Lipoproteins In Atherosclerosis Research Articles

Non-oxidative modified low-density lipoproteins: The underappreciated risk factors for atherosclerosis.

Atherosclerosis, the pathological basis of most cardiovascular diseases, is a main risk factor causing about 20 million deaths each year worldwide. Oxidized low-density lipoprotein is recognized as the most important and independent risk factor in initiating and promoting atherosclerosis. Numerous antioxidants are extensively used in clinical practice, but they have no significant effect on reducing the morbidity and mortality of cardiovascular diseases. This finding suggests that researchers should pay more attention to the important role of non-oxidative modified low-density lipoprotein in atherosclerosis with a focus on oxidized low-density lipoprotein. This review briefly summarizes several important non-oxidative modified low-density lipoproteins associated with atherosclerosis, introduces the pathways through which these non-oxidative modified low-density lipoproteins induce the development of atherosclerosis in vivo, and discusses the mechanism of atherogenesis induced by these non-oxidative modified low-density lipoproteins. New therapeutic strategies and potential drug targets are provided for the prevention and treatment of atherosclerotic cardiovascular diseases.

The Functional Role of Lipoproteins in Atherosclerosis: Novel Directions for Diagnosis and Targeting Therapy.

Dyslipidemia, characterized by a high level of lipids (cholesterol, triglycerides, or both), can increase the risk of developing and progressing atherosclerosis. As atherosclerosis progresses, the number and severity of aterial plagues increases with greater risk of myocardial infarction, a major contributor to cardiovascular mortality. Atherosclerosis progresses in four phases, namely endothelial dysfunction, fatty streak formation, lesion progression and plaque rupture, and eventually thrombosis and arterial obstruction. With greater understanding of the pathological processes underlying atherosclerosis, researchers have identified that lipoproteins play a significant role in the development of atherosclerosis. In particular, apolipoprotein B (apoB)-containing lipoproteins have been shown to associate with atherosclerosis. Oxidized low-density lipoproteins (ox-LDLs) also contribute to the progression of atherosclerosis whereas high-density lipoproteins (HDL) contribute to the removal of cholesterol from macrophages thereby inhibiting the formation of foam cells. Given these known associations, lipoproteins may have potential as biomarkers for predicting risk associated with atherosclerotic plaques or may be targets as novel therapeutic agents. As such, the rapid development of drugs targeting lipoprotein metabolism may lead to novel treatments for atherosclerosis. A comprehensive review of lipoprotein function and their role in atherosclerosis, along with the latest development of lipoprotein targeted treatment, is timely. This review focuses on the functions of different lipoproteins and their involvement in atherosclerosis. Further, diagnostic and therapeutic potential are highlighted giving insight into novel lipoprotein-targetted approaches to treat atherosclerosis.

Lipids and cardiovascular calcification: contributions to plaque vulnerability.

Cardiovascular calcification, a common feature of atherosclerotic lesions, has long been known to associate with cardiovascular risk. The roles of lipoproteins in atherosclerosis are also established, and lipid-modifying therapies have shown capacity for plaque regression. However, the association of lipid-modifying therapies with calcification is more complex, and currently no medical therapies have been found to reverse or attenuate calcification in patients. In this review, we summarize recent developments in our understanding of the interplay between lipids and cardiovascular calcification, as well as new imaging modalities for assessing calcified atherosclerotic plaque vulnerability. Recent clinical studies have highlighted the associations of lipoprotein subtypes, such as low-density and high-density lipoprotein particles, as well as lipoprotein (a) [Lp(a)], with coronary calcification and calcific aortic valve disease. Further, evidence continues to emerge for the utility of fused 18F-sodium fluoride positron-emission tomographic and computed tomographic (18F-NaF PET/CT) imaging in characterizing the microarchitecture and vulnerability of atherosclerotic plaque, in both humans and animal models. The relationship between lipids and cardiovascular calcification is complex, and new imaging techniques, such as 18F-NaF PET/CT imaging, may allow for better identification of disease-modifying therapies and prediction of calcified plaque progression and stability to help guide clinical management.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.

Comparing Primary Prevention Recommendations: A Focused Look at United States and European Guidelines on Dyslipidemia.

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.

