Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating immune complexes (CIC) containing low density lipoprotein (LDL) were recently found in the blood of patients with coronary atherosclerosis. In the present study, we investigated the chemical composition and physical characteristics of the lipoprotein constituents of these CIC. CIC were isolated from the blood of atherosclerotic patients by affinity chromatography using anti-human immunoglobulin G-agarose. Low density lipoprotein of these complexes (CIC-LDL) was obtained by ultracentrifugation. CIC-LDL was compared with free circulating LDL isolated from the blood plasma of the same patients. Plasma LDL was fractionated by lectin-chromatography on RCA120-agarose to obtain desialylated LDL (atherogenic) and sialylated LDL (nonatherogenic). Both CIC-LDL and desialylated LDL, but not native (sialylated) lipoprotein, induced a 1.8- to 3-fold increase in the intracellular contents of free and esterified cholesterol of cells cultured from grossly normal areas of human aorta. The sialic acid level in CIC-LDL was 1.3- and 2.1-fold lower than in desialylated or native LDL, respectively. The neutral lipid and phospholipid contents of CIC-LDL and desialylated LDL were reduced as compared to native LDL. The levels of lipid-oxidation products, thiobarbituric acid-reactive substances and hydroperoxides, were similar in all lipoprotein preparations. However, desialylated LDL and CIC-LDL had an elevated oxysterol content. Gradient ultracentrifugation revealed that CIC-LDL particles had a higher density than native LDL. The mean diameters of native, desialylated and CIC-LDL accounted for 24.0, 21.3 and 19.5 nm, respectively. Like desialylated LDL, CIC-LDL displayed a higher electrophoretic mobility compared with that of native LDL. Thus, LDL obtained from circulating immune complexes appears to be a multiple-modified lipoprotein possessing many similarities to desialylated LDL. It was also found that the LDL content of circulating immune complexes correlates well with the desialylated LDL level in human plasma but not with the total LDL concentration. We believe that desialylated LDL predominately interacts with antibodies forming immune complexes. Taken together, our findings suggest that multiple-modified desialylated LDL is the circulating autoantigen for anti-LDL autoantibodies.
Atherosclerosis 1996 May
PMID:Characteristics of low density lipoprotein isolated from circulating immune complexes. 876 82

Several cytotoxic stimuli of a different nature are involved in the complex etiology of atherosclerosis. Cells of the vasculature may potentially cope with the presence of these stressors through the increased synthesis of stress proteins (or heat shock proteins, hsps), an ubiquitous and conserved defense response. Evidence exists that the expression of two stress proteins of intermediate molecular weight, hsp60 and hsp70, is higher at sites of atherosclerotic lesions than it is in normal tissue. The role of hsps in atherosclerosis is controversial. While hsp70 is likely to be involved in cytoprotection, hsp60 is probably acting as an autoantigen, and may trigger both cell-mediated and antibody-mediated immune responses.
Atherosclerosis 1996 Dec 20
PMID:Stress proteins and atherosclerosis. 912 4

Cardiovascular manifestations are common in systemic lupus erythematosus (SLE). Oxidized low-density lipoprotein (oxLDL) is implicated in cardiovascular disease, especially atherosclerosis, and cross-reacts with antibodies to cardiolipin (aCL). beta 2-GPI is a plasma protein participating in the coagulating cascade, and is also cofactor for aCL, and some aCL have been shown to be directed against beta 2-GPI and/or complexes between beta 2-GPI and phospholipids. Lysophosphatidylcholine (LPC) is a phospholipid present both in oxLDL and in damaged endothelium, and we recently showed that LPC is involved in the antigenicity of oxLDL. Antibodies to endothelial cells (aEC) correlate with diseases activity in SLE and vasculitis, and we recently showed that aEC are enhanced in cardiovascular disease such as borderline hypertension and early atherosclerosis. aEC were determined using EC from adult V. Saphena Magna. Antibody levels were determined by ELISA. aEC of IgG type were enhanced in 184 patients with SLE compared with 85 healthy controls. There was a close correlation between aoxLDL, aCL, aLPC, a beta 2-GPI and aEC. Binding of sera to EC was competitively inhibited by beta 2-GPI, LPC and oxLDL. Taken together, the data indicate that EC share antigenic epitopes with beta 2-GPI and with oxLDL, especially LPC. Phospholipids in EC membranes may thus be antigenic epitopes. beta 2-GPI may bind to these phospholipids, and become an autoantigen. LPC is formed by oxidation of phospholipids and/or proinflammatory factors leading to activation of phospholipase A2, and the findings indicate the potential role of both lipid oxidation and phospholipase A2 in SLE.
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PMID:Antibodies to adult human endothelial cells cross-react with oxidized low-density lipoprotein and beta 2-glycoprotein I (beta 2-GPI) in systemic lupus erythematosus. 1019 34

