Ageing, tumour necrosis factor-alpha (TNF-alpha) and atherosclerosis

Ageing is associated with increased inflammatory activity in the blood. The purpose of this study was to investigate if age-related increased plasma levels of TNF-alpha were associated with atherosclerosis in a cohort of 130 humans aged 81 years. The elderly cohort had increased circulating levels of TNF-alpha, C-reactive protein (CRP), total cholesterol (TC), low-density lipoproteins (LDL) and a low high-density lipoprotein (HDL)/TC ratio compared with a young control group (n = 44). The elderly cohort was divided by tertiles into three subgroups with low, intermediate, and high levels of TNF-alpha, respectively. In the group with high TNF-alpha concentrations a significantly larger proportion had clinical diagnoses of atherosclerosis. Furthermore, weak correlations were found between TNF-alpha on one hand and blood concentrations of triglycerides, leucocytes, CRP and a low HDL/TC ratio on the other which are known as risk factors of atherogenesis and thromboembolic complications. No correlations were found between TNF-alpha, TC, LDL, or the body mass index. In conclusion, the present study shows that in a cohort of 81-year-old humans, high levels of TNF-alpha in the blood were associated with a high prevalence of atherosclerosis.     

Relevance of lipoprotein cholesterol levels measured by HPLC method to appearance midband on electrophoresis and remnant-like particle (RLP)-cholesterol levels

We have recently developed an HPLC method able to separate five lipoproteins (HDL, LDL, IDL, VLDL and chylomicron) followed by cholesterol measurement on each lipoprotein. As an application of this method, this study focused on analyses of triglyceride (TG)-rich lipoproteins, one of risk factor for atherosclerosis. The appearance of midband on electrophoresis is conceivably implicated in atherogenesis. The present study revealed that cholesterol levels in VLDL, IDL and LDL were significantly higher in midband-positive sera than negative sera. Cholesterol levels in remnant-like proteins, another atherogenic indicator, were significantly related to those in VLDL and Chylomicron measured by the present HPLC method. In conclusion, this novel HPLC method can provide valuable information for analyses on TG-rich lipoproteins.     

Innate immune signals in atherosclerosis

Atherosclerosis is a chronic disease characterised by lipid retention and inflammation in the arterial intima. Innate immune mechanisms are central to atherogenesis, involving activation of pattern-recognition receptors (PRRs) and induction of inflammatory processes. In a complex tissue, such as the atherosclerotic lesion, innate signals can originate from several sources and promote atherogenesis through ligation of PRRs. The receptors recognise conserved molecular patterns on pathogens and endogenous products of tissue injury and inflammation. Activation of PRRs might affect several aspects of atherosclerosis by acting on lesion resident cells. Scavenger receptors mediate antigen uptake and clearance of lipoproteins, thereby promoting foam cell formation. Signalling receptors, such as Toll-like receptors (TLRs), lead to induction of pro-inflammatory cytokines and antigen-specific immune responses. In this review we describe the innate mechanisms present in the plaque. We focus on TLRs, their cross-talk with other PRRs, and how their signalling cascades influence inflammation within the atherosclerotic lesion.     

Methods of biochemical analysis in hyperliproproteinemias

In the past years, the structure and function of the plasma lipoproteins and apolipoproteins have been elucidated. The biochemical defect of several genetic lipoprotein disorders and their role in the development of atherosclerosis are now well understood. Electrophoretic separation of lipoproteins in polyacrylamide gradient gel gives an acurate characterization of the different lipoproteins and allows the phenotyping of hyperlipoproteinemia. Abnormal concentrations of plasma lipoproteins have been known for many years to be a major risk factor in the development of premature ischemic heart disease. Although large-scale epidemiological studies have focused attention on the association between above-normal concentrations of plasma lipids and coronary atherosclerosis, recent findings have shown that quantitative lipoprotein and apoprotein determination may be a more nearly accurate predictor in the recognition of atherosclerosis. The risk for vascular disease seems to be particularly associated with an increase in the concentrations of apolipoprotein B (apo B), the major protein moiety of low density lipoproteins and a decrease in apolipoprotein Al, the major polypeptide of high-density lipoproteins.     

Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice.

