Anti-inflammatory Properties Of HDL Research Articles

Abstract P139: Diet-induced Shifts In HDL Profiles Are Associated With Changes In Immune Parameters

Introduction: Preclinical and population-based studies have demonstrated immunomodulatory and anti-inflammatory properties of HDL; however, it is unclear whether diet-induced changes in HDL profiles can directly impact markers of immune inflammation. Hypothesis: We hypothesized that daily consumption of different egg-based diets, which have been shown to differentially impact serum lipids and lipoprotein profiles, would induce changes in HDL parameters that correspond to shifts in clinical and molecular immune markers. Methods: Healthy men and women (18-35y, BMI < 30kg/m 2 or < 30% body fat for men and < 40% body fat for women, n = 26) participated in a 16-week randomized, crossover intervention trial (NCT03577223), in which they consumed an egg-free diet for 4 weeks, followed by a 4-week diet containing either 3 whole eggs or 3 egg whites per day. Participants then followed a 4-week egg-free diet washout period, before switching to the alternative whole egg or egg white diet treatment. Fasting lipoprotein profiles, complete blood cell counts, and gene expression in peripheral blood mononuclear cells (PBMCs) was measured at the end of each diet period. Results: While no changes in total HDL particles, average HDL particle diameter, or the concentration of small (7.4-8.0 nm) or medium (8.1-9.5 nm) HDL particles was observed, the concentration of large HDL particles (10.8nm) was increased by whole egg intake as compared to intake of egg whites. A trend toward increased apolipoprotein A1 during the whole egg diet period as compared to the egg-free diet period was additionally observed. In line with our hypothesis, changes in large HDL concentrations between whole egg vs. egg white periods were inversely correlated with total white blood cell counts and absolute lymphocyte counts. CD8A mRNA expression in PBMCs was inversely correlated with concentrations of total and large HDL particles. Importantly, while serum choline and betaine were increased by whole egg intake compared to the other diet periods, no differences in pro-atherogenic and inflammatory trimethylamine-N-oxide (TMAO) between diet periods was observed. Conclusion: These findings suggest that diet-induced changes in HDL profiles are directly associated with changes in immune parameters.

Effects of exercise on HDL functionality.

Low HDL-cholesterol (HDL-C) levels are a strong predictor of cardiovascular disease risk and can be improved with regular exercise. However, raising HDL-C levels pharmacologically has not shown convincing clinical benefits. Thus, research has recently focused on identifying therapies that improve HDL function, with exercise representing such a potential therapy. The purpose of this review is to summarize the effects of exercise interventions on HDL function. The effects of exercise and lifestyle interventions on the primary atheroprotective functions of HDL are reviewed, namely, cholesterol efflux, antioxidative, and anti-inflammatory properties. Differences in study design, study population, and assays are discussed to aid in the interpretation of the reviewed studies. There is mixed evidence that regular aerobic exercise improves cholesterol efflux capacity, with recent research suggesting an exercise dose threshold needs to be exceeded to produce beneficial effects. There is preliminary evidence that exercise improves the antioxidative and anti-inflammatory properties of HDL. Although exercise represents a potential therapeutic approach to improve HDL function, the heterogeneity and/or lack of findings warrants more and larger studies to determine what HDL function(s) are most responsive to regular exercise and what dose of exercise elicits the greatest improvements in HDL functionality.

Serum Paraoxonase-1 Levels are Significantly Decreased in the Presence of Insulin Resistance.

Paraoxonase-1 (PON1) is an extracellular esterase contributing to the anti-atherogenic and anti-inflammatory properties of HDL and has a protective role in the progression of atherosclerosis. The aim of the present study was to compare serum paraoxonase-1 levels between obese subjects with prediabetes and normal glucose tolerance. In this study were included 76 patients with mean age 50.7±10.7 years, divided into 2 age and BMI-matched groups - group 1 with obesity without glycemic disturbances (n=38) and group 2 with prediabetes (n=38). Oral glucose tolerance test (OGTT) with measurement of immunoreactive insulin was performed in all participants and levels of PON1 were measured using ELISA method. There was only a tendency towards higher PON1 levels in patients with prediabetes compared to controls. However, individuals with insulin resistance had significantly lower levels of PON1 compared to those without. The levels of PON1 showed a negative correlation with the blood glucose on 120th minute of OGTT, fasting IRI, HOMA index, BMI, WSR, WHR and particularly with waist circumference and positive with HDL-cholesterol. The levels of PON1 are similar in patients with and wthout prediabetes, but are significantly decreased in patients with insulin resistance and correlate with anthropometric markers of visceral adiposity.

