Low-density Lipoprotein In Atherogenesis Research Articles

Cholesterol Paradigm and Beyond in Atherosclerotic Cardiovascular Disease: Cholesterol, Sterol Regulatory Element-Binding Protein, Inflammation, and Vascular Cell Mobilization in Vasculopathy.

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). How cholesterol and its carrier lipoproteins are involved in ASCVD is still under extensive investigation. Satins are thus far the best-proven class of cholesterol-lowering medications to improve the clinical outcomes of ASCVD. Statins specifically inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase of the mevalonate pathway for cholesterol biosynthesis. The widely accepted theory is that statins inhibit the hepatic cholesterol synthesis causing upregulation of hepatocyte low-density lipoprotein (LDL) receptor; receptor-mediated LDL uptake and metabolism in the liver results in reduction of circulating LDL cholesterol, which subsequently reduces vascular deposition and retention of cholesterol or LDL in atherogenesis. Nevertheless, cholesterol biosynthesis is ubiquitous, also in extrahepatic cells including those in vascular wall, under tight regulation by sterol regulatory element-binding protein (SREBP), the master gene transcription factor governing cholesterol biosynthesis. Studies have shown that SREBP can be upregulated in vascular wall subject to injury or stent implantation. SREBP can be activated by proinflammatory and mitogenic factors in vascular cells, leading to hyperactive mevalonate pathway, which promotes vascular cell mobilization, further proinflammatory and mitogenic factor release from vascular cells, and vascular inflammation. In this article, we review the cellular cholesterol homeostasis regulation by SREBP and SREBP-mediated vascular hyperactive cholesterol biosynthesis, we term vascular hypercholesterolism, in the pathogenesis of ASCVD and vasculopathy. SREBP functions as a platform bridging cholesterol, inflammation, and vascular cell mobilization in ASCVD pathogenesis. Targeting vascular hypercholesterolism could open a new avenue in fighting against ASCVD.

Modified and Dysfunctional Lipoproteins in Atherosclerosis: Effectors or Biomarkers?

Atherosclerotic diseases are the leading cause of mortality in industrialized countries. Correspondingly, studying the pathogenesis of atherosclerosis and developing new methods for its diagnostic and treatment remain in the focus of current medicine and health care. This review aims to discuss the mechanistic role of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) in atherogenesis. In particular, the generally accepted hypothesis about the key role of oxidized LDL in atherogenesis is questioned, and an alternative concept of multiple modification of LDL is presented. The fundamental question discussed in this review is whether LDL and HDL are effectors or biomarkers, or both. This is important for understanding whether lipoproteins are a therapeutic target or just diagnostic indicators.

Modified lipoproteins as biomarkers of atherosclerosis.

Pathogenesis of atherosclerosis and the search for novel therapies and diagnostic markers remain major problems of modern medicine. Currently available therapeutic approaches are often not sufficiently effective, probably due to the complexity of the disease mechanisms. This review focuses on the evaluation of low density lipoprotein (LDL) and high density lipoprotein (HDL) as risk factors of atherosclerosis. We summarize the current paradigm of LDL involvement in atherogenesis and HDL presumably protective properties. We next discuss the available evidence for the protective effect of HDL and the consequences of HDL dysfunction. Finally, we question the currently widely accepted hypothesis of the central role of oxidized LDL in atherogenesis and present an alternative concept of multiple modification of LDL that confers its pro-atherogenic properties.

The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts.

The oxidative modification hypothesis of atherosclerosis, which assigns to oxidized low-density lipoproteins (LDLs) a crucial role in atherosclerosis initiation and progression, is still debated. This review examines the role played by oxidized LDLs in atherogenesis taking into account data derived by studies based on molecular and clinical approaches. Experimental data carried out in cellular lines and animal models of atherosclerosis support the proatherogenic role of oxidized LDLs: (a) through chemotactic and proliferating actions on monocytes/macrophages, inciting their transformation into foam cells; (b) through stimulation of smooth muscle cells (SMCs) recruitment and proliferation in the tunica intima; (c) through eliciting endothelial cells, SMCs, and macrophages apoptosis with ensuing necrotic core development. Moreover, most of the experimental data on atherosclerosis-prone animals benefiting from antioxidant treatment points towards a link between oxidative stress and atherosclerosis. The evidence coming from cohort studies demonstrating an association between oxidized LDLs and cardiovascular events, notwithstanding some discrepancies, seems to point towards a role of oxidized LDLs in atherosclerotic plaque development and destabilization. Finally, the results of randomized clinical trials employing antioxidants completed up to date, despite demonstrating no benefits in healthy populations, suggest a benefit in high-risk patients. In conclusion, available data seem to validate the oxidative modification hypothesis of atherosclerosis, although additional proofs are still needed.

