High-density Lipoprotein Protect Research Articles

Synergistic Anti-Inflammatory Activity of Apolipoprotein A-I and CIGB-258 in Reconstituted High-Density Lipoproteins (rHDL) against Acute Toxicity of Carboxymethyllysine in Zebrafish and Its Embryo.

CIGB-258 is a 3 kDa altered peptide ligand from heat shock protein (HSP) 60 that exhibits anti-inflammatory activity against the acute toxicity of carboxymethyllysine (CML) with antioxidant and anti-glycation activities via protection of high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I). It is necessary to test a synergistic interaction between apoA-I and CIGB-258 in reconstituted high-density lipoproteins (rHDL). Several rHDLs were synthesized containing palmitoyloleoyl phosphatidylcholine (POPC), cholesterol, apoA-I, and CIGB-258 at molar ratios of 95:5:1:0, 95:5:1:0.1, 95:5:1:0.5, and 95:5:1:1 for rHDL-(1:0), rHDL-(1:0.1), rHDL-(1:0.5), and rHDL-(1:1), respectively. As the CIGB-258 content in rHDL was increased, the particle size of rHDL was 1.4-times higher than rHDL-(1:0) to rHDL-(1:1), from 60 nm to 83 nm, respectively. As the CIGB-258 content was increased, the rHDL showed the most resistance to isothermal denaturation by a urea treatment, and rHDL-(1:1) exhibited the highest structural stability and the strongest antioxidant ability against LDL oxidation. Co-treatment of rHDL-(1:0), rHDL-(1:0.5), and rHDL-(1:1) resulted in up to 10%, 24%, and 34% inhibition of HDL glycation, inhibition of HDL glycation, which was caused by the CML, with protection of apoA-I. Microinjection of each rHDL into zebrafish embryos in the presence of CML showed that a higher CIGB-258 content in rHDL was associated with higher survivability with the least inflammation and apoptosis. Furthermore, an intraperitoneal injection of rHDL and CML showed that a higher CIGB-258 content in rHDL was also associated with higher survivability of zebrafish and faster recovery of swimming ability. The rHDL-(1:1) group showed the lowest triglyceride, AST, and ALT serum levels with the least production of interleukin-6, oxidized product, and neutrophil infiltration in hepatic tissue. In conclusion, CIGB-258 could bind well to phospholipids and cholesterol to stabilize apoA-I in the rHDL structure against denaturation stress and larger particle sizes. The rHDL containing CIGB-258 enhanced the in vitro antioxidant ability against LDL oxidation, the anti-glycation activity to protect HDL, and the in vivo anti-inflammatory activity against CML toxicity in zebrafish adults and embryos. Overall, incorporating apoA-I and CIGB-258 in rHDL resulted in a synergistic interaction to enhance the structural and functional correlations in a dose-dependent manner of CIGB-258.

Effect of Annurca Apple Extract on Anti-hyper Cholesterol Action of a RYR based Formulation

Recently, European Authorities imposed that any product for daily consumption shall provide less than 3 mg of monacolins from red yeast rice (RYR). This obliges to find new formulations able to guarantee an effect on cholesterol levels close to that performed by 10 mg of monacolin K. Two different formulations based on chitosan and xanthan gum containing 10 mg of lovastatin from RYR and a combination of lovastatin (3 mg) from RYR and annurca apple extract (AC), respectively, were compared to verify their anti-hyper cholesterol action in terms of inhibition of HMG-CoA reductase enzyme, protection of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) from oxidation and total free cholesterol depletion. Results highlighted that the combination of RYR and AC represents a valid alternative to the use of high dose of monacolin K. Indeed, formulations containing both nutraceuticals showed a significantly higher activity in terms of inhibition of HMG-CoA reductase, antioxidant activity towards both HDL and LDL and depletion of free cholesterol

A decreased level of high-density lipoprotein is a possible risk factor for type 2 diabetes mellitus: A review.