Abstract 169: Lipoproteins and their Modified Forms Regulate Smooth Muscle Cell Calcification

Background: Vascular calcification (VC), alongside atherogenic lipoprotein profiles, have been correlated with poor cardiovascular outcome, however there is a paucity of literature exploring the relationship between the two regarding VC progression. We therefore aim to examine the roles of lipoprotein species and their oxidised forms on both medial and intimal VC. Methods: Human aortic smooth muscle cells (HAoSMC) were pre-treated with 200 μg/ml high (HDL), low (LDL) and very low (VLDL) density lipoproteins for 24 hours before treating cells with a calcification medium (CM; Ca 2.7mM, PO 4 2.0 mM). Cells were harvested using an alizarin red (ARS) calcification assay, or at various time points for qPCR analysis. In parallel, in vivo studies using apolipoprotein E knock-out mice were fed an atherogenic diet for 40 weeks and received reconstituted HDL (rHDL) infusions containing apoA-I (20mg/kg) and 1-palmitoyl-2-linoleoyl phosphatidylcholine during the final 4 weeks of the study. Tissues were harvested and stained for plaque assessment (H&E) and calcium deposits (ARS). Results: Pre-treatment of HAoSMC with rHDL inhibited calcification (43.9%, p<0.001), whereas ox-rHDL removed its protective effects. Likewise, ox-LDL (77.1%, p<0.05) also upregulated calcium deposition and interestingly ox-VLDL significantly decreased calcification (70.5%, p<0.05) with their native counterparts having no effects. PCR measures of calcification markers Runx2, RANKL and alkaline phosphatase show a time-dependent increase in expression as calcification occurs. In animal studies, no change in weight gain, cholesterol or triglyceride levels were observed with treatment. In addition, rHDL infusions did not alter plaque size however ARS staining of the brachiocephalic artery demonstrated a significant reduction (6.58%, p<0.05) in calcification present in the atherosclerotic plaque. Conclusions: This study is the first to demonstrate the effects of lipoproteins on VC in vitro and the effects of rHDL on in vivo VC. Somewhat in accordance to the roles of lipoproteins in atherosclerosis, HDL and ox-VLDL show a reduction of calcification, where-as ox-LDL enhances calcification of HAoSMC.

Atherogenic Lipoprotein Subfractions and Carotid Atherosclerosis in Menopausal Women.

The aim of the study was to evaluate the relationship between cholesterol contained in very-low-density lipoproteins (VLDL-C), intermediate-density lipoproteins (IDL-C), low-density lipoproteins, high-density lipoproteins, and carotid intima-media thickness (cIMT) and carotid plaques in 228 postmenopausal women (63.1 ± 8.2 years) who participated in the ATENA Project and underwent clinical, biochemical (including the assay of lipoproteins using the Lipoprint system), and carotid ultrasound tests. Very-low-density lipoprotein cholesterol had a statistically significant linear association with cIMT ( P < .001), which remained significant after adjustment for age, smoking, systolic blood pressure, glucose, and body mass index ( r2 = .20, P < .05). Higher concentrations of IDL-C and cholesterol contained in triglyceride-rich lipoproteins (TRL-C, ie, VLDL-C + IDL-C) were associated with plaques in the common carotid (tertile III/tertile I: odds ratio [OR] = 2.52, 95% confidence interval [CI] = 1.21-5.32, P < .02; OR = 2.30, 95% CI = 1.05-5.01, P < .05, respectively), after adjustment for main cardiovascular risk factors. In conclusion, high concentrations of VLDL-C and TRL-C are independently associated with the presence of carotid plaques. Their assay represents a useful tool for improving our knowledge on the role of different classes of lipoproteins in atherosclerosis.

Hypercholesterolemia Enhances T Cell Receptor Signaling and Increases the Regulatory T Cell Population

Hypercholesterolemia promotes the inflammation against lipoproteins in atherosclerosis. Development of atherosclerosis is affected by the balance between pro-inflammatory effector T cells and anti-inflammatory regulatory T (Treg) cells. However, phenotype and function of T cell subpopulations in hypercholesterolemia remain to be investigated. Here, we found that cholesterol-containing diet increased the expression of the Treg cell lineage-defining transcription factor FoxP3 among thymocytes and splenocytes. Hypercholesterolemia elevated the FoxP3 expression level and population size of peripheral Treg cells, but did not prevent enhanced proliferation of stimulated T cells. Moreover, cholesterol supplementation in diet as well as in cell culture medium promoted T cell antigen receptor (TCR) signaling in CD4+ T cells. Our results demonstrate that hypercholesterolemia enhances TCR stimulation, Treg cell development as well as T cell proliferation. Thus, our findings may help to understand why hypercholesterolemia correlates with altered CD4+ T cell responses.

Developing a Strategy for Interventional Molecular Imaging of Oxidized Low-Density Lipoprotein in Atherosclerosis.