Diabetic dyslipidemia and exercise alter the plasma low‐density lipoproteome in Yucatan pigs

Although low-density lipoprotein (LDL) plays a predominant role in atherogenesis, the low-density lipoproteome has not been fully characterized. Moreover, alterations from a Western diet, diabetes, and physical inactivity on this proteome have yet to be determined. Accordingly, relative quantification was determined in LDL proteins from male Yucatan diabetic dyslipidemic (DD) swine in the early stages of atherosclerosis compared to healthy control (C) and non-diabetic hyperlipidemic (H) swine. Importantly, coronary vascular dysfunction was prevented by aerobic exercise training in these animals (DDX) without altering total LDL concentration. Using 2-DE, Western blot, label-free quantitative MS, and selected reaction monitoring, alterations in the abundance of apolipoproteins A-I, B, C-III, D, E, and J and noncovalently associated proteins were determined in LDL isolated using fast protein liquid chromatography. At least 28 unique proteins, many of which were novel, were identified with high confidence. An apolipoprotein E isoform demonstrated stronger correlation to disease (percent of coronary artery segments with intimal thickening) than some traditional risk factors (total cholesterol, LDL cholesterol, and LDL/HDL cholesterol). Taken together, this work identifies new possible biomarkers, potential therapeutic targets for atherosclerosis, and generates new hypotheses regarding the role of LDL in atherogenesis.

Promise of Low-Density Lipoprotein–Lowering Therapy for Primary and Secondary Prevention

One of the foremost medical advances of the past 2 decades has been proof that elevated low-density lipoprotein (LDL) is a cause of atherosclerotic cardiovascular disease (ASCVD) and that lowering of LDL levels will reduce risk for ASCVD.1,2 The application of this knowledge in clinical and public health arenas offers the opportunity to greatly reduce morbidity and mortality from ASCVD. This article outlines the rationale underlying this opportunity. Response by Superko and King p 573 Although several major risk factors for ASCVD exist, the realization that elevated plasma LDL is the driving force of atherogenesis highlights the possibilities for prevention. Many studies in laboratory animals have shown that high serum cholesterol levels induce atherosclerotic lesions resembling those found in humans.1 Similarly, humans with severe forms of hypercholesterolemia commonly exhibit premature atherosclerotic disease. Epidemiological studies reveal a strong association between serum cholesterol levels and ASCVD prevalence3; moreover, in populations in which cholesterol levels are low, ASCVD is correspondingly low even when other risk factors are common.4 The latter observation has recently been confirmed through genetic epidemiology; in those persons who carry a mutation causing low cholesterol levels over a lifetime, ASCVD is virtually absent even in the presence of other risk factors.5 Finally, many recent clinical trials have documented that LDL-lowering therapy reduces risk for ASCVD.6 All told, these several lines of evidence indicate that a lifetime of low LDL levels lowers risk for ASCVD by up to 80% to 90% compared with the general population of the United States,5 whereas intensive LDL-lowering therapy even in the presence of advanced atherosclerotic disease reduces risk for major ASCVD events by 40% to 50%.6–8 However, the latter response leaves 50% to 60% of risk untouched; this has called been residual risk. Because of the …

Evolution of cholesterol concept of atherogenesis from Anitchkov to our days.

Our review addresses the development of the cholesterol concept of atherogenesis from the classical investigations of Anitchkov and Chalatov (1913), who induced experimental cholesterol atherosclerosis in rabbits, to the present time. We conclude that based on data obtained to date relating to the presence of different classes of lipoproteins in blood, on the role of peroxidatively modified low density lipoproteins in atherogenesis, and on the involvement of various arterial and blood cells and other factors, the cholesterol concept of atherogenesis has not lost its significance. Moreover, cholesterol-lowering therapy has a leading role in the primary and secondary prevention of coronary heart disease events and other clinical manifestations of atherosclerosis.