Type 2 diabetes mellitus (T2DM) is characterized primarily by dyslipidemia and hyperglycemia due to insulin resistance. High-density lipoprotein (HDL) play a significant role in preventing the incidence of dyslipidemia and its complications. HDL has different protective functions, such as reducing oxidation, vascular inflammation, and thrombosis; additionally, its anti-diabetic role is one of the most significant recent discoveries about HDL and some of its constituent lipoproteins. This research reviews ongoing studies and preliminary investigations into the assessment of relation between decreased level of HDL and T2DM. The levels of HDL and its functions contribute to glucose hemostasis and the development of T2DM through four possible mechanisms, including insulin secretion by beta cells, peripheral insulin sensitivity, non-insulin-dependent glucose uptake, and adipose tissue metabolic activity. Additionally, the anti-oxidant properties of HDL protect beta cells from apoptosis caused by oxidative stress and inflammation induced by low-density lipoprotein, which facilitate insulin secretion. Therefore, HDL and its compositions, especially Apo A-I, play an important role in regulating glucose metabolism, and decreased levels of HDL can be considered a risk factor for DM. Different factors, such as hypoalphalipoproteinemia that manifests as a consequence of genetic factors, such as Apo A-I deficiency, as well as secondary causes arising from lifestyle choices and underlying medical conditions that decrease the level of HDL, could be associated with DM. Moreover, intricate connections between HDL and diabetic complications extend beyond glucose metabolism to encompass complications like cardiovascular disease and kidney disease. Therefore, the exact interactions between HDL level and DM should be evaluated in future studies.

Lipoprotein modulation of proteinuric renal injury

High-density lipoprotein (HDL) and its main protein, apolipoprotein AI (apoAI), have established benefits in various cells, but whether these cytoprotective effects of HDL pertain to renal cells is unclear. We investigated the in vitro consequences of exposing damaged podocytes to normal apoAI, HDL, and apoAI mimetic (L-4F), and the in vivo effects of L-4F on kidney and atherosclerotic injury in a podocyte-specific injury model of proteinuria. In vitro, primary mouse podocytes were injured by puromycin aminonucleoside (PAN). Cellular viability, migration, production of reactive oxygen species (ROS), apoptosis, and the underlying signaling pathway were assessed. In vivo, we used a proteinuric model, Nphs1-hCD25 transgenic (NEP25+) mice, which express human CD25 on podocytes. Podocyte injury was induced by using immunotoxin (LMB2) and generated a proteinuric atherosclerosis model, NEP25+:apoE−/− mice, was generated by mating apoE-deficient (apoE−/−) mice with NEP25+ mice. Animals received L-4F or control vehicle. Renal function, podocyte injury, and atherosclerosis were assessed. PAN reduced podocyte viability, migration, and increased ROS production, all significantly lessened by apoAI, HDL, and L-4F. L-4F attenuated podocyte apoptosis and diminished PAN-induced inactivation of Janus family protein kinase-2/signal transducers and activators of transcription 3. In NEP25+ mice, L-4F significantly lessened overall proteinuria, and preserved podocyte expression of synaptopodin and cell density. Proteinuric NEP25+:apoE−/− mice had more atherosclerosis than non-proteinuric apoE−/− mice, and these lesions were significantly decreased by L-4F. Normal human apoAI, HDL, and apoAI mimetic protect against podocyte damage. ApoAI mimetic provides in vivo beneficial effects on podocytes that culminate in reduced albuminuria and atherosclerosis. The results suggest supplemental apoAI/apoAI mimetic may be a novel candidate to lessen podocyte damage and its complications.

Exercise training prevented endothelium dysfunction from particulate matter instillation in Wistar rats

