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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endoplasmic reticulum (ER) is a major cellular 'production factory' for many membrane and soluble proteins. A quality control system ensures that only correctly folded and assembled proteins leave the compartment. The low-density lipoprotein receptor (LDLR) is the prototype of a large family of structurally homologous cell surface receptors, which fold in the ER and function as endocytic and signaling receptors in a wide variety of cellular processes. Patients with familial hypercholesterolemia carry single or multiple mutations in their LDLR, which leads to malfunction of the protein, in most patients through misfolding of the receptor. As a result, clearance of cholesterol-rich LDL particles from the circulation decreases, and the elevated blood cholesterol levels cause early onset of atherosclerosis and an increased risk of cardiac disease in these patients. In this review, we will elaborate on the structural aspects of the LDLR and its folding pathway and compare it to other LDLR family members.
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PMID:Low-density lipoprotein receptor structure and folding. 1552 54

The mechanisms involved in the cytotoxic action of oxysterols in the pathogenesis of atherosclerosis still remain poorly understood. Among the major oxysterols present in oxidized low-density lipoprotein, we show here that 7-ketocholesterol (7-Kchol) induces oxidative stress and/or apoptotic events in human aortic smooth muscle cells (SMCs). This specific effect of 7-Kchol is mediated by a robust upregulation (threefold from the basal level) of Nox-4, a reactive oxygen species (ROS)-generating NAD(P)H oxidase homologue. This effect was highlighted by silencing Nox-4 expression with a specific small interfering RNA, which significantly reduced the 7-Kchol-induced production of ROS and abolished apoptotic events. Furthermore, the 7-Kchol activating pathway included an early triggering of endoplasmic reticulum stress, as assessed by transient intracellular Ca(2+) oscillations, and the induction of the expression of the cell death effector CHOP and of GRP78/Bip chaperone via the activation of IRE-1, all hallmarks of the unfolded protein response (UPR). We also showed that 7-Kchol activated the IRE-1/Jun-NH(2)-terminal kinase (JNK)/AP-1 signaling pathway to promote Nox-4 expression. Silencing of IRE-1 and JNK inhibition downregulated Nox-4 expression and subsequently prevented the UPR-dependent cell death induced by 7-Kchol. These findings demonstrate that Nox-4 plays a key role in 7-Kchol-induced SMC death, which is consistent with the hypothesis that Nox-4/oxysterols are involved in the pathogenesis of atherosclerosis.
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PMID:NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic reticulum stress and apoptosis in human aortic smooth muscle cells. 1557 75

Human immunodeficiency virus (HIV) protease inhibitors have been successfully used in highly active antiretroviral therapy for HIV-1 infection. Treatment of patients infected with HIV with HIV protease inhibitors is unfortunately associated with a number of clinically significant metabolic abnormalities and an increased risk of premature atherosclerosis and myocardial infarction. However, the cellular/molecular mechanisms of the HIV protease inhibitor-induced lipid dysregulation and atherosclerosis remain elusive. Macrophages are the most prominent cell type present in atherosclerotic lesions and play essential roles in both early lesion development and late lesion complications. In this study, we demonstrate that three different HIV protease inhibitors (ritonavir, indinavir, and atazanavir) induce endoplasmic reticulum stress and activate the unfolded protein response in mouse macrophages. Furthermore, at therapeutic concentrations (5-15 microM), these HIV protease inhibitors were found to increase the levels of transcriptionally active sterol regulatory element binding proteins, decrease endogenous cholesterol esterification, cause the accumulation of free cholesterol in intracellular membranes, deplete endoplasmic reticulum calcium stores, activate caspase-12, and increase apoptosis in macrophages. These findings provide possible cellular mechanisms by which HIV protease inhibitors promote atherosclerosis and cardiovascular disease in HIV-1 infected patients treated with HIV protease inhibitors.
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PMID:HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease. 1597 36