EVOLUTION OF CHOLESTEROL CONCEPT OF ATHEROGENESIS FROM ANITCHKOV TO OUR DAYS

Our review addresses the development of the cholesterol concept of atherogenesis from the classical investigations of Anitchkov and Chalatov (1913), who induced experimental cholesterol atherosclerosis in rabbits, to the present time. We conclude that based on data obtained to date relating to the presence of different classes of lipoproteins in blood, on the role of peroxidatively modified low density lipoproteins in atherogenesis, and on the involvement of various arterial and blood cells and other factors, the cholesterol concept of atherogenesis has not lost its significance. Moreover, cholesterol-lowering therapy has a leading role in the primary and secondary prevention of coronary heart disease events and other clinical manifestations of atherosclerosis.

Acute and long-term effects of low-density lipoprotein (LDL)-apheresis on oxidative damage to LDL and reducing capacity of erythrocytes in patients with severe familial hypercholesterolaemia

Several studies have suggested that the oxidative modification of low-density lipoprotein (LDL) could play a key role in the early stages of atherosclerosis. The susceptibility of LDL to oxidation has been found to be greater in patients with coronary heart disease. Familial hypercholesterolaemia (FH) is a powerful clinical model in which to study the predictive role of LDL in atherogenesis. LDL-apheresis is a treatment that is able to decrease lipid levels in plasma. This study was aimed at investigating the reducing capacity of erythrocytes and the in vitro susceptibility to oxidation of LDL isolated from patients with homozygous, heterozygous and double-heterozygous FH, who were treated fortnightly with LDL-apheresis or left untreated. In 14 FH patients, at baseline and after a cycle of treatment, the susceptibility of LDL to oxidative modification was analysed by studying the kinetics of conjugate diene formation. Plasma hydroperoxides, polyunsaturated fatty acid content, LDL electrophoretic mobility on agarose, the titre of auto-antibodies against oxidized LDL and serum paraoxonase activity were also measured. Furthermore, in order to evaluate a potential relationship between LDL oxidation and redox status, erythrocyte GSH and ATP levels were determined in FH patients treated regularly or never treated previously by LDL-apheresis. Unlike in the control group, the oxidative status of LDL in all FH patients was modified by LDL-apheresis, as revealed by the higher negative charge and the increase in levels of hydroperoxides and antibodies against oxidized LDL in the plasma. Our findings suggest both an acute effect and a long-term effect of LDL-apheresis in FH patients treated with dextran sulphate cellulose apheresis. The acute effect of LDL-apheresis on the susceptibility to oxidation of plasma and LDL was demonstrated by significant decreases in plasma hydroperoxide content, total LDL concentration and polyunsaturated fatty acid content. The increased resistance of LDL to oxidation was shown by prolongation of the lag time (P<0.05) in samples after a single cycle of treatment. The long-term effect of LDL-apheresis was demonstrated by the comparable values for lag phases (obtained from the kinetics of conjugate diene formation) in patients under active treatment and controls. Compared with healthy controls and untreated patients, the erythrocyte GSH content was significantly higher (P</=0.001) in the treated group, suggesting the activation of reducing mechanisms.

Low density lipoprotein (LDL), atherosclerosis and antioxidants

A crucial and causative role in the pathogenesis of atherosclerosis is believed to be the oxidative modification of low density lipoprotein (LDL). The oxidation of LDL involves released free radical driven lipid peroxidation. Several lines of evidence support the role of oxidized LDL in atherogenesis. Epidemiologic studies have demonstrated an association between an increased intake of dietary antioxidant vitamins, such as vitamin E and vitamin C and reduced morbidity and mortality from coronary artery diseases. It is thus hypothesized that dietary antioxidants may help prevent the development and progression of atherosclerosis. The oxidation of LDL has been shown to be reduced by antioxidants, and, in animal models, improved antioxidants may offer possibilities for the prevention of atherosclerosis. The results of several on going long randomized intervention trials will provide valuahle information on the efficacy and safety of improved antioxidants in the prevention of atherosclerosis. This review a evaluates current literature involving antioxidants and vascular disease, with a particular focus on the potential mechanisms.

