Dynamic changes of the composition of plasma HDL particles in patients with cardiac disease: Spotlight on sphingosine‐1‐phosphate/serum amyloid A ratio

Several epidemiological studies reported an inverse relationship between plasma high‐density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease (ASCVD). However, therapeutic interventions targeted at raising HDL‐cholesterol failed to improve cardiovascular outcomes, suggesting that HDL components distinct from cholesterol may account for the anti‐atherothrombotic effects attributed to this lipoprotein. Sphingosine‐1‐phosphate (S1P) and the acute phase protein serum amyloid A (SAA) have been identified as integral constituents of HDL particles. Evidence suggests that S1P and SAA levels within HDL particles may be affected by inflammation and oxidative stress, which are coexisting processes underlying ASCVD. Because SAA, an inflammation‐related marker, and S1P, an anti‐atherothrombotic marker, have relatively clear opposite characteristics among the HDL‐associated proteins, the approach of assessing the two markers simultaneously may provide new insights in clinical practice (S1P/SAA Index). This review focuses on evidence in support of the concept that the S1P/SAA Index may affect the HDL atheroprotective properties and may, therefore represent a potential target for therapeutic interventions.     

The effect of poloxamer 407 on the functional properties of HDL in mice

Objectives There is an inverse relationship between high‐density lipoprotein (HDL) and heart disease. HDL possesses not only both antioxidant and anti‐inflammatory properties, but also anti‐thrombotic and endothelial function‐promoting qualities. However, it is not only the serum concentration of HDL that is important, but also the ‘functional’ quality of the HDL. The objective was to determine the functional status of HDL in a well‐established mouse model of dyslipidaemia and atherosclerosis induced by the administration of a block copolymer (poloxamer 407; P‐407). Methods C57BL/6 mice were administered a single intraperitoneal dose of P‐407 (0.5 g/kg) and blood was collected at 24 h post‐dosing. HDL was isolated from controls (control HDL) and P‐407‐treated (P‐407 HDL) mice and used to test its anti‐inflammatory properties in vitro. Additionally, antioxidant enzymes associated with HDL, namely, platelet activating factor‐acetylhydrolase (PAF‐AH) and paraoxonase (PON), were evaluated for any potential reduction in their biological activity. Key findings A single injection of P‐407 in C57BL/6 mice resulted in a marked decrease in the levels of HDL‐cholesterol and phospholipids. HDL particle size significantly increased, primarily due to remodelling of HDL with triglyceride. It was demonstrated that (i) long‐chain saturated fatty acids were higher and the n‐3/n‐6 fatty acid ratio was significantly lower for P‐407 HDL compared with control HDL, and (ii) P‐407 HDL lost its capacity to inhibit tumour necrosis factor‐α (TNF‐α)‐induced vascular cell adhesion molecule‐1 (VCAM‐1) expression compared with control HDL. Additionally, P‐407 HDL was not able to neutralize lipopolysaccharide and inhibit subsequent TNF‐α production compared with control HDL. The biological activity of platelet‐activating factor acetylhydrolase (PAF‐AH) and paraoxonase (PON) decreased in direct proportion to the circulating levels of both HDL‐cholesterol and apolipoprotein (apoA‐1). Conclusions Combination of previously reported findings in P‐407‐treated mice, such as (i) production of both oxidized LDL and malondialdehyde, and (ii) profound elevations in the soluble forms of intercellular adhesion molecule‐1 (ICAM‐1), VCAM‐1, and E‐selectin, with the present results, would strongly suggest that HDL in P‐407‐treated mice is rendered dysfunctional. Thus, these findings help to explain why P‐407‐treated mice begin to form aortic atherosclerotic lesions about one month after initiating P‐407 treatment.     

LDL‐C/HDL‐C ratio in subjects with cardiovascular disease and a low HDL‐C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

ABSTRACT

Background: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL‐C/HDL‐C) is a reliable predictor of cardiovascular risk. Low HDL‐C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events.

Objectives: This study compared the effects of rosuvastatin and atorvastatin on the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C.