Exposure to fine particulate matter (PM2.5) can result in adverse cardiovascular responses including vascular endothelial dysfunction, whereas exercise training can promote cardiovascular health. However, whether exercise training can mitigate adverse vascular response to PM2.5 has been less studied. In the present study, we aimed to investigate the preventive effect of exercise training on vascular endothelial dysfunction induced by PM2.5 instillation. Six-week old male Wistar rats (n = 32) were divided into four groups (8 rats per group) by exercise status (sedentary vs. exercised) and PM2.5 exposure (instilled vs. non-instilled). Rats received treadmill training with moderate-intensity intervals in week 1 to 6, followed by three repeated PM2.5 instillation on every other day in week 7. Body weight and blood pressure were measured for each rat regularly during exercise training and before sacrifice. At sacrifice, thoracic aortas were isolated for functional response measurement to agonists. Nitric oxide bioavailability and high-density lipoprotein (HDL) function were also assessed. We observed that exercise training significantly reduced the body weight of rats, while PM2.5 instillation had little effect. Neither exercise training nor PM2.5 instillation had significant effects on blood pressure changes. However, exercise training effectively prevented endothelium-dependent vasorelaxation dysfunction and nitric oxide bioavailability reduction from subsequent PM2.5 instillation. In addition, exercise training promoted HDL function which were characterized as increased HDL cholesterol level, cholesterol efflux capacity, and reduced oxidization index; whereas PM2.5 instillation showed limited adverse impact on HDL function. Collectively, our results indicated that exercise training could promote HDL function and protect against endothelium dysfunction from PM2.5 instillation.

Association of serum paraoxonase activity with lipid profile, APO-A and APO-B in subjects with different levels of HDL

BackgroundCoronary heart diseases are inversely related to plasma high-density lipoprotein (HDL) level. Paraoxonase-1 (PON1) is mainly associated with HDL and plays a vital role in protection of low-density lipoprotein (LDL) and HDL. The aim of this study was to investigate the association between paraoxonase activity (PON1) with lipid profile, apoA-І, apoB and apoB/apoA-І ratio in subjects with different level of HDL cholesterol (HDL-C). Methods135 subjects, 20–60 years old, contributed to this study. The subjects were divided into three groups (45 in each group) with different levels of HDL-C (High, Normal and Low). For each group, the activity of PON1 was measured using paraoxon as a substrate. Moreover, the serum level of lipid profile, ApoA and apoB were measured. The statistical analysis was performed using SPSS software. ResultsPON-1 activity and apoA-І level were decreased in subjects with lower level of HDL-C (P < 0.001). ApoB and apoB/apoA-І ratio were higher in subjects with lower level of HDL-C (P < 0.001). Serum PON-1 activity was positively correlated with TC, TG, apo A-B, and LDL-C levels (P < 0.01). ConclusionsIn conclusion, determination of serum PON1 activity and lipoproteins may play important role in earlier prediction of CAD and help to design a therapeutic for treatment of CAD toward PON1 activity regulation.

Protective role of high density lipoproteins in sepsis: basic issues and clinical implications

High density lipoproteins (HDL) are responsible of reverse cholesterol transport and play an important antiatherogenic role. In recent years, several studies suggest that HDL have additional functions, including a possible anti-inflammatory activity in infectious conditions. Furthermore, available evidence indicates that the presence of lipopolysaccharide (LPS) within the circulation during infectious states induced by gram-negative bacteria may be involved in the decrease in HDL cholesterol levels and changes in lipoprotein composition, which have been associated with a higher mortality due to sepsis in animal models and in humans. In this article, we review this subject and also discuss possible mechanisms that explain the positive impact achieved by native HDL, reconstituted HDL, or HDL apolipoprotein peptides on the inflammatory response and mortality in models of endotoxemia. In this regard, it has been proposed that one of the mechanisms by which HDL protect against sepsis may be mediated by its binding ability and/or neutralizing capacity on LPS, avoiding an excessive response of the immune system. Thus, increasing blood levels of HDL and/or parenteral HDL administration may represent a new anti-inflammatory tool for managing septic states in humans.

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this "HDL hypothesis". In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct.