Abstract 241: Anti-Inflammatory Properties of Cynomolgus Monkey and Rabbit High-Density Lipoprotein Following Treatment With Recombinant Lecithin Cholesterol Acyltransferase

Introduction: Lecithin cholesterol acyltransferase (LCAT) modulates HDL formation and increases HDL-C. Anti-inflammatory properties of HDL may be atheroprotective. We evaluated HDL from rabbits and cynomolgus monkeys treated with recombinant LCAT (rLCAT) to determine its anti-inflammatory properties. Methods: HDL from serum was isolated by ultracentrifugation. HUVECs were treated with HDL, stimulated with TNFα, and mRNA expression of VCAM-1, E-Selectin, and ICAM-1 was measured. Results: TNFα induced adhesion molecule expression in HUVECs treated with HDL (0.3 mg/mL) from rLCAT treated rabbits was reduced (E-Selectin) or similar (VCAM-1, ICAM-1) compared to pre-dose HDL. Using HDL (0.3 mg/mL) from rLCAT treated cynomolgus monkeys reduced expression of E-Selectin, VCAM-1, and ICAM-1 compared to control (pre-dose or vehicle) HDL in a rLCAT dose-dependent manner. In HUVECs treated with cynomolgus monkey HDL at concentrations normalized to serum HDL-C, adhesion molecule expression was reduced but showed a different profile. HDL after treatment with 1 or 5 mpk rLCAT reduced expression more than HDL from controls, while HDL after treatment with 20 or 150 mpk rLCAT blocked expression less than controls. Conclusions: HDL from rabbits and cynomolgus monkeys after rLCAT treatment was equally or more anti-inflammatory compared to control HDL when tested at a fixed concentration, a measure of HDL quality. To account for treatment changes to both HDL quality and quantity, HDL was tested relative to serum HDL-C. In this case, HDL from the 1 mpk group proved most efficacious in reducing TNFα stimulated adhesion molecule expression compared to vehicle HDL or HDL from higher doses.

Volumetric determination of apolipoprotein stoichiometry of circulating HDL subspecies

Although HDL is inversely correlated with coronary heart disease, elevated HDL-cholesterol is not always protective. Additionally, HDL has biological functions that transcend any antiatherogenic role: shotgun proteomics show that HDL particles contain 84 proteins (latest count), many correlating with antioxidant and anti-inflammatory properties of HDL. ApoA-I has been suggested to serve as a platform for the assembly of these protein components on HDL with specific functions - the HDL proteome. However, the stoichiometry of apoA-I in HDL subspecies is poorly understood. Here we use a combination of immunoaffinity chromatography data and volumetric analysis to evaluate the size and stoichiometry of LpA-I and LpA-I,A-II particles. We conclude that there are three major LpA-I subspecies: two major particles, HDL[4] in the HDL3 size range (d = 85.0 ± 1.2 Å) and HDL[7] in the HDL2 size range (d = 108.5 ± 3.8 Å) with apoA-I stoichiometries of 3 and 4, respectively, and a small minor particle, HDL[1] (d = 73.8 ± 2.1Å) with an apoA-I stoichiometry of 2. Additionally, we conclude that the molar ratio of apolipoprotein to surface lipid is significantly higher in circulating HDL subspecies than in reconstituted spherical HDL particles, presumably reflecting a lack of phospholipid transfer protein in reconstitution protocols.

OP0117 HDL-C and HBA1C predict the development of inflammatory polyarthritis: Results from the european prospective investigation of cancer (norfolk) and the norfolk arthritis register (EPIC-2-NOAR study)

BackgroundRheumatoid Arthritis (RA) is associated with accelerated atherosclerosis and inflammation associated with RA may increase the propensity to develop dyslipidaemia and insulin resistance. In established RA, HDL-C (HDL) and ApoA-1...

Inhibition of cholesteryl ester transfer protein by anacetrapib does not impair the anti-inflammatory properties of high density lipoprotein

