Protective Effects Of High-density Lipoprotein Research Articles

High Density Lipoprotein: A Therapeutic Target in Type 2 Diabetes

High density lipoproteins (HDLs) have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardioprotective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic β cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions.

High-Density Lipoprotein Cholesterol, High-Sensitivity C-Reactive Protein, and Cardiovascular Disease in United States Adults

High-density lipoprotein (HDL) cholesterol is inversely associated with the risk of cardiovascular disease (CVD). However, whether the protective effect of HDL becomes impaired by elevated high-sensitivity C-reactive protein (hs-CRP) is not well-established. We evaluated 13,572 United States adults aged ≥18 years who participated in the cross-sectional National Health and Nutrition Examination Survey 1999-2008. The subjects were classified according to the recognized cutpoints of HDL cholesterol elevations of ≥60 mg/dl, hs-CRP of >3 mg/L, and by a history of self-reported coronary heart disease (CHD) or CVD. Multivariate logistic regression analysis was used to assess the odds of prevalent CHD and CVD according to HDL cholesterol/hs-CRP group, after adjusting for known risk factors. Those with HDL cholesterol of ≥60 mg/dl and CRP >3 mg/L versus HDL cholesterol <60 mg/dl and CRP ≤3 mg/L had as high or a greater prevalence of CHD (5.5% and 5.3%, respectively) and CVD (8.6% and 6.9%, respectively). Compared to those with HDL cholesterol of ≥60 mg/dl and CRP ≤3 mg/L, those with HDL cholesterol ≥60 mg/dl and hs-CRP >3 mg/L had a 1.38 (95% confidence interval 0.94 to 2.02) adjusted odds of CHD and 1.38 (95% confidence interval 1.00 to 1.90) adjusted odds of CVD. Those with an HDL cholesterol <60 mg/dl and CRP >3 mg/L had the greatest adjusted odds of both CHD (1.75, 95% confidence interval 1.28 to 2.38) and CVD (1.74, 95% confidence interval 1.33 to 2.28). In conclusion, an hs-CRP >3 mg/L in the presence of HDL cholesterol of ≥60 mg/dl is associated with an attenuation in the protective association of HDL cholesterol ≥60 mg/dl and CRP of ≤3 mg/L with CHD and CVD.

LDL‐cholesterol versus HDL‐cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos

Atherosclerosis is a complex disease in which many processes contribute to lesion development. Yet, it is well accepted that high serum levels of low-density lipoproteins (LDL) play a main role in the initiation and progression of atherosclerosis. Despite currently available optimal LDL-lowering therapies, a worrisome number of clinical events still occur. The protective effect of high-density lipoproteins (HDL) in atherosclerosis, either by suppressing vascular-LDL accumulation, inflammation, oxidation, endothelial damage, and thrombosis, has supported the need of the use of HDL-raising therapies to address this residual risk. Results obtained in some studies, however, have shown that HDL quality, rather than quantity, should be the target of future pharmacological therapies. Here, we will first explore the mechanism by which excess LDL is fundamental in the development of atherosclerosis and its thrombotic complications, behaving as a factor that introduces chaos in the vascular wall. Afterwards, we will explore how functional HDL, through various cellular and molecular mechanisms, facilitates the resolution of this vascular chaos by suppression of atherosclerosis progression and induction of regression.

Lipids, menopause, and early atherosclerosis in Study of Women's Health Across the Nation Heart women

The risk of cardiovascular disease increases after menopause. Recent evidence suggests that it is possible for high-density lipoprotein (HDL) to become proatherogenic or dysfunctional in certain situations. Our objective was to evaluate whether the relationship of HDL cholesterol (HDL-C) to subclinical cardiovascular disease differed across the menopausal transition, which would provide insight for this increased risk. Aortic calcification (AC), coronary artery calcification (CAC), carotid plaque, and intima media thickness (IMT) were measured in an ancillary study of the Study of Women's Health Across the Nation. Women not using hormone therapy were stratified into premenopausal or early perimenopausal (Pre/EP, n=316) and late perimenopausal or postmenopausal (LP/Post, n=224). The inverse relationship of HDL-C to subclinical atherosclerosis measures among Pre/EP women was weaker or reversed among LP/Post women, adjusted for age, site, race, systolic blood pressure, glucose, body mass index, smoking, menopause status, and low-density lipoprotein cholesterol. Specifically, multivariable modeling demonstrated an inverse association between HDL-C level and AC and IMT among Pre/EP women; however, the protective effect of HDL-C for AC, left main CAC, carotid plaque, and IMT was not seen in LP/Post women. In a small subset (n=53), LP/Post women had more total and small HDL particles, higher triglyceride levels, and more total low-density lipoprotein particles compared with Pre/EP women (P<0.05). These results suggest that the protective effect of HDL may be diminished as women transition in menopause. Future studies should examine whether this may be due to changes in HDL size, functionality, or related changes in other lipids or lipoproteins.

Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation

The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p < 0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p < 0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p < 0.05) and 2.1-fold (p < 0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A–I transfer. In vitro, supplementation of HDL or apo A–I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-κB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality.Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-010-0690-6) contains supplementary material, which is available to authorized users.

HDL‐paraoxonase and Membrane Lipid Peroxidation: A Comparison Between Healthy and Obese Subjects

High-density lipoproteins (HDLs) play a key role in the protection against oxidative damage. The enzyme paraoxonase-1 (PON1) associated at the surface of HDL modulates the antioxidant and anti-inflammatory role of HDL. Previous studies have demonstrated a decrease of serum PON in obese patients. The aim of this study was to investigate whether modifications of PON1 activity reflect in a different ability to protect and/or repair biological membranes against oxidative damage. Thirty obese patients at different grades of obesity (BMI ranging from 30.4 to 64.0 kg/m(2)) and 62 age-matched control subjects (BMI <25 kg/m(2)) were included in the study. The ability of HDL to protect membranes against oxidative damage was studied using erythrocyte membranes oxidized with 2,2-azobis(2 amidinopropane)dihydrochloride (AAPH) (ox-membrane). The membrane lipid hydroperoxide levels were evaluated after the incubation of ox-membranes in the absence or in the presence of HDL of controls or obese patients. The results confirm that HDL exerts a protective effect against lipid peroxidation. The ability of HDL to repair erythrocyte membranes was positively correlated with HDL-PON activity and negatively correlated with lipid hydroperoxide levels in HDL. These results suggest that PON modulates the HDL repairing ability. HDL from obese patients repaired less efficiently erythrocyte membranes against oxidative damage with respect to HDL from healthy subjects. A negative relationship has been established between BMI of obese patients and the protective effect of HDL. In conclusion, the decrease of HDL-PON activity and the lower HDL protective action against membrane peroxidation in obese patients could contribute to accelerate the cellular oxidative damage and arteriosclerosis in obesity.

High-Density Lipoprotein: Key Molecule in Cholesterol Efflux and the Prevention of Atherosclerosis

Accumulation of cholesterol by macrophages, leading to their transformation into foam cells is a key event in the initiation of atherosclerosis. As maintenance of cholesterol homeostasis in macrophages is essential to prevent foam cell formation, mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years. Several epidemiological studies have shown that plasma levels of high-density lipoprotein (HDL) cholesterol are inversely correlated with the risk of atherosclerosis. The protective effect of HDL against macrophage foam cell formation and atherosclerosis is primarily attributed to its role in reverse cholesterol transport (RCT), a process by which excess cholesterol in peripheral tissues is transported to the liver for excretion. The present review discusses current knowledge on the biological activities of the major apolipoproteins, enzymes, lipid transfer proteins, receptors, and lipid transporters associated with HDL function and levels. In addition, current views on the molecular mechanisms underlying the atheroprotective functions of HDL beyond promotion of RCT, including the anti-oxidant, anti-thrombotic, anti-inflammatory and anti-apoptotic properties of HDL are summarized.

Relevance of Sphingolipids in the Pleiotropic Protective Effects of High-Density Lipoproteins

Atherosclerosis is the major cause of cardiovascular morbidity and mortality. A multitude of pro-atherogenic mediators are known liable for the initiation and progression of atherogenic vascular lesions. Only few endogenous molecules are known so far with cardiovascular protective properties, whereas high-density lipoprotein (HDL) is one of the most important. Beside cholesterol efflux, many pleiotropic cell-mediated functions of HDL are known so far. HDL is a spherical particle that contains different proteins and lipids. Especially sphingolipids, like sphingosine-1-phosphate (S1P), has gained great attention. The HDL associated S1P seems to be responsible for many of the pleiotropic effects of HDL by activating special S1P receptors. This review focuses on HDL associated sphingolipids as mediators of known protective pleiotropic effects of HDL and their possible therapeutic relevance.

