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.

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.