM and suggests that strategies targeted to decrease oxidation of HDL by the Hp 2-Hb complex may improve HDL function.

EPIGENETIC REGULATION OF REVERSE CHOLESTEROL TRANSPORT: THE ROLE OF MICRO-RNAS

2019 ◽  
Vol 17 (2) ◽  
Author(s):  
K.A. Aitbaev ◽  
R.R. Tuhvatshin ◽  
V.V. Fomin ◽  
I.T. Murkamilov ◽  
M.T. Talaibekov
Keyword(s):  
Epigenetic Regulation ◽  
Reverse Cholesterol Transport ◽  
Cholesterol Transport ◽  
Micro Rnas
Sign in / Sign up

Export Citation Format

Share Document