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)

Apolipoprotein E- (apoE) deficient (E-/-) mice develop severe hyperlipidemia and diffuse atherosclerosis. Low-dose expression of a human apoE3 transgene in macrophages of apoE-deficient mice (E-/-hTgE+/0), which results in about 5% of wild-type apoE plasma levels, did not correct hyperlipidemia but significantly reduced the extent of atherosclerotic lesions. To investigate the contribution of apoE to reverse cholesterol transport, we compared plasmas of wild-type (E+/+), E-/-, and E-/-hTgE+/0 mice for the appearance of apoE-containing lipoproteins by electrophoresis and their capacity to take up and esterify 3H-labeled cholesterol from radiolabeled fibroblasts or J774 macrophages. Wild-type plasma displayed lipoproteins containing apoE that were the size of high density lipoprotein and that had either electrophoretic alpha or gamma mobilities. Similar particles were also present in E-/-hTgE+/0 plasma. Depending on incubation time, E-/- plasma released 48-74% less 3H-labeled cholesterol from fibroblasts than E+/+ plasma, whereas cholesterol efflux into E-/-hTgE+/0 plasma was only 11-25% lower than into E+/+ plasma. E-/-hTgE+/0 plasma also released 10% more 3H-labeled cholesterol from radiolabeled J774 macrophages than E-/- plasma. E+/+ and E-/-hTgE+/0 plasma each esterified significantly more cell-derived 3H-labeled cholesterol than E-/- plasma. Moreover, E-/- plasma accumulated much smaller proportions of fibroblast-derived 3H-labeled cholesterol in fractions with electrophoretic gamma and alpha mobility than E+/+ and E-/-hTgE+/0 plasma. Thus, low-dose expression of apoE in macrophages nearly restored the cholesterol efflux capacity of apoE-deficient plasma through the formation of apoE-containing particles, which efficiently take up cell-derived cholesterol, and through the increase of cholesterol esterification activity. Thus, macrophage-derived apoE may protect against atherosclerosis by increasing cholesterol efflux from arterial wall cells.
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PMID:Low-dose expression of a human apolipoprotein E transgene in macrophages restores cholesterol efflux capacity of apolipoprotein E-deficient mouse plasma. 963 93

Apolipoprotein E (apo-E) allele and genotype frequencies were evaluated in offspring with positive (MI-offspring) and negative (control-offspring) parental history of myocardial infarction (MI). The apo-E allele frequencies in MI- and control-offspring were as follows: epsilon2: 9.04 and 2.08% (p < 0.02), epsilon3: 84.04 and 87.5%, epsilon4: 6.91 and 10.41%, respectively. The frequencies of the E2-genotypes were significantly lower in offspring of controls (4.2%, 17.0%, respectively, p < 0.03). The epsilon2-allele is associated with raised plasma triglyceride concentrations in subjects on a diet high in saturated fat. We therefore hypothesize that offspring carrying an epsilon2-allele are predisposed to develop disturbance of plasma triglyceride metabolism when exposed to a traditional Slovak high-fat diet and/or weight gain, resulting in altered lipid levels and increased predisposition to atherosclerosis.
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PMID:Apolipoprotein E genotypes in offspring with a positive and negative family history of premature myocardial infarction. 966 58

Atherosclerotic plaques develop in the arterial wall from complex multicellular processes following the early recruitment of circulating monocytes. Infiltration of monocytes is mediated by cell adhesion molecules (CAMs), including vascular cell adhesion molecule-1 (VCAM-1) which is rapidly induced in endothelial cells in response to cytokines. Apolipoprotein E (apo E), a 34-kDa polypeptide, helps protect against atherosclerosis, in part, because apo E phospholipid particles secreted by macrophages may have local protective effects within lesions. Here we have investigated whether purified plasma apo E, complexed with dimyristoyl phosphatidylcholine (DMPC) vesicles, can inhibit cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression in human umbilical vein endothelial cells (HUVECs). Expression of VCAM-1 in endothelial cells after exposure to tumour necrosis factor-alpha (TNF-alpha) or interleukin 1beta (IL-1beta) was quantified by ELISA and shown to be partially inhibited by 17beta-estradiol (40-60% inhibition) or by S-nitroso-L-glutathione, a nitric oxide donor (20-25%). However, preincubations with physiological concentrations (10-100 microg protein/ml) of apo E DMPC did not downregulate VCAM-1 expression, even with extended preincubation times. These findings were confirmed using a fluorescence-activated cell sorter (FACS) for analysis which indicated additionally that apo E-DMPC had no effect on sub-populations within the HUVEC cultures. Finally, apo E-DMPC vesicles were also unable to suppress TNF-alpha-induced upregulation of E-selectin or intercellular adhesion molecule-1 (ICAM-1). We conclude that plasma apo E is unlikely to be important in limiting endothelial activation.
Atherosclerosis 1998 Jul
PMID:Apolipoprotein E and regulation of cytokine-induced cell adhesion molecule expression in endothelial cells. 969 92