Previous in vitro and in vivo studies have suggested that macrophage colony-stimulating factor (M-CSF) plays a role in atherogenesis. To examine this hypothesis, we have studied atherogenesis in osteopetrotic (op/op) mice, which lack M-CSF due to a structural gene mutation. Atherogenesis was induced either by feeding the mice a high fat, high cholesterol diet or by crossing op mice with apolipoprotein E (apo E) knockout mice to generate mice lacking both M-CSF and apo E. In both the dietary and apo E knockout models, M-CSF deficiency resulted in significantly reduced atherogenesis. For example, in the apo E knockout model, homozygosity for the op mutation totally abolished aortic atherogenesis in male mice and reduced the size of the lesions approximately 97% in female mice. Mice heterozygous for the op mutation also exhibited a significant decrease in lesion size. Among apo E knockout mice, the frequency of atherosclerosis in aortic arch was 0/6 (op/op), 1/15 (op/+), and 12/16 (+/+). The effect of the M-CSF on atherosclerosis did not appear to be mediated by changes in plasma lipoproteins, as the op mice exhibited higher levels of atherogenic lipoprotein particles. The effects of the op mutation on atherogenesis may have resulted from decreased circulating monocytes, reduced tissue macrophages, or diminished arterial M-CSF.     

Atherosclerosis and metabolic disease

Cholesterol plays an important role in atherogenesis. Cholesterol-ester that has been carried by circulating low-density lipoprotein particles accumulates in the atherosclerotic plaque. Statins are considered the most potent and effective agents for reducing low-density lipoprotein cholesterol and the incidence of cardiovascular events. Total cholesterol and LDL cholesterol levels, however, are not always a useful marker for distinguishing patients with or without cardiovascular disease. Low levels of high-density lipoprotein cholesterol are the most predictive marker for cardiovascular disease. Low HDL cholesterol levels originate in some genetic and acquired diseases and conditions. Most cases of low HDL cholesterol associated with the development of atherosclerosis are of secondary origin, especially those associated with increasing triglyceride-rich lipoprotein. These conditions are present in insulin-resistant syndrome, namely metabolic syndrome. Type 2 diabetes mellitus and the closely related metabolic syndrome are associated with a significant risk for cardiovascular disease. Recent evidence suggests that both conditions are increasing in epidemic proportions. Dyslipidemia is characterized by increased triglyceride-rich lipoproteins; low high-density lipoprotein cholesterol; small, dense low-density lipoprotein particles; and increased postprandial lipemia. All these lipoprotein disturbances accelerate atherosclerosis. It is likely that many patients will need lipid-modifying therapy to help prevent cardiovascular disease.     

Dietary fats, lipoproteins and atherogenesis

Important developments were recently observed concerning the relations between dietary fats, lipoproteins and atherogenesis. A better understanding of the metabolism of lipoproteins, mainly LDL and HDL, resulted in hypotheses on the role of dietary fatty acids in the development of atherosclerosis and ischemic cardiovascular diseases. Consecutive prospects in the field of the dietary prevention os ischemic cardiovascular disease begin to appear more clearly.     

Genetic-epidemiological studies of apolipoprotein(a) polymorphism and its significance in nephrological diseases and type I diabetes mellitus

Lipoprotein(a) is a highly atherogenic particle. The plasma concentrations of this lipoprotein are strongly related to a genetically determined size polymorphism of apolipoprotein(a). This article reviews some pathogenetic characteristics of the apolipoprotein(a) polymorphism besides its known effect on the lipoprotein(a) plasma concentrations. Those are the relation of the apolipoprotein(a) phenotype with atherogenesis, the apolipoprotein(a) phenotype-specific elevation of lipoprotein(a) in hemodialysis patients and the advantages of this polymorphism for the atherosclerosis risk evaluation in high-risk patients. It furthermore discusses the observed association between the low molecular weight apolipoprotein(a) phenotype and Type I diabetes mellitus.     