Cholesteryl ester transfer protein (CETP) is a target of therapeutic intervention for coronary heart disease. Anacetrapib, a potent inhibitor of CETP, has been shown to reduce LDL-cholesterol by 40% and increase HDL-cholesterol by 140% in patients, and is currently being evaluated in a phase III cardiovascular outcomes trial. HDL is known to possess anti-inflammatory properties, however with such large increases in HDL-cholesterol, it is unclear whether CETP inhibition perturbs HDL functionality such as anti-inflammatory effects on endothelial cells. The purpose of the present study was to determine whether CETP inhibition by anacetrapib affects the anti-inflammatory properties of HDL. HDL was isolated from either hamsters treated with vehicle or anacetrapib for 2weeks, or from normal human subjects treated either placebo, 20mg, or 150mg anacetrapib daily for 2weeks. Anacetrapib treatment increased plasma HDL cholesterol levels by 65% and between 48 and 82% in hamsters and humans, respectively. Pre-incubation of human aortic endothelial cells with HDL isolated from both control and anacetrapib treated hamsters suppressed TNFα induced expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Similar results were obtained with human HDL samples pre and post treatment with placebo or anacetrapib. Further, HDL inhibited TNFα-induced MCP-1 secretion, monocyte adhesion and NF-κB activation in endothelial cells, and the inhibition was similar between control and anacetrapib treated groups. These studies demonstrate that anacetrapib treatment does not impair the ability of HDL to suppress an inflammatory response in endothelial cells.

Prophylactic Effect of Tadalafil on Bladder Function in a Rat Model of Chronic Bladder Ischemia

We investigated the effect of tadalafil on chronic ischemia related bladder dysfunction. Adult male Sprague-Dawley® rats were divided into control, arterial endothelial injury and arterial endothelial injury with tadalafil treatment groups. The arterial injury and arterial injury-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet after injury. Arterial injury-tadalafil rats received tadalafil (2 mg/kg per day) orally for 8 weeks after injury. The control group received a regular diet. At 8 weeks urodynamic investigation was performed. Bladder tissue was harvested for pharmacological studies, and histological examination of the iliac arteries and bladders was performed. Iliac arteries from arterial injury and arterial injury-tadalafil rats showed neointimal formation and luminal occlusion. In the arterial injury group the micturition interval was significantly shorter (mean ± SEM 5.4 ± 0.5 vs 11.1 ± 1.1 minutes), and bladder capacity and voided volume were less than in controls. Contractile responses of bladder strips to KCl, electrical field stimulation and carbachol were significantly less after arterial injury than in controls. The arterial injury group showed a significantly increased percent of collagen compared with controls (mean 37.4% ± 1.8% vs 21.5% ± 1.8%). In the arterial injury-tadalafil group intimal formation and luminal occlusion were not prevented. However, there were significant improvements in all functional and morphological parameters compared with the arterial injury group. Arterial occlusive disease may lead to chronic bladder ischemia and bladder hyperactivity. Chronic treatment with tadalafil protects bladder function and morphology, resulting in decreased bladder hyperactivity. If valid for humans, the data support phosphodiesterase 5 inhibition as treatment for chronic ischemia related bladder dysfunction.

Apolipoprotein A-I and A-I mimetic peptides: a role in atherosclerosis

Cardiovascular disease remains a major cause of morbidity and mortality in the westernized world. Atherosclerosis is the underlying cause of most cardiovascular diseases. Atherosclerosis is a slowly evolving chronic inflammatory disorder involving the intima of large and medium sized arteries that is initiated in response to high plasma lipid levels, especially LDL. Cells of both the innate and adaptive immunity are involved in this chronic inflammation. Although high plasma LDL levels are a major contributor to most stages of the evolution of atherosclerosis, HDL and its major protein apoA-I possess properties that attenuate and may even reverse atherosclerosis. Two major functions are the ability to induce the efflux of cholesterol from cells, particularly lipid-loaded macrophages, in the artery wall for transfer to the liver, a process referred to as reverse cholesterol transport, and the ability to attenuate the pro-inflammatory properties of LDL. The removal of cellular cholesterol from lipid-loaded macrophages may also be anti-inflammatory. One of the most promising therapies to enhance the anti-atherogenic, anti-inflammatory properties of HDL is apoA-I mimetic peptides. Several of these peptides have been shown to promote cellular cholesterol efflux, attenuate the production of pro-inflammatory cytokines by macrophages, and to attenuate the pro-inflammatory properties of LDL. This latter effect may be related to their high affinity for oxidized lipids present in LDL. This review discusses the functional properties of the peptides and their effect on experimental atherosclerosis and the results of initial clinical studies in humans.