Apolipoprotein E-(apoE) deficient mice exhibit hypercholesterolemia, accelerated atherosclerosis and increased infarct size after middle cerebral artery occlusion (MCAO). This study examined whether worsened ischemic outcome is attributable to effects of apoE deficiency on cerebral circulation. Wild type and apoE-deficient mice underwent MCAO and autoradigraphic measurement of cerebral blood flow. Circle of Willis anatomy was examined in non-ischemic animals. Both groups exhibited similar reduction in blood flow. Both groups had 100% incidence of filling of the anterior communicating artery. The posterior communicating artery (PcomA) filled in 70% of wild type and 80% of apoE-deficient mice. Both groups had considerable variability in relative sizes of the PcmA. This study indicates that worsened outcome from MCAO of apoE-deficient mice is not attributable to any detectable vascular effects and offers validity to use of apoE-deficient mice for study of apoE as a factor in cerebral ischemic pathophysiology.
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PMID:Regional CBF in apolipoprotein E-deficient and wild type mice during focal cerebral ischemia. 972 43

The purpose of this study was to concurrently assess the relationship of Apolipoprotein E (APOE) with both dementias and vascular illnesses in the very old. Nine hundred and fifty nine subjects (mean age 85 years) in a long-term care facility were genotyped and cognitively tested with the Mini Mental State Exam. All subjects were studied for the relationship of APOE with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. Four hundred fifty individuals met criteria for inclusion into one of the following groups: Alzheimer's disease (n = 318), vascular dementia (n = 49), or not demented controls (n = 83) and were investigated for the relationship between APOE and these diagnostic categories. APOE epsilon4 was not associated with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. The APOE epsilon3 allele was more common in men with atherosclerotic heart disease. In contrast, the APOE epsilon4 allele was more common in patients with Alzheimer's disease (22%) and vascular dementia (26%) than in not demented controls (7%). APOE epsilon4 is associated with dementias in the very old, whereas its relationship with either peripheral or central nervous system vascular disease without dementia is not as robust.
Atherosclerosis 1998 Sep
PMID:The relationship between apolipoprotein E, dementia, and vascular illness. 973 29

Apolipoprotein E (apoE)-knockout mice develop severe atherosclerosis associated with high levels of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) in plasma. To investigate the atherogenic role of VLDL and IDL, the lipoprotein fraction containing both VLDL and IDL (apoEko-VLDL/IDL) was isolated from plasma of apoE-knockout mice by ultracentrifugation, and its interaction with macrophages was studied. When peritoneal macrophages obtained from apoE-knockout mice were incubated with apoEko-VLDL/IDL, the level of cellular cholesteryl esters (CE) increased with the concentration of apoEko-VLDL/IDL. The level of cellular cholesteryl [3H]oleate formed reached 15.1 nmol/mg of cell protein upon incubation with 50 microg/mL apoEko-VLDL/IDL for 18 h, which was an 8.4-fold increase over the corresponding level induced by low-density lipoprotein (LDL). The cellular CE mass was also significantly increased by apoEko-VLDL/IDL. Morphologically, after exposure to apoEko-VLDL/IDL, macrophages became strongly stained with Sudan black B. The total binding of [125I]apoEko-VLDL/IDL to macrophages was effectively replaced by more than 80% by an excess of the unlabeled ligand. Specific binding, calculated by subtracting the nonspecific binding from the total binding, exhibited a saturation pattern. Similar results were obtained with cell association and degradation experiments. In addition, the endocytic degradation of [125I]apoEko-VLDL/IDL was partially inhibited by LDL, whereas acetyl-LDL did not show any effect. These results indicated that apoEko-VLDL/IDL in its unmodified form produced significant CE accumulation in macrophages through a specific and apoE-independent pathway. This pathway may explain, in part, the mechanisms of foam cell formation in arterial walls and the subsequent development of atherosclerosis in apoE-knockout mice.
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PMID:The very low- and intermediate-density lipoprotein fraction isolated from apolipoprotein E-knockout mice transforms macrophages to foam cells through an apolipoprotein E-independent pathway. 975 60

This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ETA receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 +/- 3 vs. 99 +/- 2%, P < 0.0001) and plasma nitrate were reduced (57.9 +/- 4 vs. 93 +/- 10 micromol/liter, P < 0.01). Treatment with the ETA receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 +/- 3 to 93 +/- 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 +/- 4 to 80 +/- 8.3 micromol/liter, P < 0.05). Chronic ETA receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ETA receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ETA receptor blockade may have therapeutic potential in patients with atherosclerosis.
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PMID:Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. 982 6