Ox-LDL increases OX40L in endothelial cells through a LOX-1-dependent mechanism

Oxidative low-density lipoprotein (Ox-LDL) is a key risk factor for the development of atherosclerosis, and it can stimulate the expression of a variety of inflammatory signals. As a new and highly sensitive inflammation index, OX40L may be a key to understanding the mechanisms that regulate interactions between cells within the vessel wall and inflammatory mediators during the development of atherosclerosis. To investigate whether Ox-LDL regulates OX40L expression through an oxidized LDL-1 receptor (LOX-1)-mediated mechanism, we investigated the effect of different concentrations of Ox-LDL (50, 100, 150 µg/mL) on endothelial cell proliferation and apoptosis. Stimulation with Ox-LDL increased OX40L protein 1.44-fold and mRNA 4.0-fold in endothelial cells, and these effects were inhibited by blocking LOX-1. These results indicate that LOX-1 plays an important role in the chronic inflammatory process in blood vessel walls. Inhibiting LOX-1 may reduce blood vessel inflammation and provide a therapeutic option to limit atherosclerosis progression.     

Role of oxidative modifications in atherosclerosis

This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an "oxidative response to inflammation" model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.     

Triglyceride (TG) and remnant lipoproteins

Lowering low-density lipoprotein (LDL) cholesterol (LDL-C) can reduce the risk of cardiovascular disease (CVD) by approximately 30%, and the remaining 70% should be the second front of CVD risk reduction. Such residual risks include high triglyceride (TG) concentrations and low levels of high-density lipoprotein (HDL) cholesterol (HDL-C) in terms of dyslipidemia. TG-rich lipoproteins are heterogenous and composed of a variety of subfractions, all of which are not necessarily relevant to atherosclerosis and CVD risk. However, remnant lipoproteins, TG-rich lipoproteins, are atherogenic and related to CVD risk. Two different methods (RLP-C and RemL-C) have been developed to measure cholesterol levels of remnant lipoproteins. Although there is a difference in affinity to intermediate-density lipoprotein (IDL) between the two methods, they may be better qualified as biomarkers of CVD risk than TG itself. TG measurements play a certain role in the evaluation of CVD risk, but the remnant lipoprotein cholesterol measurement can provide better screening for patients at high CVD risk than TG and may be a useful examination in both quantity and quality.     

Viral infection and atherosclerosis

Several risk factors have been described for the pathogenesis of atherosclerosis. Infectious diseases are suggested to be a causative factor, and some viruses have been studied for their relation with atherosclerotic diseases. Studies report two hypotheses, direct and indirect effects, for the role of viral infections in atherogenesis. Viruses are able to initiate atherosclerosis by two different pathways. They can exert their direct effects on atherogenesis by infecting vascular cells and then inducing inflammation in the endothelium and smooth muscle cells. Alternatively, they can also apply indirect effects by infecting non-vascular cells and inducing systemic inflammation. In this review, we consider the available data about the effects and correlations of DNA and RNA viruses on atherosclerosis.     

Role of hepatic and lipoprotein lipase in lipoprotein metabolism and atherosclerosis: studies in transgenic and knockout animal models and somatic gene transfer

Hepatic lipase (HL) and lipoprotein lipase (LPL) are the two major lipolytic enzymes responsible for the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins. Both lipases are attached to the vascular endothelium via cell surface proteoglycans. HL is primarily involved in the metabolism of chylomicron remnants, intermediate density lipoproteins and high-density lipoproteins whereas LPL catalyzes the hydrolysis of triglycerides from chylomicrons and very low-density lipoproteins. In addition to their traditional function as lipolytic enzymes, HL and LPL appear to serve as ligands that mediate the interaction of lipoproteins to cell surface receptors and/or proteoglycans. Over the past several years significant advances have been made in our understanding of new, alternative mechanisms by which HL and LPL modulate lipoprotein metabolism and the development of atherosclerosis in vivo. This review will summarize some of the new insights generated from the study of transgenic and knockout HL and LPL animal models as well as somatic gene transfer of these two lipases.     

Current views on the pathogenesis of atherosclerosis from the position of infectious pathology

The role of immune inflammation at atherogenesis is studied in the paper. Two etiological factors of atherosclerosis pathogeny are under examination: the role of modified low density lipoproteins (mLDL) and essential parasites (Chlamydia pneumoniae and Cytomegaloviruses). Generality of immune response during persistent infection into a blood vessel wall and deposit or formation of mLDL are discussed. The point of view is substantiated that the development of atherosclerotic damages of blood vessels is speeded up by a combination of the two mentioned etiological factors.     