Effect of homocysteinylation on high density lipoprotein physico-chemical properties

High density lipoproteins (HDL) exert a protective effect against homocysteinylation due to the activity of the enzyme paraoxonase/thiolactonase associated to the lipoprotein surface. However, a small amount of N-homocysteinylated HDL (N-Hcy-HDL) is present in human plasma, suggesting that homocysteinylation of plasma lipoproteins occurs in vivo. Aim of the present study was to investigate the effect of homocysteinylation on apoprotein structure and physico-chemical properties of HDL using the analysis of the fluorescent emission spectra of tryptophan and Laurdan (6-dodecanoyl-2-dimethyl-aminonaphthalene). Our results demonstrated that the increase in -SH groups in HDL homocysteinylated in vitro (Hcy-HDL) was associated with apoprotein conformational changes and modifications of physico-chemical properties. A significant decrease of paraoxonase and lactonase activity of HDL bound PON1 has also been observed in Hcy-HDL. A significant decrease of the enzyme activity has been observed also in purified PON1 homocysteinylated following the same experimental conditions used for HDL. Moreover, we demonstrated that oxidized HDL were more susceptible to homocysteinylation with respect to control HDL. The modifications of apoprotein conformation and physico-chemical properties in Hcy-HDL and the decrease of paraoxonase-1 activity could affect the protective effect of HDL against oxidative damage and/or homocysteinylation and could contribute to accelerated atherosclerosis in patients affected by diseases associated with oxidative damage, in renal disorders and in patients affected by genetic or nutritional disorders of homocysteine or folate metabolism.

Low- and High-Density Lipoproteins Modulate Function, Apoptosis, and Proliferation of Primary Human and Murine Pancreatic β-Cells

A low high-density lipoprotein (HDL) plasma concentration and the abundance of small dense low-density lipoproteins (LDL) are risk factors for developing type 2 diabetes. We therefore investigated whether HDL and LDL play a role in the regulation of pancreatic islet cell apoptosis, proliferation, and secretory function. Isolated mouse and human islets were exposed to plasma lipoproteins of healthy human donors. In murine and human beta-cells, LDL decreased both proliferation and maximal glucose-stimulated insulin secretion. The comparative analysis of beta-cells from wild-type and LDL receptor-deficient mice revealed that the inhibitory effect of LDL on insulin secretion but not proliferation requires the LDL receptor. HDL was found to modulate the survival of both human and murine islets by decreasing basal as well as IL-1beta and glucose-induced apoptosis. IL-1beta-induced beta-cell apoptosis was also inhibited in the presence of either the delipidated protein or the deproteinated lipid moieties of HDL, apolipoprotein A1 (the main protein component of HDL), or sphingosine-1-phosphate (a bioactive sphingolipid mostly carried by HDL). In murine beta-cells, the protective effect of HDL against IL-1beta-induced apoptosis was also observed in the absence of the HDL receptor scavenger receptor class B type 1. Our data show that both LDL and HDL affect function or survival of beta-cells and raise the question whether dyslipidemia contributes to beta-cell failure and hence the manifestation and progression of type 2 diabetes mellitus.

Stimulation of Cell Surface F 1 -ATPase Activity by Apolipoprotein A-I Inhibits Endothelial Cell Apoptosis and Promotes Proliferation

Several findings argue for a protective effect of high-density lipoproteins (HDLs) against endothelial dysfunction. The molecular mechanisms underlying this protective effect are not fully understood, although recent works suggest that the actions of HDL on the endothelium are initiated by multiple interactions between HDLs (lipid or protein moiety) and cell surface receptors. We previously showed that the mitochondrial related F(1)-ATPase is a cell surface receptor for HDLs and their main atheroprotective apolipoprotein (apoA-I). Herein we test the hypothesis that the cell surface F(1)-ATPase may contribute to the ability of apoA-I and HDLs to maintain endothelial cell survival. Cell imaging and binding assays confirmed the presence of the F(1)-ATPase at the surface of human umbilical vein endothelial cells (HUVECs) and its ability to bind apoA-I. Cell surface F(1)-ATPase activity (ATP hydrolysis into ADP) was stimulated by apoA-I and was inhibited by its specific inhibitor IF(1)-H49K. Furthermore the antiapoptotic and proliferative effects of apoA-I on HUVECs were totally blocked by the F(1)-ATPase ligands IF(1)-H49K, angiostatin and anti-betaF(1)-ATPase antibody, independently of the scavenger receptor SR-BI and ABCA1. This study suggests an important contribution of cell surface F(1)-ATPase to apoA-I-mediated endothelial cell survival, which may contribute to the atheroprotective functions of apoA-I.