ANTI-INFLAMMATORY PROPERTIES OF HDL AFTER SHORT-TERM EXERCISE TRAINING WITHOUT ANY SPECIFIC DIET IN PATIENTS WITH METABOLIC SYNDROME

Introduction: Recent study showed that short-term exercise, associated with diet and weight loss, improves the anti-inflammatory properties of HDL in metabolic syndrome (MetS). However, diet and weight loss, per se, can alter the functionality of HDL and, in real life many patients do not follow the medical counseling of diet and exercise simultaneously. We showed previously that the antioxidative characteristics and the capacity to accept lipids of HDL are early improved by short-term exercise training (Tr) with no diet associated. (1). Objectives: We sought to verify whether the anti-inflammatory properties of HDL are affected by Tr, without any diet associated, in patients with MetS. Methods: Forty sedentary persons (30 withMetS,10 controls) were evaluated. Twenty of those with MetS were subjected to a 3 times/week training load(45 min/day) for 3 months on a bicycle ergometer. Plasma high-sensitivity C-reactive protein (hs-CRP) was analyzed and HDL subfractions were obtained by plasma ultracentrifugation. (2). Endothelial cells were cultured, stimulated with TNF-_ and lipopolysacharide, and coincubated with HDL sub fractions obtained before and after Tr. Sequentially, those cultures of endothelial cells were coincubated with THP-1 cells labeled with a fluorescent marker. The labeled THP-1 cells that adhered on endothelial cells were counted under fluoroscopic microscope. Results: Baseline plasma levels of HDL-C were lower in the MetS group compared to controls and Tr did not change neither HDL-C nor weight in MetS group. Hs-CRP plasma levels from patients with MetS were higher than controls (3.0 _ 1.5 vs1.5 _ 1.5 mg/L respectively, p_0.05) and did not change after Tr (3.0 _ 1.5 vs2.8 _ 1.8 mg/L, before and after Tr respectively, p_0.05). The number of adhered labeled THP-1 cells coincubated with endothelial cells did not change significantly when mixed with HDL2a or HDL3b from patients with MetS after Tr, compared with HDL2a or HDL3b obtained before Tr. Conclusion: Our results showed that Tr did not change an inflammatory serum marker (hs-CRP) and the adherence of THP-1 cells on endothelium cells, suggesting that the anti-inflammatory properties of HDL are not early improved by short-term exercise, when there is no diet associated.

Dual effect of hypochlorite in the modification of high density lipoproteins

HDL-cholesterol levels are inversely correlated to the risk of cardiovascular disease. In recent years the concept that not only the quantity, but also the quality of HDL is related to their atheroprotective function has gained momentum. In fact several studies have showed that HDL can shift their properties from anti-atherogenic to pro-atherogenic upon chemical or enzymatic “modification”. However, not all kind of modifications affect the antiatherogenic properties of HDL. For example, tyrosylation of HDL improves its ability to remove cholesterol from cultured cells and inhibits mice atherosclerotic lesion formation; oxidation of HDL 3 with 15-lipoxygenase or with copper ions for short time induce the formation of pre-β-migrating particles that are highly effective as cholesterol acceptors from lipid laden cells. Myeloperoxidase modifies HDL and apoA-I and reduces their ability to promote ABCA1-mediated cholesterol efflux. In the present study we show that modification with low concentration HOCl (a myeloperoxidase product) induces the formation of pre-β-migrating particles, thus improving the function of HDL in the reverse cholesterol transport, without affecting the anti-inflammatory activity. At higher HOCl concentration, pre-β-migrating particles were not detectable and the anti-inflammatory properties of HDL were lost. These findings suggest that during early phases of inflammation, when a low HOCl concentration is generated, changes in HDL occur that increase their ability to remove cholesterol and sparing anti-inflammatory properties; later during acute inflammation, when higher HOCl concentration are present changes in HDL occur that severely decrease their ability to remove cholesterol from macrophages and to protect endothelial cells from pro-inflammatory stimuli.

L-4F Differentially Alters Plasma Levels of Oxidized Fatty Acids Resulting in more Anti-Inflammatory HDL in Mice

To determine in vivo if L-4F differentially alters plasma levels of oxidized fatty acids resulting in more anti-inflammatory HDL. Injecting L-4F into apoE null mice resulted in a significant reduction in plasma levels of 15-HETE, 5-HETE, 13-HODE and 9-HODE. In contrast, plasma levels of 20-HETE were not reduced and plasma levels of 14,15-EET, which are derived from the cytochrome P450 pathway, were elevated after injection of L-4F. Injection of 13(S)-HPODE into wild-type C57BL/6J mice caused an increase in plasma levels of 13-HODE and 9-HODE and was accompanied by a significant loss in the anti-inflammatory properties of HDL. The response of atherosclerosis resistant C3H/HeJ mice to injection of 13(S)-HPODE was similar but much more blunted. Injection of L-4F at a site different from that at which the 13(S)-HPODE was injected resulted in significantly lower plasma levels of 13-HODE and 9-HODE and significantly less loss of HDL anti-inflammatory properties in both strains. i) L-4F differentially alters plasma levels of oxidized fatty acids in vivo. ii) The resistance of the C3H/HeJ strain to atherosclerosis may in part be mediated by a reduced reaction of this strain to these potent lipid oxidants.