Hyperhomocysteinemia is a risk factor for cardiovascular disease and stroke. During the last decade, considerable progress in delineating the mechanisms that underlie the atherogenic effects of hyperhomocysteinemia has been achieved through the use of experimental animal models. Among the most informative animal models are those that use genetic and dietary approaches to produce hyperhomocysteinemia in mice. Recent findings demonstrate that hyperhomocysteinemia can accelerate the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Hyperhomocysteinemia also is a potent inducer of endothelial dysfunction, particularly in small vessels such as cerebral arterioles. Mechanisms of endothelial dysfunction may include inhibition of endothelial nitric oxide synthase by its endogenous inhibitor, asymmetric dimethylarginine, and oxidative inactivation of nitric oxide mediated by upregulation of prooxidant enzymes and downregulation of antioxidant enzymes. There also is good evidence from animal models that hyperhomocysteinemia produces endoplasmic reticulum stress, which may contribute to atherosclerosis and endothelial dysfunction by activating signal transduction pathways leading to inflammation, oxidative stress, and apoptosis.
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PMID:Mechanisms of the atherogenic effects of elevated homocysteine in experimental models. 1604 68

Paraoxonase 1 (PON1) is a serum enzyme closely associated with high-density lipoprotein (HDL), which may protect against atherosclerosis by hydrolyzing lipid peroxides and several organophosphorus compounds. The purpose of the present study was to test the hypothesis that lipid peroxidation modifies the activity and protein mass of PON1 in humans and rats. Our findings revealed that the bulk of the activity monitored by the hydrolysis of paraoxon and phenyl acetate was confined to liver intracellular endoplasmic reticulum-derived microsomes and was mostly recovered in circulating HDL3. Confirmation was obtained by the determination of PON1 expression by Western blot. It is noteworthy that PON1 levels were consistently decreased in human sera, HDL, and liver microsomes compared with rat counterparts. Concomitant with iron-ascorbate-mediated lipid peroxidation, there was a decline in PON1 activity and protein in both HDL3 and microsomes, which was attenuated by butylated hydroxytoluene antioxidant treatment. The current data indicate that PON1 localization in microsomes and HDL3 could represent a selective cellular and lipoprotein response to oxidative stress. This was tested by the iron-ascorbate oxygen-radical generating system. It is also proposed that the increased PON1 level may have a function related to the well-known atherosclerosis resistance of rats.
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PMID:Iron-ascorbic acid-induced oxidant stress and its quenching by paraoxonase 1 in HDL and the liver: comparison between humans and rats. 1605 86

Elevation of plasma homocysteine level is a risk factor for cardiovascular disease, stroke, and venous thromboembolism. It is still uncertain, however, whether hyperhomocysteinemia is a causative factor or a marker of vascular disease. The strongest evidence that homocysteine plays a causal role in atherothrombosis has been provided by studies using animal models. In the past decade, considerable progress in defining the vascular effects of hyperhomocysteinemia was achieved through the use of genetic and dietary approaches to induce hyperhomocysteinemia in experimental animals. A key vascular phenotype observed in hyperhomocysteinemic animals is endothelial dysfunction, manifested by decreased bioavailability of endothelium-derived nitric oxide. Impairment of endothelial function may be mediated by either accelerated oxidative inactivation of nitric oxide or inhibition of nitric oxide production caused by the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Hyperhomocysteinemia also increases susceptibility to arterial thrombosis and accelerates the development of atherosclerosis in susceptible models such as the apolipoprotein E-deficient mouse. Mechanisms of atherothrombosis may include homocysteine-induced thiolation or acylation of plasma or endothelial proteins and endoplasmic reticulum stress, which activates signal transduction pathways leading to inflammation and apoptosis.
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PMID:Mechanisms of homocysteine-induced atherothrombosis. 1610 30

Acyl-coenzyme A:cholesterol transferase (ACAT) is an integral membrane protein localized in the endoplasmic reticulum. ACAT catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl coenzyme A. The cholesteryl esters are stored as cytoplasmic lipid droplets inside the cell. This process is very important to the organism as high cholesterol levels have been associated with cardiovascular disease. In mammals, two ACAT genes have been identified, ACAT1 and ACAT2. ACAT1 is ubiquitous and is responsible for cholesteryl ester formation in brain, adrenal glands, macrophages, and kidneys. ACAT2 is expressed in the liver and intestine. The inhibition of ACAT activity has been associated with decreased plasma cholesterol levels by suppressing cholesterol absorption and by diminishing the assembly and secretion of apolipoprotein B-containing lipoproteins such as very low density lipoprotein (VLDL). ACAT inhibition also prevents the conversion of macrophages into foam cells in the arterial walls, a critical event in the development of atherosclerosis. This review paper will focus on the role of ACAT in cholesterol metabolism, in particular as a target to develop novel therapeutic agents to control hypercholesterolemia, atherosclerosis, and Alzheimer's disease.
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PMID:Potential role of acyl-coenzyme A:cholesterol transferase (ACAT) Inhibitors as hypolipidemic and antiatherosclerosis drugs. 1618 Jan 16