High-density lipoproteins: the guardian angel of the cell membrane

High-density lipoproteins (HDL) plasma levels are inversely correlated with the risk of atherosclerosis and coronary heart disease. The protective effect of HDL has been related to their role in the cholesterol reverse transport and to their ability to inhibit oxidation of low-density lipoproteins (LDL). Several lines of evidence suggest that the protective effect of HDL is at least partially related to the enzyme paraoxonase (PON1), a calcium-dependent esterase associated with the HDL surface. It has been hypothesised that PON1 may have two independent antiatherogenic roles: (a) by preventing the accumulation of oxidised lipids from oxidised lipoproteins (LDL and HDL) and thereby inhibiting the atherogenic and inflammatory response induced by lipid peroxidation products; (b) by detoxifying homocysteine thiolactone (HTL), a toxic metabolite of homocysteine. Recently, it has been reported that HDL-associated PON1 could also play a regulatory role in HDL binding to cell membranes and in HDL-mediated cholesterol efflux in macrophages. Several papers have reported that HDL are also able to protect and/or repair oxidative damage of cell membranes and we have recently demonstrated that the protective role of HDL is related to PON1 activity.

High-density lipoprotein/apolipoprotein A-I infusion therapy

Strategies to decrease the progression and burden of atherosclerosis by capitalizing on the protective effect of high-density lipoprotein (HDL) and/or apolipoprotein A1 (apoA-I) levels remain active. Although efforts to raise HDL through the administration of oral agents are still being pursued, the disappointing results demonstrated with torcetrapib, an agent that elevated serum HDL and apoA-I levels through the inhibition of cholesterol ester transfer protein, have raised questions regarding this approach. An alternate strategy that consists of short-term infusions of reconstituted HDL or apoA-I is currently under evaluation. Several infusion compounds have been evaluated in clinical trials that utilize cardiovascular imaging technologies and biomarkers to assess potential clinical efficacy. Although these compounds are still in early-stage development, the results of these trials have supported the viability of this line of investigation. This review addresses the potential of HDL and/or apoA-I infusions as a possible therapeutic strategy for the treatment of coronary artery disease.

A simple and precise method for measuring HDL-cholesterol subfractions by a single precipitation followed by homogenous HDL-cholesterol assay

HDL consists of two major subfractions, HDL2 and HDL3. This paper describes a simple method for assaying HDL subspecies by combining a single precipitation with a direct high density lipoprotein-cholesterol (HDL-C) assay. A precipitation reagent (0.06 ml) containing 1,071 U/ml heparin, 500 mmol/l MnCl2) and 12 mg/ml dextran sulfate was added to a serum (0.3 ml). The sample was incubated and centrifuged at 10,000 rpm for 10 min. HDL3-C was measured by a homogenous HDL-C assay in the supernatant, and HDL2-C was estimated by subtracting the HDL3-C from the direct HDL-C. The HDL3-C and HDL2-C values determined by the precipitation method were identical to those determined by ultracentrifugation, and there were excellent correlations between the methods in the measurements of HDL3-C and HDL2-C (r = 0.933 and 0.978, respectively; n = 102). The two methods also proved to be highly correlated in the measurement of apolipoprotein A-I and A-II in HDL subfractions. The HDL-C subfractions determined by ultracentrifugation were more closely associated with the homogenous HDL-C assay than with the total cholesterol assay, especially in the hypertriglyceridemic samples. Our method is far simpler and more precise than the classical dual precipitation method for HDL-C subfractions, and it can be easily performed in a routine chemical laboratory.