Involvement of 4E-BP1 in the Protection Induced by HDLs on Pancreatic β-Cells

High-density lipoproteins (HDLs) protect pancreatic beta-cells against apoptosis. This property might relate to the increased risk to develop diabetes in patients with low HDL blood levels. However, the mechanisms by which HDLs protect beta-cells are poorly characterized. Here we used a transcriptomic approach to identify genes differentially modulated by HDLs in beta-cells subjected to apoptotic stimuli. The transcript encoding 4E-binding protein (4E-BP)1 was up-regulated by serum starvation, and HDLs blocked this increase. 4E-BP1 inhibits cap-dependent translation in its non- or hypophosphorylated state but it loses this ability when hyperphosphorylated. At the protein level, 4E-BP1 was also up-regulated in response to starvation and IL-1beta, and this was blunted by HDLs. Whereas an ectopic increase of 4E-BP1 expression induced beta-cell death, silencing 4E-BP1 increase with short hairpin RNAs inhibited the apoptotic-inducing capacities of starvation. HDLs can therefore protect beta-cells by blocking 4E-BP1 protein expression, but this is not the sole protective mechanism activated by HDLs. Indeed, HDLs blocked apoptosis induced by endoplasmic reticulum stress with no associated decrease in total 4E-BP1 induction. Although, HDLs favored the phosphorylation, and hence the inactivation of 4E-BP1 in these conditions, this appeared not to be required for HDL protection. Our results indicate that HDLs can protect beta-cells through modulation of 4E-BP1 depending on the type of stress stimuli.

Antiinflammatory Actions of HDL

Atherosclerosis is an inflammatory disorder characterized by the accumulation of macrophages and T-lymphocytes in the arterial intima. The macrophages are derived from blood monocytes that adhere to, and transmigrate across, an activated or injured endothelial surface. The firm adhesion of monocytes to the endothelium requires expression of integrins such as CD11/CD18 on the monocyte surface and endothelial expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. Monocytes that are firmly tethered to the endothelium transmigrate into the subendothelial space in a process that is dependent on endothelial expression of chemokines such as monocyte chemotactic protein-1 (MCP-1).1 See accompanying article on page 2071 After entering the artery wall, monocytes differentiate into macrophages in processes that are mediated by macrophage colony stimulating factor (CSF) and granulocyte-macrophage CSF.2 Macrophages express a range of scavenger receptors that bind and internalize modified LDL in an unregulated manner. This leads to a progressive accumulation of lipids in the macrophages and the formation of foam cells: the hallmark cells of atherosclerotic lesions. The results of numerous epidemiological studies have established that …

Features of the metabolic syndrome and the risk of non-vertebral fractures: The Tromsø study

We wanted to examine whether the features of the metabolic syndrome carried an increased risk of non-vertebral fracture. This is a population-based, 6-year follow-up of 27,159 subjects from the municipality of Tromsø, followed from 1994 until 2001. Age range was 25-98 years. Non-fasting serum levels of high-density lipoprotein (HDL), triglycerides and glucose, blood pressure (BP), weight and height were measured at baseline. All non-vertebral fractures were registered by computerised search in radiographic archives. A total of 1,249 non-vertebral fractures were registered. Increasing number of metabolic syndrome features was associated with significantly reduced fracture risk in both men and women, p= 0.004 and p<0.0001, respectively. High BP was protective against fracture in men [relative risk (RR) 0.89; 95% confidence interval (CI) 0.8-0.99)] while increased body mass index (BMI) was protective in women (RR 0.91; 95% CI 0.84-0.98). Increasing non-fasting serum levels of HDL increased fracture risk in women (RR 1.12; 95% CI 1.05-1.21). BMI modified the effect of HDL in men. Accordingly, high HDL increased fracture risk in men with high BMI (RR 1.51; 95% CI 1.2-1.9). Increasing burden of metabolic syndrome features protects against non-vertebral fractures. Reduced non-vertebral fracture risk was associated with high BP in men and increased body mass in women. Lower non-fasting serum levels of HDL protect against fractures in women and obese men.