Methods: Patients aged 40–80 years with established cardiovascular disease and HDL‐C < 1.0?mmol/L (< 40?mg/dL) entered a 6‐week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10?mg (n = 230) or atorvastatin 20?mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg, and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks.

Results: After 6 weeks of treatment, mean percentage change from baseline in LDL‐C/HDL‐C ratio was –47.0% in the rosuvastatin group and –41.9% in the atorvastatin group (?p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was –53.0% and –57.3%, respectively, for rosuvastatin, compared with –47.9% and –49.6%, respectively, for atorvastatin (?p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL‐C, total cholesterol and non-HDL‐C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL‐C and apolipoprotein B/A‐I ratios.

Conclusions: Rosuvastatin 10, 20 and 40?mg is significantly more effective than atorvastatin 20, 40 and 80?mg, respectively, in improving the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

Design, synthesis, and biological evaluation of sulfonic acid ester and benzenesulfonamide derivatives as potential CETP inhibitors

Epidemiological studies have established an inverse relationship between plasma high-density lipoprotein (HDL) cholesterol concentration, and incidence of coronary artery disease (CAD); thus, the development of novel therapies that attempt to exploit the atheroprotective functions of HDL is a major goal. Inhibition of cholesteryl ester transfer protein (CETP) is one of the approaches targeted to increase HDL cholesterol concentration. CETP is a glycoprotein involved in transporting lipoprotein particles and neutral lipids between HDL and low-density lipoproteins (LDL), and therefore CETP inhibitors could be useful agents in the future for treating dyslipidemia and related disorders. Guided by our previously reported pharmacophore and QSAR models for CETP inhibition, we synthesized and bioassayed a series of sulfonic acid ester and benzenesulfonamide derivatives that can serve as a promising lead compounds for the development of potential and selective CETP inhibitors. The most potent compound 6k illustrated an IC₅₀ of 3.4?μM.     

Can monocyte/HDL show inflammatory activity of isotretinoin treatment in acne patients?

Abstract

Aim: There are reports that isotretinoin causes some important diseases such as teratogenicity, inflammatory bowel disease and sacroiliitis by triggering inflammation. (Monocyte/HDL (high density lipoprotein) ratio) MHR is closely related to inflammation and is thought to be an indicator of atherosclerotic development. We aimed to investigate how isotretinoin (ISO) affects the immunoinflammatory response in acne patients.

Materials and Methods: In this study, 116 nodulocystic acne patients who received ISO treatment for at least three months were evaluated retrospectively. ISO treatment was given to patients at a dose of 0.5–1?mg/kg. Pre-treatment and post-treatment white blood cell (WBC), neutrophil, lymphocyte, monocyte, platelet, mean platelet volume (MPV), platelet, plateletcrit, platelet distribution width (PDW), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), total cholesterol, LDL cholesterol, triglyceride, HDL cholesterol and MHR were evaluated.

Results: MPV and MHR values were significantly increased after 3?month treatment (p?<?0.05). There was no significant change in NLR and PLR values (p?>?0.05). There was a significant decrease in neutrophil count (p?<?0.05). There were no significant changes in WBC, lymphocyte, monocyte, platelet, plateletcrit values (p?>?0.05). Total cholesterol, LDL cholesterol and triglyceride levels were significantly increased after three months of treatment (p?<?0.05). HDL cholesterol levels decreased significantly after three months of treatment (p?<?0.05).

Conclusion: We concluded that ISO treatment may trigger inflammation due to the increase in MPV and MHR value. MHR can show inflammation after ISO treatment.     