An apolipoprotein A-I mimetic dose-dependently increases the formation of preβ1 HDL in human plasma

Prebeta1 HDL is the initial plasma acceptor of cell-derived cholesterol in reverse cholesterol transport. Recently, small amphipathic peptides composed of D-amino acids have been shown to mimic apolipoprotein A-I (apoA-I) as a precursor for HDL formation. ApoA-I mimetic peptides have been proposed to stimulate the formation of prebeta1 HDL and increase reverse cholesterol transport in apoE-null mice. The existence of a monoclonal antibody (MAb 55201) and a corresponding ELISA method that is selective for the detection of the prebeta(1) subclass of HDL provides a means of establishing a correlation between apoA-I mimetic dose and prebeta1 HDL formation in human plasma. Using this prebeta1 HDL ELISA, we demonstrate marked apoA-I mimetic dose-dependent prebeta1 HDL formation in human plasma. These results correlated with increases in band density of the plasma prebeta1 HDL, when observed by Western blotting, as a function of increased apoA-I mimetic concentration. Increased prebeta1 HDL formation was observed after as little as 1 min and was maximal within 1 h. Together, these data suggest that a high-throughput prebeta1 HDL ELISA provides a way to quantitatively measure a key component of the reverse cholesterol transport pathway in human plasma, thus providing a possible method for the identification of apoA-I mimetic molecules.

Valores de colesterol HDL en la población infantil y riesgo trombótico

There is evidence of the protective effect of high-density lipoprotein (HDL)-cholesterol against atheroma plaque formation and of its role in cholesterol efflux from cells, as well as its anti-oxidative and inflammatory modulating response properties. Low HDL-cholesterol levels have been associated with a prothrombotic state. To determine the relationship between HDL-cholesterol and lipidic and hemostatic parameters. We studied 110 children (50 girls, 60 boys) aged between 6 and 7 years old. Lipid profile, D-dimer, plasminogen activator inhibitor (PAI) and fibrinogen were determined. The mean values of the studied parameters were as follows: total cholesterol (192.92+/-26.01 mg/dl), HDL-cholesterol (72.87+/-15.69 mg/dl), low-density lipoprotein-cholesterol (109.46+/-23.30 mg/dl), triglycerides (56.24+/-20.35 mg/dl), apolipoprotein B (91.96+/-14.93 mg/dl), apolipoprotein A1 (168.4+/-24.55 mg/dl), lipoprotein(a) logarithm (1.76+/-1.36 mg/dl), plasminogen activator inhibitor-1 logarithm (PAI-1) (3.77+/-3.93 U/ml), D-dimer logarithm (5.53+/-0.49 ng/ml) and fibrinogen (268.61+/-48.59 mg/dl). When the sample was divided into two groups according to HDL-cholesterol levels, children with lower levels showed significantly higher values of total cholesterol/HDL-cholesterol, fibrinogen and PAI. HDL-cholesterol levels were directly and significantly associated with total cholesterol and apolipoprotein A1 and negatively and significantly associated with the total cholesterol/HDL-cholesterol ratio, fibrinogen and PAI. The children studied had high HDL-cholesterol levels, which could be responsible for the high total cholesterol levels. High values of HDL-cholesterol are significantly associated with a reduction in thrombotic risk.

Association of oxidative stress and PON1 with LDL and HDL particle size in middle‐aged subjects

Alterations in plasma lipoprotein subclass distributions affect atherosclerosis risk. Smaller, denser low-density lipoprotein (LDL) particles (sdLDL) are more susceptible to oxidation. In contrast, most of the protective effects of high-density lipoproteins (HDL) are attributable to larger particles. This study investigates the connection between LDL and HDL particle heterogeneity and oxidative stress, antioxidative defence (AOD) and paraoxonase (PON1) status in a healthy middle-aged Serbian population. LDL and HDL particle sizes and subclass distributions were measured by gradient gel electrophoresis in 104 men and 103 women, aged 53 +/- 9.4 years. PON1 activities and PON1(Q192R) phenotypes were determined with paraoxon and diazoxon as substrates. The oxidative stress/AOD status was estimated by measuring malondialdehyde (MDA) and superoxide-anion (O2*(-)) levels and superoxide-dismutase (SOD) activity. Subjects with sdLDL had significantly higher MDA (P < 0.001) and O2*(-)(P < 0.05) levels and greater diazoxonase (DZOase) activity (P < 0.05) compared to subjects with larger LDL particles. A high MDA concentration was a significant predictor of the sdLDL phenotype (P < 0.005). Increased levels of and MDA were associated with smaller HDL(3) subclass abundance. Reduced HDL particle size was associated with lower DZOase activity (P < 0.01). Even in the absence of symptoms of atherosclerosis, sdLDL particles are associated with increased oxidative stress, which may stimulate a compensatory rise in PON1 DZOase activity. Elevated oxidative stress may significantly affect HDL subclass distribution, resulting in the accumulation of smaller, denser HDL particles with diminished antioxidative capacity.