脂蛋白脂酶基因多态性和冠状动脉粥样硬化

脂蛋白脂酶基因是冠心病的候选基因 ,其编码产物脂蛋白脂酶是脂代谢过程中的关键酶。脂蛋白脂酶基因的多态性可影响脂蛋白脂酶活性、血脂代谢 ,从而影响血脂水平和动脉粥样硬化 ,与冠心病的发生和发展有密切关系。     

Lipoprotein (a). An additional marker of atherosclerosis

Lipoprotein Lp(a) is a plasma lipoprotein which possesses many similarities to low density lipoprotein (LDL) in its physical and chemical properties. The major protein constituent of both lipoproteins is apolipoprotein B100 (apo B100); however, Lp(a) is unique in that it contains an additional distinct antigen, the (a)-antigen, attached to apo B100 by one or more disulphide bridges. The (a)-glycoprotein has recently been shown to have a striking amino-acid sequence homology with plasminogen; so, Lp(a) seems to be a potential bridge between the fields of atherosclerosis and thrombosis. Metabolic studies have made it clear that Lp(a) is not a product derived from other apo B-containing lipoproteins, but is secreted by the liver as a distinct mature lipoprotein. Although a relationship between elevated serum Lp(a) levels and the occurrence of atherosclerotic diseases had been postulated by several investigators, little is known today about the role of this lipoprotein and/or the mechanism whereby it might predispose to atheroma. However, the new knowledge on the structure of Lp(a) being more and more rapidly acquired, should facilitate the understanding of the mechanism of its atherogenicity and its physiopathological role.     

Is HDL function as important as HDL quantity in the coronary artery disease risk assessment?

Over the past several decades, it has been clearly established that higher plasma concentrations of high-density lipoprotein (HDL) are related to lower risk of coronary artery disease (CAD). According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, the HDL level of <40 mg/dL is considered low and is one of the CAD risk predictors. However, in the last decade, several studies have indicated the importance of the quality of HDL as another potential measure for CAD risk assessment. The loss of normal biological function of HDL particles as a result of multifactorial actions of chronic inflammation and acute phase responses has suggested a new potential pathway in the pathophysiology of atherosclerosis. The concept of “dysfunctional HDL” or “proinflammatory HDL,” which exhibits chameleon-like properties of converting a positive force protecting arteries to a negative one, enhancing atherogenesis is now under active investigation. Measurements of this dysfunctional quality of HDL in cell-based or cell-free assays by analyzing anti-inflammatory functions may link these changes to in vivo assessments of vascular disease. This review provides details on functional and dysfunctional HDL and summarizes recent studies into dysfunctional HDL and its potential links to CAD.     

Effects of ethanol on lipids and atherosclerosis.

Moderate alcohol consumption is associated with an increase in plasma high density lipoprotein (HDL) cholesterol concentration and a decrease in low density lipoprotein (LDL) cholesterol concentration. Changes in the concentration and composition of lipoproteins are estimated to account for more than half of alcohol's protective effect for coronary heart disease. Alcohol intake also affects plasma proteins involved in lipoprotein metabolism: cholesteryl ester transfer protein, phospholipid transfer protein, lecithin:cholesterol acyltransferase, lipoprotein lipase, hepatic lipase, and phospholipases. In addition, alcohol intake may result in acetaldehyde modification of apolipoproteins. Furthermore, "abnormal" lipids, phosphatidylethanol and fatty acid ethyl esters are formed in the presence of ethanol and are associated with lipoproteins in plasma. Ethanol and ethanol-induced modifications of lipids may modulate the effects of lipoproteins on the cells in the arterial wall. The molecular mechanisms involved in these processes are complex, requiring further study to better understand the specific effects of ethanol in the pathogenesis of atherosclerosis. This review discusses the effects of ethanol on lipoproteins and lipoprotein metabolism, as well as the novel effects of lipoproteins on vascular wall cells.     

The antiatherogenic effect of allicin: possible mode of action.

OBJECTIVE: Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models. METHODS AND RESULTS: Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO(4)-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with (3)H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu(2+) binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. CONCLUSIONS: By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.