Impact of short‐term low‐dose atorvastatin on low‐density lipoprotein and high‐density lipoprotein subfraction phenotype

Statins can significantly reduce low‐density lipoprotein–cholesterol (LDL‐C) and modestly raise or not alter high‐density lipoprotein–cholesterol (HDL‐C). However, their impact on high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) subfractions has been less examined. The aim of the present study was to investigate the short‐term impact of low‐dose atorvastatin on HDL and LDL subfractions in humans. In this randomized study, data from 52 subjects were analysed. Thirty‐seven patients with atherosclerosis were randomized to treatment with atorvastatin 10 mg/day (n = 17) or 20 mg/day (n = 20) for 8 weeks, with 15 healthy subjects without therapy used as a control group. The lipid profile and lipoprotein subfractions were determined using the Lipoprint system at baseline and at 8 weeks. The data suggest that atorvastatin treatment (10 and 20 mg/day) for 8 weeks significantly decreases LDL‐C levels and reduces the cholesterol concentration of all LDL subfractions, which is accompanied by an increase of the mean LDL particle size. Although 10 mg/day atorvastatin treatment for 8 weeks had no impact on the HDL subfraction, 20 mg/day atorvastatin for 8 weeks significantly increased the cholesterol concentration of large HDL particles and decreased the cholesterol concentration of small HDL particles without changing serum HDL‐C levels in patients with atherosclerosis. Therefore, the results suggest that 20 mg/day atorvastatin treatment for 8 weeks may result in a favourable modification of the HDL subfraction phenotype in addition to its effects on the cholesterol concentration of all LDL subfractions and mean LDL particle size.     

Atheroprotective effects of HDL: beyond reverse cholesterol transport

The risk of atherosclerosis is inversely related to circulating levels of high density lipoprotein (HDL) cholesterol. Notably, in large-scale epidemiologic studies, this association is independent of plasma levels of low density lipoprotein cholesterol levels. Pharmacologic agents, such as fibrates and niacin that increase HDL cholesterol levels have been associated with decreased cardiovascular events and beneficial effects on the coronary and carotid arteries. Furthermore, there is evidence that the risk of restenosis following vascular interventions is inversely related to HDL levels. This review considers the available data from mainly murine models on potential mechanisms by which HDL may exert these anti-atherogenic effects, namely through its role in reverse cholesterol transport, its effects on endothelial cells, and its anti-inflammatory/anti-oxidant activities. In addition to discussing a role for HDL in retarding atherosclerosis progression, we will also review how HDL may play a role in promoting regression of atherosclerotic lesions.     

Animal and cellular models for hypolipidemic drugs

Background: The development of effective and safe lipid-lowering agents should set out from and rely on robust preclinical investigation. Objective: To accomplish this aim, the selection of proper cellular and animal models is crucial. Results: Because lipid-lowering agents are ultimately supposed to reduce the atherosclerotic burden in the arterial wall, they need to tackle directly or indirectly the multifactorial nature of atherosclerotic disease. Hence, these drugs may essentially prevent triglyceride-rich lipoprotein assembly or enhance low-density lipoprotein (LDL) clearance through the LDL or related receptors in the liver. Established animal models such as the apolipoprotein E- and the LDL-receptor knockout mice are widely used to test drug actions on these pathways. A different approach is testing the ability of candidate drugs to increase plasma high-density lipoprotein (HDL) levels. More recently, the focus has shifted to drugs enhancing HDL function rather than just plasma HDL levels. This in turn requires in vitro and particularly in vivo models of reverse cholesterol transport, which have become available by now. Conclusion: A positive outcome of preclinical studies is necessary but not sufficient for an investigational new drug to be eventually approved for clinical use.     

Investigational CETP antagonists for hyperlipidemia and atherosclerosis prevention

Introduction: Reverse cholesterol transport (RCT) is a function of high-density lipoproteins (HDL) in humans and higher species. It is enabled by the cholesteryl ester transfer protein (CETP), a high molecular weight protein exchanging cholesteryl esters in HDL for triglycerides in very low-density lipoproteins (VLDL). Inhibition of CETP may provide a useful strategy to raise HDL, the protective lipoprotein fraction in plasma.

Areas covered: Evaluation based on clinical and experimental findings of the three drugs developed or in advanced development for CETP inhibition.