Molecular regulation of macrophage reverse cholesterol transport

Macrophage reverse cholesterol transport is one of the key mechanisms mediating the protective effects of high-density lipoproteins on atherosclerosis. This review focuses on the recent developments in our understanding of molecular mechanisms of macrophage reverse transport and regulators that play important roles during this process. Macrophage reverse cholesterol transport is promoted by apolipoprotein A-I overexpression and reduced in the setting of apolipoprotein A-I deficiency. A liver X receptor agonist markedly increases macrophage reverse cholesterol transport. ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 are liver X receptor-responsive macrophage genes that promote cholesterol efflux to lipid-free apolipoprotein A-I and mature high-density lipoprotein, respectively. The direct roles of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 in macrophage reverse cholesterol transport in vivo remain unclear. Therapeutically promoting macrophage reverse cholesterol transport has been recognized as one of the promising means to prevent atherosclerosis. Increasing evidence has suggested that ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1 are involved in macrophage reverse cholesterol transport. In-depth understanding of the molecular mechanisms will enable us to develop new therapeutic means to protect against atherosclerosis.

Emerging HDL-based therapies for atherothrombotic vascular disease

Statin therapy has been a significant advance in the management of dyslipidemia and atherothrombotic cardiovascular disease with a resultant 30% to 40% reduction in cardiovascular events; however, a significant number of events continue to occur in statin-treated patients, including in patients treated with high-dose statins targeted to achieve mean low-density lipoprotein cholesterol levels in the range of 60 to 80 mg/dL. Therefore, development and testing of new therapies that exploit the vascular protective effects of high-density lipoprotein (HDL) constitutes a rational and complementary approach. A number of HDL-based therapies are in various stages of development and testing. It is hoped that one or more of these new HDL-based therapies, if proven effective and safe, will become a part of our armamentarium against vaso-occlusive cardiovascular disease. A paradigm could emerge in which patients recovering from acute coronary syndromes and at high risk of recurrent events could be treated with rapid-acting HDL-based therapy, such as infusions of recombinant HDL or even HDL delipidation, followed by more sustained long-term HDL-based therapies, such as oral agents and perhaps even HDL-based gene therapy.

Molecular Mechanisms Responsible for the Anti-Inflammatory and Protective Effect of High-Density Lipoprotein on the Endothelium

In addition to their role in reverse cholesterol transport, high-density lipoproteins (HDLs) exert several beneficial effects, including the prevention and correction of endothelial dysfunction. HDLs promote endothelium proliferation and diminish endothelial apoptosis; they play a key role in vasorelaxation by increasing the release of nitric oxide and prostacyclin through the induction of the expression and the activity of endothelial nitric oxide synthase and the coupling of cyclo-oxygenase 2 and prostacyclin synthase. In addition, HDLs affect coagulation, fibrinolysis, platelet adhesion, adhesion molecules and protease expression, and exert antioxidant activity. These effects are achieved at the gene expression level and are dependent on the activation of several intracellular signalling pathways, including PI3K/Akt, extracellular signal-regulated kinase (ERK) 1/2, protein kinase C, and p38MAPK (mitogen-activated protein kinase). The complexity of the signalling pathways modulated by HDL reflects the different effects of the components of this class of lipoproteins such as apolipoproteins or lipids on endothelial cell gene expression and the subsequent observed modulation of endothelial function. The in vivo relevance of these findings to endothelial recovery during physiological or pathological conditions remain to be addressed; nevertheless, the results of clinical studies with synthetic HDL, apolipoprotein A-I mimetics and drugs selectively affecting HDL plasma levels and biological functions that are becoming available support the importance of the correction of endothelial function by HDL.