Estrogens and immunity against LDL could be important in atherogenesis. Herein, we describe the development of atherosclerotic lesions and cellular immune responses to modified LDL in male and female apoE knockout (E0) mice over time, and the effect of 17beta-estradiol on atherosclerosis-related cellular immunity. Animals were studied after 16 or 48 weeks of normocholesterol diet. Aortic lesions, lymphocyte populations, and the cellular immune response against modified LDL, with or without 17beta-estradiol, were analyzed. Atherosclerotic lesions were larger and more advanced in young female than in male E0 mice. In older mice, no significant difference in lesion size or maturity was discerned between males and females. In spleen cell cultures of young females, addition of 17beta-estradiol induced a proliferative T-cell response to oxidized LDL, while no such effect was seen in males. In similar cultures from old E0 mice, T-cells from female animals were activated by oxidized LDL even in the absence of exogenous estrogens. These data show important sex differences in the development of atherosclerosis. They suggest that these differences may be related to sex differences in the cellular immune responses to the atherosclerosis-related autoantigen, oxidized LDL.
Atherosclerosis 1999 Aug
PMID:Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice. 1048 57

The modern view of atherosclerosis is of a chronic inflammatory disorder. In accord with this paradigm, the process of uninhibited influx of fat to the vessel wall results from an 'adequate' response to various forms of injury (i.e. turbulence, infections, modified lipoproteins). This idea has been further extended by several groups, to assume that the atherosclerotic lesion can be the target of an autoimmune mediated attack. According to this hypothesis, the site of initiation of the plaque should bear/express the target autoantigen, whereas concomitantly a respective immune response is generated in the periphery. The examples illuminating this notion are beta2GPI as a target autoantigen, HSP60/65 an oxidized-LDL. Herein we present evidence to support the involvement of autoimmune mechanisms in atherogenesis based on the experience from experimental models and human studies.
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PMID:Autoimmunity in atherosclerosis: lessons from experimental models. 1080 92

Atherosclerosis is an inflammatory disease induced by a lipid metabolic disturbance at sites of hemodynamic strain in the vasculature. Studies in both man and experimental animal models show an involvement of innate and adaptive immune mechanisms in the disease process. Our recent studies in apoE-knockout mice show that the level of hypercholesterolemia affects the functional properties of the immune response. Modulating immune activity by injections of polyclonal immunoglobulins inhibits disease progression, suggesting that immunomodulation may be useful to treat atherosclerosis. Analysis of T cell receptor (TCR) mRNA in atherosclerotic lesions shows expansions of T cells expressing TCR-V beta 6, a receptor type that is also expressed by T cells recognizing oxidized low density lipoprotein (oxLDL). This suggests that oxLDL is an autoantigen that induces strong, local T cell responses in the plaque. Further characterization of this and other candidate antigens, such as heat shock proteins and macromolecular components of Chlamydia pneumoniae, may provide important information on which specific interference with the disease process could be based.
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PMID:The role of adaptive immunity in atherosclerosis. 1086 25

beta(2)-glycoprotein I (beta(2)-GPI=apolipoprotein H) is an important autoantigen in patients with the antiphospholipid syndrome. It also plays a role in lipoprotein metabolism, such as anti-atherogenic property, triglyceride removal, and enhancement of lipoprotein lipase. Serum beta(2)-GPI concentration of 812 apparently healthy Japanese individuals was measured by sandwich EIA. Two families with complete beta(2)-GPI deficiency were identified. In one family, all affected had increased serum LDL-cholesterol levels or smaller particle sizes of LDL, while the other had no apparent abnormality in lipid metabolism. Individuals investigated had no history of thrombosis or overt abnormalities in hemostatic tests. A thymine corresponding to position 379 of the beta(2)-GPI cDNA was deleted in every beta(2)-GPI deficient individual. The incidence of this heterozygous deficiency determined by RFLP was 6. 3% in Japanese and none in Caucasians. Heterozygotes had significantly lower concentrations of serum beta(2)-GPI than did those without the mutation, yet no significantly different lipid profiles, such as total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, apoA-I, apoB and Lp(a), were observed. A low concentration of beta(2)-GPI seemed not to be associated with apparent abnormality in lipoprotein metabolism.
Atherosclerosis 2000 Oct
PMID:beta(2)-glycoprotein I deficiency: prevalence, genetic background and effects on plasma lipoprotein metabolism and hemostasis. 1099 61