Expert opinion: Inhibition of CETP, both inherited and drug induced, at times leads to dramatic elevations of HDL-cholesterol (HDL-C) levels. Epidemiological data presently available do not, however, provide convincing evidence that reduced CETP levels or activity due to genetic factors and associated with HDL-C elevations, reduce cardiovascular risk. Indeed, the opposite may be true in some instances. All the three CETP inhibitors were the object of experimental and clinical evaluation. Large clinical trials with torcetrapib led to very negative findings, that is, raised cardiovascular morbidity and mortality in addition to raised risk of cancer and sepsis. Off-target effects of the drug, such as aldosterone retention and raised blood pressure, were believed to provide an explanation for these negative findings. The two newer agents, dalcetrapib and anacetrapib, do not exert off-target effects. The two drugs differ because anacetrapib has a more dramatic effect on HDL cholesterolemia (+139%) versus more moderate effects of dalcetrapib (+20–30%). Anacetrapib, however, may impair formation of pre-β HDL, that is, the primary particles in the process of cholesterol removal. The initial large trial with anacetrapib (DEFINE study) in coronary patients on statin treatment, appeared to confirm a remarkable HDL raising property, together with some reduction in vascular end points, in particular coronary procedures. The issue of other potentially harmful effects of CETP inhibition (sepsis and others) has yet to be clarified. Large clinical end-point trials, however, will be necessary to provide convincing evidence that, in addition to raising HDL-C, CETP inhibitors provide a valid additional treatment, for example, to statins in patients with coronary heart disease (CHD) or at high risk of CHD.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

Introduction: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia.

Areas covered: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material.

Expert opinion: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Poloxamer 407 as a general lipase inhibitor: its implications in lipid metabolism and atheroma formation in C57BL/6 mice

Objectives The aims of this investigation were to determine if the activity of endothelial lipase was inhibited in vitro by the polymeric surfactant, poloxamer 407 (P‐407), and to review the action of P‐407 on the biological activity of several other critical lipases involved in lipid metabolism. The overall goal was to suggest a possible explanation for the observed dyslipidaemia and formation of aortic atherosclerotic lesions when present and previous findings, along with key findings proposed by others, were combined and reviewed in the context of the P‐407‐induced mouse model of atherogenesis. Key findings Endothelial lipase was expressed using a recombinant adenovirus; subconfluent COS cells were exposed to recombinant adenoviruses and triglyceride lipase activity was determined using standard assay methods. It was demonstrated that P‐407 inactivates endothelial lipase in vitro. Endothelial lipase was inhibited in vitro by P‐407, with an IC50 of approximately 11.3 µm . It is suggested that one possible explanation for the eventual formation of aortic atherosclerotic lesions in the P‐407‐induced mouse model of atherogenesis may be related to the capacity of P‐407 to inhibit the activity of several critical lipases involved in lipid metabolism. Conclusions The following physiological and biochemical processes are all observed in the P‐407‐induced mouse model of dyslipidaemia and atherosclerosis: inactivation of endo‐thelial lipase (both in vitro and in vivo), hepatic lipase and lipoprotein lipase by P‐407; reduced plasma levels of high‐density lipoprotein cholesterol; no activation of either human or mouse peroxisome proliferator‐activated receptor α (as well as peroxisome proliferator‐activated receptor γ) in vitro or in vivo; increased plasma concentrations of soluble vascular cell adhesion molecule 1, soluble intercellular adhesion molecule 1 and soluble E‐selectin; and aortic atherosclerotic lesion formation following 12–16 weeks of P‐407 administration (0.5 g/kg administered every 3 days by intraperitoneal injection). This biochemical‐based pathway, or series of events, may contribute, in part, to the dyslipidaemia and eventual formation of aortic atherosclerotic lesions observed in the P‐407‐induced mouse model of atherogenesis.     

Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy

ABSTRACT

Objective: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL?C) goal on statin monotherapy.

Research design: Systematic review and meta-analysis.

Methods: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10?mg/day or placebo added to current statin therapy.

The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL?C, and high-density lipoprotein cholesterol (HDL?C), and number of patients achieving LDL?C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model.

Results: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (–16.1% (–17.3, –14.8); p < 0.0001), LDL?C (–23.6% (–25.6, –21.7); p < 0.0001) and HDL?C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL?C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin (?p < 0.0001) for TC and LDL?C but was no longer significant for HDL?C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments.