The identification of vulnerable coronary artery atherosclerotic plaques offers the prospect of either localized or systematic therapeutic targeting in order to prevent myocardial infarction. Molecular imaging of atherosclerosis adds to morphological imaging by focusing on the immunobiology hidden in and behind the endothelium and therefore may be able to improve the identification of prospective culprit lesions. Our focus has been on identifying arterial accumulation of oxidized low-density lipoprotein (oxLDL) by exploiting advances in knowledge of vascular pathobiology. Here, we reflect on our work developing near-infrared fluorescence imaging of oxLDL using LO1, a monoclonal autoantibody generated in our laboratory. We detail progress to date and discuss our vision on taking the work through the early translational pipeline toward a multitargeted approach in imaging rupture-prone atherosclerotic plaques. Ultimately, molecular imaging of coronary arteries should be able to assess the regional risk that is specific to a lesion, which can then be used in concert with global risk factors to personalize the therapeutic strategy for patients in a way that goes beyond generalized population-based therapies.

The Future of Vascular Biology and Medicine.

During the past several decades, landmark discoveries in the field of vascular biology have evolved our understanding of the biology of blood vessels and the pathobiology of local and systemic vascular disease states and have led to novel disease-modifying therapies for patients. In 1980, Furchgott and Zawadzki1 radically changed our focus in blood vessel research with the discovery of endothelium-derived nitric oxide and its effects on vascular tone. This seminal discovery redefined blood vessels as dynamic organs with autocrine, paracrine, and endocrine functions that are capable of regulating their own environment. The later recognition that many risk factors associated with vascular disease perturb nitric oxide-mediated homeostatic mechanisms lent further credence to the concept of blood vessels as complex organs rather than inert tubes. In the decades to follow, research in vascular biology predominantly targeted 3 facets of vascular function: vasomotor tone, inflammation, and the balance between thrombosis and thrombolysis. This occurred because atherosclerotic cardiovascular disease reached epidemic levels and atherothrombosis was found to feature disturbances in these functions that preceded visible pathology and clinical manifestations of the disease. Furthermore, modification of responsible causal factors reversed impaired vascular function (eg, lowering levels of low-density lipoproteins in atherosclerosis), and clinical studies began to validate the importance of preclinical vascular biology research in the treatment of hypertension, atherosclerosis, pulmonary vascular disease, erectile dysfunction, Raynaud phenomenon, and neointimal proliferation after mechanical vascular intervention. More recently, advances in molecular biology and –omics technologies have facilitated in vitro and in vivo studies that revealed that blood vessels regulate their own redox milieu, metabolism, mechanical environment, and phenotype, in part, through complex interactions between cellular components of the blood vessel wall and circulating factors. These interactors include stem, progenitor, and differentiated cells; microRNAs, long noncoding RNAs, and DNA; and, hormones, proteins, and lipids. Dysregulation of these …

Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

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.

Oxidized LDL in Inflammation: From Bench to Bedside

Oxidized LDL in Inflammation: From Bench to Bedside

Immune response to lipoproteins in atherosclerosis.

Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL) has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.

Lipids and Lipoproteins in Atherosclerosis

Atherosclerosis is a focal disease of the arterial wall that leads to cardiovascular disease (CVD), the biggest cause of morbidity and mortality in Western societies. Atherosclerosis is a complex, ...

W52 PROTECTION AGAINST ATHEROSCLEROSIS IN CAV-1 IS DUE TO CAV-1 −/− IN NON-HEMATOPOIETIC CELLS

Oxidized LDL (Ox-LDL) and chylomicron (CM) remnants have been suggested to be the most atherogenic lipoproteins that initiate and exacerbate coronary atherosclerosis. In this review, we propose a hypothesis of the causal lipoproteins in atherosclerosis based on our recent findings on postprandial remnant lipoproteins (RLP). Plasma RLP-C and RLP-TG increased significantly after food intake, especially a fat load. More than 80% of the TG increase after the fat load consisted of the TG in RLP, which contained significantly greater apoB100 than apoB48 particles as VLDL remnants. The majority of the LPL in non-heparin plasma was found in RLP as an RLP-LPL complex and released into the circulation after hydrolysis. Plasma LPL did not increase after food intake, which may have caused the partial hydrolysis of CM and VLDL as well as the significant increase of RLP-TG in the postprandial plasma. LPL was inversely correlated with the RLP particle size after food intake. We showed that VLDL remnants are the major atherogenic lipoproteins in the postprandial plasma associated with insufficient LPL activity and a causal factor in the initiation and progression of atherosclerosis. We also propose “LPL bound TG-rich lipoproteins” as a new definition of remnant lipoproteins based on the findings of the RLP-LPL complex in the non-heparin plasma.