AHA Science Advisory. Monounsaturated fatty acids and risk of cardiovascular disease. American Heart Association. Nutrition Committee.

This report summarizes our current understanding of how monounsaturated fatty acids (MUFAs) affect risk for cardiovascular disease (CVD). This is a topic that has attracted considerable scientific interest,1 2 3 in large part because of uncertainty regarding whether MUFA or carbohydrate should be substituted for saturated fatty acids (SFAs) and the desirable quantity of MUFA to include in the diet. MUFAs are distinguished from the other fatty acid classes on the basis of having only 1 double bond. In contrast, polyunsaturated fatty acids (PUFAs) have 2 or more double bonds, and SFAs have none. The position of the hydrogen atoms around the double bond determines the geometric configuration of the MUFA and hence whether it is a cis or trans isomer. In a cis MUFA, the hydrogen atoms are present on the same side of the double bond, whereas in the trans configuration, they are on opposite sides. The American Heart Association Nutrition Committee recently published a scientific statement regarding the relationship of trans MUFA to CVD risk,4 and the present statement, therefore, will be limited to a discussion of dietary cis MUFAs, of which oleic acid ( cis C18:1) comprises ≈92% of cis MUFAs. In the United States, average total MUFA intake is 13% to 14% of total energy intake, an amount that is comparable to (or slightly greater than) SFA intake. In contrast, PUFAs contribute less (ie, 7% of energy). The major emphasis of current dietary guidelines involves replacing SFAs with complex carbohydrates to achieve a total fat intake of ≤30% of calories. There is evidence suggesting that the substitution of MUFA instead of carbohydrate for SFA calories may favorably affect CVD risk.5 6 7 The American Heart Association dietary guidelines for healthy American adults recommend a diet that provides <10% of calories from SFA, up …

Diabetes, Oxidative Stress, and Platelet Activation

Diabetes mellitus is a major source of morbidity in developed countries and, among its comorbid conditions, atherosclerosis is perhaps the most important. Since the availability of insulin, up to three fourths of all deaths among diabetics can be directly attributed to coronary artery disease (CAD).1 In adult patients with diabetes, the risk of CAD is 3- to 5-fold greater in than nondiabetics despite controlling for other known CAD risk factors.1 In patients with IDDM, up to one third will die of CAD by the age of 50 years.2 A number of known risk factors for CAD, such as hypertension, central obesity, and dyslipidemia, are more common in diabetics than in the general population.1 Despite this prevalence of risk factors, no more than 25% of the excess CAD risk in diabetes can be accounted for by known risk factors.2 Thus diabetes represents a major contributing factor to the CAD burden in the developed world, and most of the excess attributed risk of CAD in diabetics cannot be readily quantified with the use of traditional risk factor analysis. Diabetes is associated with a variety of metabolic abnormalities, principle among which is hyperglycemia. The relation between hyperglycemia and CAD is the subject of considerable debate because serum glucose does not consistently predict the existence of CAD.2 Presumably, this confusion stems from the reliance on a single blood glucose measurement, as recent prospective data have clearly established a link between a marker for chronic average glucose levels (HbA1C) and cardiovascular morbidity and mortality.3 There is considerable controversy with respect to the precise mechanism by which hyperglycemia may contribute to the development of CAD in diabetes. Established sequelae of hyperglycemia, such as cytotoxicity, increased extracellular matrix production, and vascular dysfunction, have all been implicated in the pathogenesis …

Oxidized low density lipoproteins in atherogenesis: role of dietary modification.

The development of atherosclerosis is a complex and multistep process. There are many determinants in the pathogenesis of this condition, with different factors presumably playing key roles at different times in the evolution of the atherosclerotic plaque. It has been suggested that oxidation of low density lipoproteins (LDL) by cells in the artery wall leads to a proatherogenic particle that may help initiate early lesion formation. For this reason, understanding the determinants of LDL susceptibility to oxidation is essential for developing therapeutic strategies to inhibit this process. Oxidation of LDL begins with the abstraction of hydrogen from polyunsaturated fatty acids; thus, LDL fatty acid composition undoubtedly contributes to the process of LDL oxidation. Since dietary fatty acids influence the fatty acid composition of LDL and cell membranes, the amount and type of fat in the diet may effect susceptibility of LDL and cells to oxidative damage. Additionally, since cell membrane fatty acid composition also influences cellular formation of reactive oxygen species, dietary fatty acids may help determine the prooxidant activity of artery wall cells. Both cells and lipoproteins contain a variety of antioxidants that provide protection against oxidative stress. A major source of these antioxidants is the diet. Enrichment of the diet with foods high in such antioxidants as vitamin E, beta-carotene, or vitamin C, or supplementation of the diet with antioxidant vitamins, may inhibit oxidation and the process of atherosclerosis.

The Role of Oxidized Low Density Lipoprotein in Atherogenesis

An elevated level of low density lipoprotein (LDL) cholesterol constitutes a major risk factor for atherosclerotic disease. Although the precise mechanism(s) via which LDL promotes atherogenesis remains to be elucidated, the oxidative modification of LDL may be a crucial mechanism. Several lines of evidence support a role for oxidatively modified LDL in atherogenesis. LDL can be oxidatively modified in cell-free systems by transition metals and by all the major cells of the arterial wall. Oxidatively modified LDL (Ox-LDL) is taken up by macrophage scavenger receptors, promoting cholesterol ester accumulation and foam cell formation. It also promotes atherosclerosis by recruitment and retention of monocytes in the intima, by its cytotoxicity toward endothelial cells and by stimulating monocyte adhesion to the endothelium. Several lines of evidence support the in vivo existence of Ox-LDL. The LDL of patients with atherosclerosis are more prone to oxidation; antibodies against epitopes on Ox-LDL have been positively correlated with the progression of atherosclerosis. The oxidation of LDL has been shown to be reduced by antioxidants, and in animal models, these antioxidants decrease atherosclerotic lesion formation. Thus, much evidence supports a role for oxidized LDL in atherogenesis.

Oxidized Low Density Lipoproteins in Atherogenesis: Role of Dietary Modification

The development of atherosclerosis is a complex and multistep process. There are many determinants in the pathogenesis of this condition, with different factors presumably playing key roles at different times in the evolution of the atherosclerotic plaque. It has been suggested that oxidation of low density lipoproteins (LDL) by cells in the artery wall leads to a proatherogenic particle that may help initiate early lesion formation. For this reason, understanding the determinants of LDL susceptibility to oxidation is essential for developing therapeutic strategies to inhibit this process. Oxidation of LDL begins with the abstraction of hydrogen from polyunsaturated fatty acids; thus, LDL fatty acid composition undoubtedly contributes to the process of LDL oxidation. Since dietary fatty acids influence the fatty acid composition of LDL and cell membranes, the amount and type of fat in the diet may effect susceptibility of LDL and cells to oxidative damage. Additionally, since cell membrane fatty acid composition also influences cellular formation of reactive oxygen species, dietary fatty acids may help determine the prooxidant activity of artery wall cells. Both cells and lipoproteins contain a variety of antioxidants that provide protection against oxidative stress. A major source of these antioxidants is the diet. Enrichment of the diet with foods high in such antioxidants as vitamin E, β-carotene. or vitamin C, or supplementation of the diet with antioxidant vitamins, may inhibit oxidation and the process of atherosclerosis.

Antioxidants and the Prevention of Coronary Heart Disease

Oxygen-free radical reactions have been implicated in many chronic disease processes, including atherosclerotic cardiovascular disease. Recent studies of lipid metabolism have suggested that oxidative modification of low-density lipoprotein accelerates atherogenesis. Micronutrient antioxidants, including alpha-tocopherol and beta-carotene, however, can neutralize oxygen-free radicals and inhibit low-density lipoprotein oxidation. This review examines (1) the role of oxidized low-density lipoprotein in atherogenesis, (2) the association between nutritional antioxidant intake and atherosclerosis, and (3) observational and clinical trial data on the effect of antioxidants in reducing the risk of coronary heart disease. While evidence suggests that antioxidant supplements protect against coronary heart disease, definitive recommendations await results from ongoing randomized trials of primary and secondary prevention.