Conclusions: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL?C goal on statin therapy alone, allowing more patients to reach their LDL?C goal.     

Lipoprotein lipase and atherosclerosis

Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoprotein such as very low density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and decrease in high density lipoprotein (HDL) cholesterol. The increase in plasma TG and decrease in HDL cholesterol are risk factors of coronary heart disease. However, whether LPL directly or indirectly promotes or protects against atherosclerosis remains unclear as two contrary views exist in this regard: one where LPL promotes atherosclerosis and one where LPL protects against atherosclerosis. Many studies have been carried out to investigate whether LPL is an anti-atherogenic or atherogenic enzyme by using animals with genetic defects or with an excess of this enzyme. From these studies, much evidence has been acquired showing that LPL is an anti-atherogenic enzyme. We hypothesized that elevating LPL activity would cause a reduction of plasma TG and increase in HDL cholesterol, resulting in protection against the development of atherosclerosis. To test this hypothesis, we studied the effects of the LPL activator NO-1886 in animals. NO-1886 has been shown to increase LPL mRNA in adipose tissue and myocardium, and increase LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 has also been shown to decrease plasma TG levels accompanied by a concomitant rise in HDL cholesterol. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortae. The results of multiple regression analysis in these studies suggest that the increase in plasma HDL cholesterol and the decrease in TG protect against atherosclerosis. We have determined in our studies that the atherogenic lipid profile is changed to an anti-atherogenic lipid profile by increasing LPL activity, resulting in protection against the development of atherosclerosis. Therefore, we believe that high activity of LPL is anti-atherogenic, whereas a low activity of LPL is atherogenic.     

Modulatory effect of Inula racemosa Hook. f. (Asteraceae) on experimental atherosclerosis in guinea‐pigs

Objectives Inula racemosa Hook. f. is indicated for precordial chest pain in Ayurveda. In this study, the effects of a hexane (IrH) and an alcohol extract (IrA) of Inula racemosa on atherosclerosis induced by a high‐fat diet in guinea‐pigs were investigated. Methods After 30 days on a high‐fat diet (guinea‐pig pellet diet + 0.2% w/w cholesterol) six animals were killed and evaluated for the onset of early atherosclerotic changes in coronary artery, aorta and major organs. The remaining animals were assigned to 5 groups of six animals each and fed for the following 90 days with a pellet diet + 0.15% w/w cholesterol (positive control) along with 100 mg/kg IrA, 100 mg/kg IrH or 10 mg/kg atorvastatin calcium. The normal control group received only the pellet diet. At the end of experimental period, serum lipid levels, heart and liver antioxidant status, area of lipophilic aortic lesions and histopathology of coronary artery were estimated. Key findings IrA decreased total cholesterol, triglycerides, low‐density lipoprotein cholesterol and the atherogenic index, and increased high‐density lipoprotein cholesterol compared with the positive control. It scavenged thiobarbituric acid reactive substances and increased reduced glutathione in liver, and enhanced superoxide dismutase and glutathione peroxidase in heart. Aortic lesion area and % bodyweight increase was least in the IrA‐treated group. Coronary artery changes due to the high‐fat diet were reversed by the extracts. The observed effects are presumably mediated by phenolics in IrA and sesquiterpene lactones in IrH. Conclusions The results demonstrate the anti‐atherogenic effect of I. racemosa, thus validating the cardioprotective and anti‐obesity claims in traditional medicine.     

Apolipoprotein A-I/HDL infusion therapy for plaque stabilization-regression: a novel therapeutic approach

LDL-lowering therapies, predominantly involving statins, have been shown to significantly reduce cardiovascular events in asymptomatic subjects as well as in subjects with clinically established atherosclerotic cardiovascular disease. However, despite statin therapy, significant number of cardiovascular events continue to occur indicating the need for additional targets for atherosclerosis management. A number of pre-clinical studies have suggested that several HDL based therapies have the potential to stabilize or regress atherosclerosis consistent with epidemiologic evidence of an inverse relationship between coronary heart disease and HDL cholesterol levels. One such therapeutic approach involves direct infusion of HDL or HDL like molecules for rapid remodeling and stabilization of atherosclerosis. Pre-clinical and proof of concept type preliminary clinical studies suggest the feasibility and potential efficacy of this emerging new therapeutic paradigm.     