Abstract 4905: High Density Lipoprotein is Dysfunctional in Primary Antiphospholipid Syndrome and is Associated With Impaired Vascular Function

Objectives: Antiphospholipid syndrome is characterised by increased thrombogenicity and/or pregnancy morbidity in the presence of raised levels of antiphospholipid antibodies (aPL). Increased oxidative properties of HDL (decreased activity of paraoxonase (PON) and accelerated atherosclerosis have been described in this syndrome. In this study, we assessed the functional properties of HDL and evaluated its impact on the vasculature in aPL positive patients and matched controls. Methods: We studied 77 women with positive aPL (APL) aged 46.6 ± 1.2 yrs (mean ± SE) and matched Controls of 77 women aged 47.5 ± 1.2 yrs. In all subjects, carotid intima media thickness (IMT), flow mediated dilatation (FMD) and pulse wave velocity (PWV) were measured. PON activity was assessed by measuring p-nitrophenol formation. HDL was isolated in APL (N = 6) and Controls (N = 6). The impact of HDL on human aortic endothelial cell (HAEC) nitric oxide (NO) and superoxide production were determined. Anti-inflammatory properties of HDL were examined by analyzing the effect of HDL on endothelial cell VCAM-1 expression and monocyte adhesion to activated HAEC. Results: APL had significantly increased IMT and PWV compared to Controls (0.75 ± 0.02mm vs 0.65 ± 0.01mm, p < 0.001 and 9.14 ± 0.18 m/s vs 8.56 ± 0.21m/s, p < 0.05 respectively) and decreased FMD (6.2 ± 0.5% vs 9.6 ± 0.5%, p < 0.001). PON activity was significantly reduced in APL compared to Controls (p = 0.006). PON activity was inversely associated with cIMT and PWV in APL (p < 0.05 for both) but not in Controls. HDL from Controls increased endothelial cell NO production, whereas in marked contrast HDL from APL reduced NO production by 20% (p < 0.0001). The beneficial effect of HDL on endothelial VCAM-1 expression, superoxide production and monocyte adhesion was diminished in APL (p < 0.05 for all). Conclusions: APL is associated with impaired vascular function and structure. PON activity is decreased in APL and is inversely associated with IMT and PWV. HDL in APL is associated with decreased endothelial NO production and has impaired anti-inflammatory and anti-oxidant properties. These findings suggest that HDL is dysfunctional in APL and support its role in promoting early vascular changes in antiphospholipid syndrome.

Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL

HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.

Mo-P1:114 Evidence that glycation of apolipoprotein A-I inhibits the anti-inflammatory properties of HDL in vivo

Mo-P1:114 Evidence that glycation of apolipoprotein A-I inhibits the anti-inflammatory properties of HDL in vivo

Anti-inflammatory properties of HDL.

Anti-inflammatory properties of HDL.

ApoA-II Versus ApoA-I

Apolipoprotein A-I (apoA-I), the major protein of HDL, is probably among the most intensively studied of all proteins. It functions in HDL assembly, in the removal of excess cholesterol from cells, and in the transport of cholesterol from peripheral tissues to the liver, a process known as “reverse cholesterol transport.” It is a cofactor for lecithin:cholesterol acyl transferase (LCAT), the enzyme responsible for cholesterol esterification in HDL, and it stabilizes certain antioxidant enzymes, such as serum paraoxonase, that are carried on HDL.1,2 Rare null mutations of apoA-I in human populations are associated with early coronary heart disease,3 and overexpression of apoA-I in transgenic mice protects against atherogenesis.4 An exciting recent development was the 4-angstrom-resolution x-ray structure for the helical part of apoA-I, encompassing residues 44 to 243 (reviewed by Segrest et al5). See page 1977 In contrast, apolipoprotein A-II (apoA-II), the second most abundant protein of HDL, has no known function, and it has been the subject of few detailed studies. Its presence in HDL has been reported to decrease,6 or have no influence on, cholesterol efflux from cells,7,8 nor is it a cofactor for any known enzyme. Rare individuals lacking apoA-II appear to have normal plasma lipids.9 In fact, all of the known effects of apoA-II are deleterious. In studies with mice and humans, apoA-II levels have been associated with increased susceptibility to atherosclerosis,10–13 increased free fatty acid levels,14,15 increased body fat,15,16 and increased insulin resistance.15,17 Undoubtedly, apoA-II has some unknown beneficial functions, possibly related to fatty acid metabolism or host defense. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , …