Oxidized LDL and HDL: antagonists in atherothrombosis (original) (raw)
Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology
Antioxidants & Redox Signaling, 2010
Oxidative modification of LDL is known to elicit an array of pro-atherogenic responses, but it is generally underappreciated that oxidized LDL (OxLDL) exists in multiple forms, characterized by different degrees of oxidation and different mixtures of bioactive components. The variable effects of OxLDL reported in the literature can be attributed in large part to the heterogeneous nature of the preparations employed. In this review, we first describe the various subclasses and molecular composition of OxLDL, including the variety of minimally modified LDL preparations. We then describe multiple receptors that recognize various species of OxLDL and discuss the mechanisms responsible for the recognition by specific receptors. Furthermore, we discuss the contentious issues such as the nature of OxLDL in vivo and the physiological oxidizing agents, whether oxidation of LDL is a prerequisite for atherogenesis, whether OxLDL is the major source of lipids in foam cells, whether in some cases it actually induces cholesterol depletion, and finally the Janus-like nature of OxLDL in having both pro-and anti-inflammatory effects. Lastly, we extend our review to discuss the role of LDL oxidation in diseases other than atherosclerosis, including diabetes mellitus, and several autoimmune diseases, such as lupus erythematosus, anti-phospholipid syndrome, and rheumatoid arthritis. Antioxid. Redox Signal. 13, 39-75.
Atherogenesis, the oxidative LDL modification hypothesis revisited
Advances in Bioscience and Biotechnology, 2013
The commonly-accepted "oxidized LDL hypothesis of atherogenesis" is based on a large number of indirect evidence that shows that oxidatively-modified LDL plays a role in atherogenesis. Yet, the exact role is not clear. Some researchers think that oxidatively modified biomolecules initiate atherogenesis; others believe that they "only" promote this multifactorial process. Regardless of the exact mechanism responsible for the effect of peroxidation on atherogenesis, the "oxidative theory of AS" is apparently inconsistent with the results of meta-analysis, in which (the "expected") significant correlation between CVD and oxidative stress (OS) was found only when the OS was evaluated on the basis of the plasma concentrations of malondialdehyde (MDA), often based on the concentration of thiobarbituric acid reactive substances (TBARS). Notably, even this association is questionable due to 1) poor reliability of the laboratory assay of MDA and 2) possible publication bias. Hence, it appears that the commonly accepted paradigm regarding the role of oxidative damage in the pathogenesis of CVD has been overestimated. Furthermore, the hypothesis is apparently inconsistent with the disappointing results of most of the clinical trials that were designed to reduce OS by means of supplementation of antioxidants, mostly vitamin E. These apparent inconsistencies do not contradict the oxidative modification hypothesis of AS. The source of the apparent contradictions is probably the oversimplified considerations on which the predictions have been based. Many reasonable arguments can be raised to explain the apparent contradictions, which means that our current knowledge is insufficient to test the relationship of oxidative stress to cardiovascular disease.
Oxidized Low-Density Lipoprotein and its Atherogenic Potential
International Journal of Biomedicine
The emergence of oxidized low-density lipoprotein (OxLDL) is crucial for the progression of cardiovascular diseases (CVD) linked to atherosclerosis. OxLDL stimulates endothelial activation and smooth muscle proliferation and has an atherosclerotic-promoting effect. The measurement of OxLDL correlates with the presence of CVD and may be a prognostic marker for future health outcomes. Circulating OxLDLs can be used as biomarkers since their levels rise in patients with advanced atherosclerosis. Immunological methods have proven to be very useful methodologies. Anti-OxLDL monoclonal antibodies have been developed that bind strongly to OxLDL and are used in ELISA for OxLDL measurements. Routine inclusion of OxLDL estimation in an at-risk population can help the clinicians understand the disease initiation and progression and improve early intervention and management.
Oxidized Low-Density Lipoprotein Cholesterol and Coronary Artery Disease
Cardiology, 2011
In contrast to the plethora of vasculopathies to which oxidized low-density lipoprotein cholesterol (ox-LDL) can be linked, there are no data linking ox-LDL to myocardial (dys)function in the community. We tested whether ox-LDL, a marker of oxidative stress, was linked to early cardiac structural and functional damage in the general population. The Asklepios Study is a random sample of 2524 male and female volunteers, comparable to the Belgian population between 35 and 55 years free from overt cardiovascular disease. Cardiac morphology, systolic, and early and late diastolic tissue Doppler mitral annulus velocities were recorded during an echocardiography, followed by a vascular examination (carotid and femoral arteries). Serum ox-LDL was measured by sandwich ELISA using the mAb-4E6 monoclonal antibody. Effects of ox-LDL were assessed after adjustment for age, gender, lipid fractions, blood pressure, heart rate, height, weight, glycemia, smoking, and drug treatment. Mean ox-LDL was 96.0Ϯ38.9 U/L. After adjustment, increasing ox-LDL levels were associated with a more spherical left ventricular cavity (minor/major axis dimensions; PϽ0.001) and decreasing diastolic (early diastolic tissue Doppler mitral annulus velocity; PϽ0.001, more pronounced in women) and systolic function (amplitude of systolic tissue Doppler mitral annulus velocity; Pϭ0.008, more pronounced in men). These results remained unaffected when further adjustments were made for inflammatory markers, lifestyle, or vascular damage (atherosclerosis and arterial stiffening). These results are the first "proof of concept" that ox-LDL impacts cardiac structure and function at a community level, independent of classic risk factors, lifestyle, inflammation, and prevalent vascular damage. Our data suggest that ox-LDL is a risk marker for early ventricular remodelling. However, the effect size in the general population is small.
Oxidized Low-Density Lipoprotein
Methods in Molecular Biology, 2009
Oxidized low-density lipoprotein (Ox-LDL) has been studied for over 25 years. Numerous proand anti-atherogenic properties have been attributed to Ox-LDL. Yet, Ox-LDL has neither been defined nor characterized, as its components and composition change depending on its source, method of preparation, storage, and use. It contains unoxidized and oxidized fatty acid derivatives both in the ester and free forms, their decomposition products, cholesterol and its oxidized products, proteins with oxidized amino acids and cross-links, and polypeptides with varying extents of covalent modification with lipid oxidation products, and many others. It seems to exist in vivo in some form not yet fully characterized. Until its pathophysiological significance, and how it is generated in vivo are determined, the nature of its true identity will be only of classical interest. In this review, its components, their biological actions and methods of preparation will be discussed.
Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis
Oxidative Medicine and Cellular Longevity
Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a cle...
Role of oxidized low-density lipoprotein cholesterol concentration in atherosclerosis
Experimental and clinical cardiology
It is assumed that oxidized LDL (ox-LDL) plays a key role in the inflammatory response in the arterial vessel wall. This study aimed to investigate the association between oxidized low density lipoprotein cholesterol and carotid intima-media thickness, a measure used to diagnose the extent of carotid atherosclerotic vascular disease. Four groups of subjects were included in the study: a control group that included 15 normocholesterolemic healthy subjects (82% males, 18% females), 30 subjects with clinical signs of coronary artery disease (68% males, 32% females), 15 patients with arterial hypertension (66% males, 34% females), and 17dyslipidemic patients (64% males, 36% females). Lipid profiles of the patients were measured by enzymatic methods. Carotid IMT was measured by high-resolution Bmode ultrasound and ox-LDL by a commercially available sandwich ELISA (Mercodia AB, Uppsala, Sweden). Serum ox-LDL levels were higher in coronary artery disease patients (93.9 ± 7.35 U/L) and dyslipidemic patients (72 ± 14.34 U/L) compared with hypertensive (54 ± 12.03 U/L) and control subjects (55 ± 6.79 U/L). A positive, moderate correlation between ox-LDL and carotid IMT was found only in coronary artery disease group (r=0.56, p<0.001). No significant correlation was found between ox-LDL and carotid IMT in control (r=0.48, p<0.001), hypertensive (r=0.12, p<0.001) and dyslipidemic groups (r=0.14, p=0.05).
Oxidants and antioxidants in atherogenesis: an appraisal
Journal of Lipid Research, 1999
Oxidized low density lipoprotein (Ox-LDL) has a plethora of components that are not present in native LDL. Their presence and quantity depends on the nature, type, and extent of oxidation. Lipids esterified to oxidized fatty acids are the major components formed during the early phase of oxidation and these show a number of proatherogenic properties in in vitro cell culture systems. Recently, evidence has been forthcoming to suggest that some of these oxidized lipids also could elicit "antioxidant-antiatherogenic" responses from cells. Moreover, some of the cellular effects of Ox-LDL that were previously interpreted as atherogenic could also be reinterpreted to suggest an antiatherogenic cellular response. In addition to the above, the antioxidants that are carried in lipoproteins could have anomalous behavior attributable to their metabolism, ability to be internalized by arterial cells, and the presence of oxidative systems that could render them prooxidants. In conclusion, there are numerous contributing factors that need to be studied and understood before antioxidant therapy becomes an option for the treatment for cardiovascular diseases.
LDL oxidation: therapeutic perspectives
Atherosclerosis, 1998
The peroxidation step of lipid transormation is considered to be essential in the pathogenesis of atherosclerosis. Although data concerning the mechanisms by which lipid peroxidation occurs in vivo are scarce, several lines of evidence suggest that some endogenous and exogenous compounds with antioxidant activity could have some beneficial effects in the prevention of atherosclerosis. Ascorbic acid (vitamin C) and a-tocopherol (vitamin E) act as the most important hydrophilic and lipophilic antoxidants, respectively in vivo. Accordingly, animal and human studies suggest that these compounds may have some preventive effect against the development of clinical coronary heart disease. Many plant phenols and flavonoids may be important dietary antioxidants and it has been speculated that these compounds in red wine or in the Mediterranean diet could explain the 'French paradox'. Several studies show that antioxidants such as probucol and butylated hydroxytoluene cari inhibit development of atherosclerotic lesions in Watanabe and cholesterol-fed rabbits. Some drugs such as /3-blockers, calcium antagonists, hypolipodemie drugs,.. . appear to have at least in vitro antioxidant effects but the clinical relevance of these properties remains unkonwn. Moreover, some interventions aimed to decrease the LDL-oxidative susceptibility have not been shown to attenuate atherogenesis when cholesterol levels remain markedly elevated.
Current Concepts of the Role of Oxidized LDL Receptors in Atherosclerosis
Current Atherosclerosis Reports, 2012
Atherosclerosis is characterized by accumulation of lipids and inflammatory cells in the arterial wall. Oxidized low-density lipoprotein (ox-LDL) plays important role in the genesis and progression of atheromatous plaque. Various scavenger receptors have been recognized in the past two decades that mediate uptake of ox-LDL leading to formation of foam cells. Inhibition of scavenger receptor A and CD36 has been shown to affect progression of atherosclerosis by decreasing foam cell formation. Lectin-type oxidized LDL receptor 1 (LOX-1) participates at various steps involved in the pathogenesis of atherosclerosis, and in experimental studies its blockade has been shown to affect the progression of atherosclerosis at multiple levels. In this review, we summarize the role of ox-LDL and scavenger receptors in the formation of atheroma with emphasis on effects of LOX-1 blockade.
Atherosclerosis, 2005
The antiatherogenic role of high-density lipoprotein (HDL) has been related to its ability to increase the activity of endothelial nitric oxide synthase (eNOS) and to protect low-density lipoprotein (LDL) against oxidative modification. The present study was aimed to determine whether and how HDL antagonizes oxidized LDL (oxLDL) that has been formed and accumulated in circulation. Pre-infusion of rats with HDL effectively prevented oxLDL-induced renal vascular constriction. Consistently, pre-incubation of human saphenous vein endothelial cells with HDL (100 g/ml) reversed the oxLDL-induced suppression of endothelium-dependent cyclic-GMP production in co-cultured smooth muscle cells. However, the changes of Akt phosphorylation and eNOS activity in endothelial cells in response to lipoprotein treatments under our assay condition were not significant. Intriguingly, pretreatment of human umbilical vein endothelial cells with HDL (50 g/ml) for only 30 s effectively reduced the level of free radicals generated by oxLDL or H 2 O 2 . In kidneys of living rats, renal arterial infusion of oxLDL greatly enhanced ischemia/reperfusion-induced free radicals, which could be attenuated by HDL pretreatment. We conclude that HDL may antagonize oxLDL on endothelial function through an Akt-independent pathway in which HDL preserves nitric oxide bioactivity by attenuating oxLDL-triggered free radical generation.
Oxidized LDLs influence thrombotic response and cyclooxygenase 2
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002
Oxidative modification of low-density lipoproteins (LDLs) plays a key role in the development of atherosclerosis and the onset of coronary artery disease. LDL oxidation alters the antithrombotic balance of human endothelial cells inducing surface tissue factor (TF) pathway activity, which results in enhanced fibrin deposition. Fibrinolysis, which is strictly regulated by plasminogen activator inhibitor-1 (PAL-1) and tissue-type plasminogen activator (tPA). Is also dysregulated by LDL oxidation with a net increase in the inhibitory rate. Oxidized LDLs (oxLDLs) also affect many aspects of macrophage function linked to the inflammatory response of these cells,In particular, oxLDLs downregulate inducible cyclooxigenase (Cox-2) in human monocytederived macrophages exposed to bacterial lipopolysaccharide.This observation may support the hypothesis that, within atheromata, the transformation macrophages into foam cells results in the attenuation of the inflammatory response, thus contributing to the progression of athrogenesis. Among lipid constituents of oxLDLs, Ox-PAPC, a mixture of oxidized arachidonic acid-containing phospholipids, prevents Cox-2 expression, suggesting that it could be considered responsible for the biological activity of oxLDLs. &
Oxidised LDL, HDL cholesterol, LDL cholesterol levels in patients of coronary artery disease
Indian Journal of Clinical Biochemistry, 2006
Coronary artery disease is a major cause of morbidity and has various risk factors. Lipid profile i.e. low HDL-cholesterol, high LDL cholesterol, high total cholesterol, high triglycerides playing important role in its causation. Recently interest has been shown in the oxidized fraction of LDL as one of the risk factors. In the present study 60 age and sex matched normal healthy individuals were taken as controls and 60 patients of CAD were taken. Cholesterol was measured by enzymatic method, HDL cholesterol by phosphotungstate precipitation method. Serum levels of LDL fraction of cholesterol was measured by a new and simpler method of precipitation. Result was expressed as mol/L of diene conjugates. It was observed that LDL cholesterol, VLDL cholesterol, total cholesterol, total cholesterol: HDL cholesterol, LDL cholesterol: HDL cholesterol were significantly raised and HDL cholesterol was significantly low in patients. (p
Atherosclerosis, 1998
Oxidation of low density lipoproteins (LDL) is considered a key event in the pathogenesis of atherosclerotic lesions. Disturbed generation of coagulatory and anticoagulatory factors by endothelial cells contributes to thrombosis and the progression of atherosclerosis in coronary arteries. In this study, the effects of native LDL (n-LDL) and oxidized LDL (ox-LDL) on human coronary endothelial cells were measured. The reaction of coronary endothelial cells to LDL were compared with those of cardiac microvascular endothelial cells grown under comparable conditions. LDL was isolated by ultracentrifugation and copper oxidized. The degree of oxidation was expressed as malondialdehyd (MDA) equivalents and was 0.78 9 0.14 nM MDA/mg LDL for native LDL and 13.63 91.18 nmol MDA/mg LDL for ox-LDL. Basal secretion of t-PA and PAI-1 activity were higher in macrovascular endothelial cells. Incubation of n-LDL in concentrations ranging from 3 to 100 vM/ml LDL-protein did not change t-PA-secretion, PAI-1 activity or procoagulant activity in both cell types. Ox-LDL (3 to 100 vM/ml LDL protein) decreased t-PA secretion in a concentration dependent manner from 30.9 9 1.7 to 13.79 30 ng/ml per 24 h per 10 6 cells (PB 0.01), increased PAI-1 antigen from 27729 587 to 44419766 ng/ml per 24 h per 10 6 cells (P B0.05) as well as PAI-1 activity from 349 6 to 559 9 AU/ml per 24 h per 10 6 cells (PB0.05) in macrovascular endothelial cells but had only minor effects on microvascular endothelial cells. Procoagulant activity measured as coagulation time, similarly increased only in macrovascular endothelial cells from 197 96 to 7696 s/24 h per 10 6 cells (PB 0.05). The effect on PAI-1 secretion showed a dependency to the degree of oxidation and could be completely blocked by the antioxidant probucol. The angiotensin converting enzyme (ACE), which represents an endothelial enzyme not related to coagulation, remained unchanged during incubation with ox-LDL. Basal ACE activity was higher in microvascular endothelial cells. The higher susceptibility of macrovascular endothelial cells to ox-LDL may partially determine the localization of thrombus formation and the development of atherosclerotic plaques in hyperlipidemic patients.
Journal of Lipid Research, 2004
For more than two decades, there has been continuing evidence of lipid oxidation playing a central role in atherogenesis. The oxidation hypothesis of atherogenesis has evolved to focus on specific proinflammatory oxidized phospholipids that result from the oxidation of LDL phospholipids containing arachidonic acid and that are recognized by the innate immune system in animals and humans. These oxidized phospholipids are largely generated by potent oxidants produced by the lipoxygenase and myeloperoxidase pathways. The failure of antioxidant vitamins to influence clinical outcomes may have many explanations, including the inability of vitamin E to prevent the formation of these oxidized phospholipids and other lipid oxidation products of the myeloperoxidase pathway. Preliminary data suggest that the oxidation hypothesis of atherogenesis and the reverse cholesterol transport hypothesis of atherogenesis may have a common biological basis. The levels of specific oxidized lipids in plasma and lipoproteins, the levels of antibodies to these lipids, and the inflammatory/antiinflammatory properties of HDL may be useful markers of susceptibility to atherogenesis. Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides may both promote a reduction in oxidized lipids and enhance reverse cholesterol transport and therefore may have therapeutic potential. -Navab, M.,