Dual Therapy With Statins and Antioxidants Is Superior to Statins Alone in Decreasing the Risk of Cardiovascular Disease in a Subgroup of Middle-Aged Individuals With Both Diabetes Mellitus and the Haptoglobin 2-2 Genotype

Diabetes Mellitus (DM) is associated with a state of increased oxidative stress.1 Paradoxically, however, antioxidants have not been found to provide CVD benefit to DM individuals in several prospective clinical trials.2–11 However, the inability to demonstrate benefit may have been attributable to inadequate patient selection as antioxidants may only benefit those with particularly high levels of oxidative stress.12 A polymorphism in the Haptoglobin (Hp) gene, an antioxidant protein, appears to permit identification of individuals with high oxidative stress and who may benefit from antioxidant therapy.13 There exists 2 classes of alleles at the Hp genetic locus, 1 and 2, and the antioxidant capacity of the Hp 2 protein is inferior to the Hp 1 protein.14–18 Robust clinical data has shown that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), 40% of DM individuals, have an up to 500% increased risk of CVD.19–22 A vast amount of basic science, animal, and epidemiological data has provided the logic for targeting vitamin E administration specifically to DM individuals with the Hp 2-2 genotype.13 Most importantly we have recently reported in the ICARE study (Israel CArdiovascular events Reduction with vitamin E [ClinicalTrials.gov# NCT00220831]) a prospective randomized placebo controlled trial of vitamin E therapy in DM individuals with the Hp 2-2 genotype, that vitamin E therapy results in a 50% reduction in CVD events.22 …

Is lipid lowering treatment aiming for very low LDL levels safe in terms of the synthesis of steroid hormones?

Today atherosclerotic diseases are among the most important causes of death in the world. Epidemiological, clinical, genetic, experimental and pathological studies have clearly shown the role of lipoproteins in atherosclerosis. LDL is the major atherogenic lipoprotein and has been defined as the primary target of lipid lowering treatment by NCEP. Although the level of LDL, the primary target in the treatment of dyslipidemia, has been set as below 100 mg/dl in coronary heart diseases (CHD) and CHD risk equivalents, this level has been pulled down to below 70 mg/dl for the group defined as very high risk group by the ATP (Adult Treatment Panel) guide that has been updated following the new clinical studies. As we already know, cholesterol is the precursor of glucocorticoids, mineralocorticoids and sex steroids, besides being a structural component of the cell membrane. Both adrenal and non-adrenal (ovarian+testicular) all steroid hormones are primarily synthesized using the LDL-cholesterol in the circulation. In addition to this, there is 'de novo' cholesterol synthesis in both the adrenals and gonads controlled by the HMG-CoA reductase enzyme. A third pathway, which under normal circumstances has little contribution as compared to the first two, is the use of circulatory HDL-cholesterol by the adrenal and gonadal tissues for the synthesis of steroids. Our knowledge on extremely lowered LDL levels is quite limited. However, since statins both decrease circulatory LDL and inhibit de novo cholesterol synthesis, they are likely to affect the synthesis of steroid hormones.

Cell Biology and Lipoproteins in Atherosclerosis

Atherosclerosis is an inflammatory process, triggered by the presence of lipids in the vascular wall, and encompasses a complex interaction among inflammatory cells, vascular elements, and lipoproteins through expression of several adhesion molecules and cytokines. Subendothelial retention of lipoproteins is the key initiating event in atherosclerosis, provoking a cascade of events to pathogenic response. High levels of plasma lipids, particularly low-density (LDL) and very-low-density lipoproteins (VLDL) are among the pathophysiologic stimuli that induce endothelial dysfunction. Endothelial cells regulate coagulation, thrombosis and the fibrinolytic system; the endothelium modulates the activity of smooth muscle cells (vascular tone/proliferation) and controls the traffic of macromolecules and inflammatory cells to the vessel wall. Furthermore, LDLs have been implicated in the induction of changes in permeability, cell adhesion and secretion of vasoactive molecules (nitric oxide [NO]), while VLDLs seem to modulate the fibrinolytic system [tissue plasminogen activator (TPA) and plasminogen activator inhibitor-1 (PAI-1)]. In this review, we will focus on the pathophysiologic functions of lipoproteins in the vascular wall.

Current understanding of the role of high-density lipoproteins in atherosclerosis and senescence

Numerous epidemiologic and interventional studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well documented HDL functions that may account for the antiatherogenic effects of this lipoprotein. The best recognized of these is the capacity of HDL to transport cholesterol from the periphery to the liver, and thereby prevent cholesterol deposition in the arterial wall. Further properties of HDL that may also be antiatherogenic include its potent anti oxidative and anti-inflammatory action. In addition, HDL seems to be involved in processes related to senescence at both the cellular and whole-organism level. Both protein components of HDL (such as apolipoprotein A-I) and its lipid components (such as, lysosphingolipids) appear to mediate the antiatherogenic and anti-aging effects of HDL. The purpose of this review is to summarize the novel functions of HDL that may protect from atherosclerosis and senescence.