Atherosclerosis is accompanied by a local immune response in plaque, but its role in the pathogenesis of the disease is still unclear. Although we might expect that an (auto)immune response would be an aggravating factor, some of its consequences could be protective. Studies of human plaques and of lesion formation in apo E-0 mice show that CD4+ T cells and macrophages form an inflammatory infiltrate. Both cell types are activated and secrete proinflammatory cytokines. CD4+ cells respond immunospecifically to oxidized LDL, suggesting that oxidation induces antigenic epitopes on LDL and converts it to an autoantigen. The pathophysiological consequences of this response are probably mediated largely via cytokine secretion and cell-cell contacts. Th1 cytokines dominate and may promote vascular inflammation; this is enhanced by the increased capacity for activation of NF-kappaB in intimal smooth muscle cells. The net effect of such activity appears to be proatherogenic, as can be deduced by cell transfer into immunodeficient apoE-0 x SCID mice. These data emphasize the importance of inflammation and immune responses in the pathogenesis of atherosclerosis.
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PMID:Regulation of immune mechanisms in atherosclerosis. 1179 63

Atherosclerosis is an autoimmune/inflammatory disease associated with infectious, inflammatory, and autoimmune factors. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and/or progression of atheromatous lesions. Heat-shock protein (hsp), oxidized low-density lipoprotein (LDL), and beta2-GPI have been reported to elicit humoral and cellular immune response in both experimental animals and humans. These autoantigens are expressed within atherosclerotic lesions. Immunization with the given autoantigens elicits an immune response that influences lesion progression. Atherosclerosis susceptibility can be transferred by autoantigen-sensitized lymphocytes from immunized animals. Patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have a high risk for atherosclerotic cardiovascular events. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS. Immunological alterations, such as antibodies to oxidized LDL, antiphospholipid antibodies (aPL), antibodies to beta-2 Glycoprotein (anti-beta2-GPL), anti-prothrombin antibodies, may play a role in premature atherosclerosis in SLE and APS. Paraoxonase (PON1) is an enzyme with antioxidant activity attached to the circulating high-density lipoprotein (HDL) in plasma. Its function is to prevent oxidation of LDL, thereby accounting for the antioxidant properties and the atherosclerotic protective effects of HDL. The relationship between PON1 and aPL has been recently suggested. IgG anti-HDL and IgG anti-beta2-GPI antibodies were associated with reduced PON1 activity in patients with SLE and primary APS. The determination of classic and new factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis in SLE and PAPS. Therapeutic strategies, including early control of disease and other risk factors, are essential to reduce morbidity and mortality.
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PMID:Atherosclerosis and antiphospholipid syndrome. 1279 63

Recent evidence indicates that infections or a pathogen burden contribute to the development and progression of atherosclerosis. While the mechanism of infection contributing to the pathogenesis is not fully elucidated, I hypothesize that heat shock proteins may be a link between infections and atherosclerosis. Heat shock proteins are a highly conserved family of proteins expressed in most cell types and have been shown to play a general role in protecting cells in response to stress. It has been demonstrated that Chlamydia and human HSP60 coexist in atherosclerotic lesions. Bacterial and human heat shock proteins have been found in soluble form in the general circulation of patients with atherosclerosis. Both heat shock proteins can stimulate cells to express adhesion molecules and proinflammatory cytokines. Certain organisms synthesize heat shock proteins that have close structural homology with human heat shock proteins. Because of the immunologic molecular mimicry between bacterial and human HSP60, it could be an autoantigen involved in eliciting cell-mediated and humoral immune responses that cause vessel injury leading to atherosclerosis. The aim of this review is to provide an update overview on the involvement of heat shock proteins in the pathogenesis of atherosclerosis in response to infections.
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PMID:Infections, heat shock proteins, and atherosclerosis. 1285 20


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