High‐density lipoprotein: A potent inhibitor of inflammation

1. Inflammation is an important process, driving the progression of atherosclerosis. Stemming inflammation may be a mechanism to inhibit the progression of this disease. 2. High‐density lipoprotein (HDL), a particle inversely related to cardiovascular disease, has been described as having a number of anti‐inflammatory functions. It has been shown that HDL inhibits endothelial inflammation in both in vitro and in vivo models, reducing the expression of key cell adhesion molecules. In addition, HDL has been shown to have an effect on the coagulation pathway by inhibiting platelet activation and reducing thrombus formation. Furthermore, by reducing the activation of leucocytes, HDL can inhibit leucocyte recruitment to the endothelium. 3. High‐density lipoprotein infusion studies conducted in patients with inflammatory diseases have shown that acute treatment with HDL can effectively inhibit inflammation in vivo. Thus, HDL has been proven to be a potent inhibitor of inflammation, acting on a number of pathways, and this may suggest that HDL could be applied as an anti‐inflammatory molecule for a number of diseases. 4. The present review highlights these important studies and reviews data on the anti‐inflammatory effects of HDL from in vitro and in vivo studies, in both humans and animal models of atherosclerosis and inflammatory‐related diseases.     

Severity of coronary atherosclerosis related to lipoprotein concentration.

The influence of individual lipoproteins on the severity of coronary atherosclerosis was studied in 41 patients undergoing coronary angiography. The extent of athero-sclerosis was quantified by a coronary atherosclerosis score (CAS) based on the number and severity of lesions in eight proximal segments of the coronary circulation. The concentration of high-density lipoprotein (HDL) showed a strong inverse association with CAS, which was independent of the effects of age and other lipoproteins. On multivariate analysis concentrations of other lipids--namely, total plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and the combined effect of LDL cholesterol plus very-low-density lipoprotein triglyceride--showed direct, significant correlations with CAS, but these were weaker than that of HDL. This study shows that concentrations of several circulating lipoproteins are related to the severity of coronary atherosclerosis, HDL having an apparent retarding effect. These findings may partly explain the influence of lipoproteins on the development of clinical coronary heart disease.     

Reconstituted high‐density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component

Human apolipoprotein A‐I preparations reconstituted with phospholipids (reconstituted high‐density lipoprotein [HDL]) have been used in a large number of animal and human studies to investigate the physiological role of apolipoprotein A‐I. Several of these studies observed that intravenous infusion of reconstituted HDL might cause transient elevations in plasma levels of hepatic enzymes. Here we describe the mechanism of this enzyme release. Observations from several animal models and in vitro studies suggest that the extent of hepatic transaminase release (alanine aminotransferase [ALT]) correlates with the movement of hepatic cholesterol into the blood after infusion. Both the amount of ALT release and cholesterol movement were dependent on the amount and type of phospholipid present in the reconstituted HDL. As cholesterol is known to dissolve readily in phospholipid, an HDL preparation was loaded with cholesterol before infusion into rats to assess the role of diffusion of cholesterol out of the liver and into the reconstituted HDL. Cholesterol‐loaded HDL failed to withdraw cholesterol from tissues and subsequently failed to cause ALT release. To investigate further the role of cholesterol diffusion, we employed mice deficient in SR‐BI, a transporter that facilitates spontaneous movement of cholesterol between cell membranes and HDL. These mice showed substantially lower movement of cholesterol into the blood and markedly lower ALT release. We conclude that initial depletion of hepatic cholesterol initiates transient ALT release in response to infusion of reconstituted HDL. This effect may be controlled by appropriate choice of the type and amount of phospholipid in reconstituted HDL. Copyright © 2015 John Wiley & Sons, Ltd.