Role of low-density lipoproteins in atherogenesis and development of coronary heart disease

There is a strong association between increased blood concentrations of low-density lipoprotein (LDL) and severity of coronary atherosclerosis. Multiple mechanisms affect hypercholesterolemia, e.g., diet, aging, hormones, and genetics. LDL receptors apparently are also important--through down-regulation, defects in structure, or decreased numbers--as are changes in LDL binding characteristics caused by alterations in apolipoprotein B content or structure. Current concepts of LDL metabolism are extensively reviewed, including the role of modified or oxidized LDL in atherogenesis.

The role of oxidized low-density lipoprotein in atherogenesis

Oxidized LDL have been shown to both stimulate and inhibit functions of vascular wall cells, contributing to all stages of the atherosclerotic reaction. It is becoming clear that the family of oxidation products in LDL, like the cytokine family, has many members with varying effects on different cell types. Identification of the products of oxidized LDL that contribute to the pathogenesis of atherosclerosis will have a considerable impact on future strategies for identification of indices of clinical assessment, for prevention, and for the treatment of coronary heart disease.

Role of oxidised low density lipoprotein in atherogenesis.

Overview of the concept ofoxidative modification ofLDL There can be no doubt now that there is a continuum of increasing risk for complications ofatherosclerosis when plasma levels exceed 160-180 mg/dl. Many types of experimental and clinical evidence substantiate the cholesterol hypothesis. Many primary and secondary prevention trials, including the recent angiographic trials(CLAS andFATS) document that reduction of plasma is as powerful as has been predicted in slowing the progression and clinical expression ofcoronary atherosclerosis. However, the cellular and molecular mechanisms linking hypercholesterolemia to atherogenesis and its sequelae remain unclear. Iflowering ofLDL is efficacious in ameliorating the atherogenic process, why then should one bother to understand the mechanisms? Simply because loweringLDL will not be a total solution. Although it may be true that ifcholesterol levels were reduced to < 150 mg/dl there would be little if any coronary artery disease (CAD),' it is not likely that this will occur any time soon. At any given level ofLDL there is great variability in the clinical expression of the disease. Patients with heterozy

Evaluation of Oxidized Low-Density Lipoprotein and Large Molecular Size Low-Density Lipoproteins in Atherosclerosis

To study the roles of modified low-density lipoprotein (LDL) and the molecular size of LDL in atherogenesis, the following studies were carried out. Eight white male rabbits fed a standard oriental diet with 1% cholesterol were used to isolate LDL and to observe changes in the molecular size of LDL due to cholesterol feeding. The tissue LDLs in the aorta were analyzed to confirm the existence of modified LDL (namely, LDL with peroxidized cholesteryl ester) by thin-layer chromatography. In addition, plasma LDLs were isolated from 18 patients with myocardial infarction and 11 patients with angina pectoris to confirm the existence of LDL with peroxidized cholesteryl ester. Each LDL separated consisted of 3 fractions; namely, IDL (1.006-1.018), LDL1 (1.019-1.052) and LDL2 (1.053-1.063) by sequential ultracentrifugation. The molecular sizes of LDL were measured by a planimeter from electron microscopic photographs, with negative staining. The estimation of peroxidized cholesteryl linoleate in LDL was performed using our method. The modified LDLs with peroxidized cholesteryl ester were poorly estimated in the LDL separated from the plasma of cholesterol-fed rabbits and from the aorta extraction after 16 weeks of feeding. The peroxidized cholesteryl ester was clearly identified in the plasma LDLs of the patients with myocardial infarction and angina pectoris, and in whole extracts from human aortic atheroma, although it was not clearly identified in the tissue LDL fraction. The molecular sizes of LDL1 enlarged week by week with cholesterol feeding, but two fractions of IDL and LDL2 did not change in size. The infusion of cholesterol-rich LDL of large molecular size or LDL with peroxidized cholesteryl ester into the vessels led to fixation, on the surface of the arteries of many platelets, red cells, and white cells, and to marked irregularities in the endothelial folds. The evidence suggests that atheromas, formed in a short period in rabbits with cholesterol feeding, are caused mainly by the increase in LDL1 of large molecular size, and that foam cells, formed in human atheromas, are caused mainly by the production of modified LDL with peroxidized cholesteryl ester.