The toxic oil syndrome (TOS) caused by ingestion of rapeseed oil adulterated with aniline is characterized by symptoms of an allergic and/or autoimmune illness associated with vessel wall lesions similar to those of atherosclerosis. Fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP) have been incriminated as the etiologic agents of TOS. However, the pathogenesis of TOS is yet unknown. Here, we addressed whether PAP fatty acid esters are incorporated into lipoproteins, which after transport to vascular endothelial cells are taken up to initiate TOS vasculopathy. After loading (14)C-dioleyl-ester of PAP into LDL labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindolcarbocyanine (DiI) we assessed receptor mediated endocytosis and intracellular localization of these lipopoproteins in vascular endothelial cells. Our data suggest that these lipoprotein-derivatives are internalized into endothelial cells by LDL receptor mediated endocytosis. Confocal microscopy revealed that DiI-LDL loaded with dioleyl-ester of PAP and incubated for 60 min with endothelial cells colocalizes with the lysosomotropic compound LysoTracker Green, indicating that internalized PAP-loaded LDL are targetted to the endolysosomal compartment for further processing. Subcellular fractionation of endothelial-like ECV-304 cells after incubation with LDL loaded with the (14)C-dioleyl-ester of PAP for 6h showed that the radioactive label accumulated in fractions containing endosomes, the Golgi apparatus and the endoplasmic reticulum.
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PMID:Endocytosis and intracellular trafficking of fatty acid esters of phenylaminopropanediol, the putative etiologic agents of the toxic oil syndrome (TOS). 1634 24

Diabetes is a major independent risk factor for cardiovascular disease and stroke; however, the molecular and cellular mechanisms by which diabetes contributes to the development of vascular disease are not fully understood. Our previous studies demonstrated that endoplasmic reticulum (ER) stress-inducing agents, including homocysteine, promote lipid accumulation and activate inflammatory pathways-the hallmark features of atherosclerosis. We hypothesize that the accumulation of intracellular glucosamine observed in diabetes may also promote atherogenesis via a mechanism that involves ER stress. In support of this theory, we demonstrate that glucosamine can induce ER stress in cell types relevant to the development of atherosclerosis, including human aortic smooth muscle cells, monocytes, and hepatocytes. Furthermore, we show that glucosamine-induced ER stress dysregulates lipid metabolism, leading to the accumulation of cholesterol in cultured cells. To examine the relevance of the ER stress pathway in vivo, we used a streptozotocin-induced hyperglycemic apolipoprotein E-deficient mouse model of atherosclerosis. Using molecular biological and histological techniques, we show that hyperglycemia is associated with tissue-specific ER stress, hepatic steatosis, and accelerated atherosclerosis. This novel mechanism may not only explain how diabetes and hyperglycemia promote atherosclerosis, but also provide a potential new target for therapeutic intervention.
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PMID:Glucosamine-induced endoplasmic reticulum dysfunction is associated with accelerated atherosclerosis in a hyperglycemic mouse model. 1638 Apr 81

CD1 molecules are a family of major histocompatibility complex (MHC)-related glycoproteins that present lipid and glycolipid antigens to T cells. Interestingly, it has been demonstrated that CD1d-restricted T cells have a pathogenic role in atherosclerosis. Recent studies suggest an association between the cellular machinery that loads CD1 molecules with glycolipids and several key proteins in lipid metabolism. These proteins include the sphingolipid activator proteins (SAPs), microsomal triglyceride transfer protein (MTP) and apolipoprotein E (apoE). MTP and SAPs seem to be crucial for loading CD1d with lipids in the endoplasmic reticulum and endosomal compartments, respectively, whereas apoE facilitates efficient uptake and delivery of exogenous lipid antigens to CD1d in endosomal compartments. These studies reveal new and unexpected relationships between lipid metabolism and antigen presentation by CD1 molecules. Targeting this pathway of immune activation might have therapeutic potential for the treatment of chronic inflammatory diseases.
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PMID:Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. 1665 Oct 26


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