1113. Spliceosome Mediated RNA Trans-Splicing (SMaRT™) Strategy To Increase the Production of Human Apolipoprotein (ApoA1)

Cardiovascular disease (CVD) is the most common cause of death in Western societies, and its worldwide prevalence is increasing. A very strong predictor of CVD risk is the plasma concentration of high-density lipoprotein (HDL) or of its major protein component, ApoA-1. HDL and ApoA-1 levels exhibit an inverse relationship with the development of atherosclerosis and coronary heart disease1,2,3 and exogenous ApoA1 and HDL protect against atherosclerosis and plaque development 4,5,6,7. The present study was undertaken to determine if RNA trans-splicing could be used to increase blood levels of human ApoA-1 (hApoA1). To this end we targeted a pre-trans-splicing molecule (PTM) encoding human ApoA1 to the highly abundant albumin pre-messenger RNA (pre-mRNA). Trans-splicing between the PTM and the albumin pre-mRNA results in the production of human ApoA1 protein with two residual albumin amino acids. This fusion protein was expressed, processed and secreted as well as authentic hApoA1 and indeed the fusion protein had full activity in ATP-binding cassette transporter protein (ABC1)-mediated transfer of cellular cholesterol efflux assays.

Lecithin/cholesterol acyltransferase induces estradiol esterification in high-density lipoprotein, increasing its antioxidant potential.

Endogenous estrogens protect against atherosclerosis, but the exact mechanisms remain unclear. One possibility is inhibition of lipoprotein oxidation. To act as antioxidants, estrogens reportedly need to be converted to lipophilic estrogen fatty acyl esters in a reaction catalyzed by lecithin/cholesterol acyltransferase (LCAT). To demonstrate directly that estradiol (E2) esters formed by LCAT and incorporated in high-density lipoprotein (HDL) increase its antioxidant potential, we investigated the copper-induced oxidation of purified HDL after incubations of: 1) HDL alone; 2) HDL in the presence of exogenous E2; 3) HDL in the presence of exogenous LCAT; 4) HDL in the presence of both E2 and LCAT; and 5) HDL in the presence of E2, LCAT, and the LCAT inhibitor DTNB. We used this in vitro model system with supraphysiological concentrations of E2 and purified LCAT to produce E2 ester-containing HDL particles for studies of oxidation resistance. The lag time of HDL oxidation significantly increased with increasing contents of HDL-associated E2 esters. In conclusion, our results clearly demonstrated the role of LCAT in E2 esterification and its involvement in antioxidant protection of HDL. Elucidation of the possible in vivo role of HDL-associated estrogen esters requires further critical studies including experiments with physiological hormone concentrations.

The role of oxidized HDL in monocyte/macrophage functions in the pathogenesis of atherosclerosis in Rhesus monkeys

The effect of oxidative modification of high-density lipoprotein (HDL) was assessed by incubation of normal HDL (obtained from Rhesus monkeys fed a stock diet) with 5 microM CuSO4 at 37 degrees C for 12 h/24 h. The physicochemical properties of oxidized-HDL (Ox-HDL) were found to be affected in terms of lipid peroxidation, as observed by the increased level of thiobarbituric acid reactive substances (nmol MDA/mg HDL protein). The biological properties of HDL were altered, since a decrease in the efflux of free cholesterol into the medium was found in the presence of Ox-HDL24h compared with normal HDL (N-HDL). The binding, uptake and degradation of 125I-LDL by macrophages increased in the presence of Ox-HDL24h. The activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione-peroxidase) was reduced in monocytes in the presence of Ox-HDL. However, in the presence of N-HDL, the levels of antioxidant enzymes were maintained at a higher level than in the control (in the absence of HDL) monocytes. Furthermore, the number of monocytes adhered to aortic endothelium were found to be increased in the presence of Ox-HDL. These findings suggest that HDL is susceptible to oxidative modification. Since the parameters selected in the present study are involved in the pathogenesis of atherosclerosis, it can be postulated that the in vivo protection of HDL in atherosclerosis can be reversed in the circumstances in which HDL undergoes oxidative modification like low-density lipoprotein (LDL).

Plasma High-Density Lipoproteins

WHY all the recent excitement about highdensity lipoproteins (HDL)? Because of the strong inverse relation between plasma levels of HDL and mortality from cardiovascular disease.1,2 Increased serum levels of HDL protect against atherosclerosis, and decreased levels predispose to it.3 In this review, we discuss the measurement and normal levels of HDL, their chemical composition, the properties of the molecules making up HDL and our view of the structure of different HDL particles. The present evidence suggests that HDL or its precursors are produced by both the intestine and the liver. Further-more, HDL precursors are both directly secreted into plasma . . .