Apolipoprotein E (apo E) plays a central role in lipoprotein metabolism as a ligand for LDL-, VLDL- and remnant receptors. It is mainly synthesized by hepatocytes and also by monocytes-macrophages. There are three common codominant isoforms E2, E3 and E4. Apo E2 binds defectively to LDL- and to remnant-receptors. Apo E alleles frequency varies from population to population around the world. In Europe, E4 allele frequency increases from south to north along the cardiovascular disease frequency gradient. On the other hand, the association between E2 allele and these diseases remains to be proved except for type III hyperlipoproteinemia. Apo E4 role in atherosclerosis could be explained, at least in part, by its high solubility in apo B lipoproteins. The average cholesterolemia of E4/E3 subjects is higher than E3/E3 subjects and E3/E3 subjects' cholesterolemia is higher than in E3/E2 subjects, probably because of a faster uptake of chylomicrons and VLDL remnants in E4/E3 subjects. The E4 allele also seems to play a role not only in diet response in combination with other genetic factors such as the Eco RI polymorphism of apo B but also in hypolipemic treatment. Apo E plays also a role in triglyceridemia control in association with other genetic and environmental factors such as lipoprotein lipase, apo B, LDL receptor and diet. Models of apo E knockout mice suggest a protective effect of monocyte-macrophageapo E in the vessel wall and HDL-apo E probably induces a high cholesterol efflux from macrophages. This effect counteracts the proatherogenic effect of VLDL- and IDL-apo E. The balance between these effects could be influenced by apo E phenotype.
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PMID:[Apolipoprotein E and its alleles in healthy subjects and in atherosclerosis]. 985 24

Apolipoprotein E (apoE) is a multifunctional protein synthesized by the liver and tissue macrophages. ApoE-deficient mice have severe hyperlipidemia and develop accelerated atherosclerosis on a chow diet. Both liver-derived and macrophage-derived apoEs have been shown to reduce plasma lipoprotein levels and slow the progression of atherosclerosis in apoE-deficient mice, but regression of atherosclerosis has not been demonstrated in this model. We utilized second-generation adenoviruses to achieve hepatic expression of human apoE in chow-fed, apoE-deficient mice with established atherosclerotic lesions of different stages. As expected, hepatic expression of human apoE3 significantly reduced plasma cholesterol levels. Liver-derived apoE also accumulated substantially within preexisting atherosclerotic lesions, indicating that plasma apoE gained access to the arterial intima. Hepatic expression of human apoE3 for 6 weeks resulted in significant quantitative regression of both early fatty streak lesions as well as advanced, complex lesions in both the aortic root and the aortic arch. In addition, hepatic expression of apoE induced substantial morphological changes in lesions, including decreased foam cells and increased smooth muscle cells and extracellular matrix content. In parallel, human apoE4 and apoE2 were also expressed in the liver by using recombinant adenoviruses. ApoE4 reduced cholesterol levels to the same extent as did apoE3 and also prevented progression but did not induce significant regression of preexisting lesions. ApoE2 reduced cholesterol levels to a lesser degree than did apoE3 and apoE4 and lesion progression was reduced, but regression was not induced. In summary, (1) regression of preexisting atherosclerotic lesions in apoE-deficient mice can be rapidly induced by hepatic expression of apoE, despite the absence of macrophage-derived apoE; (2) the morphological changes seen in this model of regression resemble those in other animal models, induced over longer periods of time; (3) liver-derived apoE gained access to and was retained by intimal atherosclerotic lesions; and (4) apoE4 was less effective in inducing regression, despite its effects on plasma lipoproteins that were similar to those of apoE3. The rapid regression of preexisiting atherosclerotic lesions induced by apoE gene transfer in apoE-deficient mice could provide a convenient murine model for investigation of the molecular events associated with atherosclerosis regression.
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PMID:Rapid regression of atherosclerosis induced by liver-directed gene transfer of ApoE in ApoE-deficient mice. 1047 59

The goal of the present study was to assess whether the effect of the apolipoprotein E polymorphism on postprandial lipemia explained part of the risk attributable to familial history of coronary heart disease. Cases (n = 407) were students, aged between 18 and 28 years, whose fathers had a proven myocardial infarction before the age of 55 years. Age-matched controls (n = 415) were recruited from the corresponding student registers. Blood was obtained after an overnight fast and at 2, 3, 4 and 6 h after ingestion of a fatty meal for triglyceride measurements. Apolipoprotein E phenotype was associated with postprandial triglyceride variability in both cases and controls. However, the apolipoprotein E-dependent triglyceride response was not significantly heterogeneous between cases and controls. In the pooled data, postprandial triglyceride levels were higher in carriers of the E2 and, to a lesser extent, of the E4 isoform, than in E3/3 homozygotes, independently of fasting triglyceride levels. At 6 h, triglyceride levels were increased by 21.2% (P < 0.01) in E2 carriers and 11.5% (P = 0.053) in E4 carriers by comparison to E3/3 subjects. These effects were not significantly different between regions. In conclusion, the effects of the apolipoprotein E polymorphism on postprandial triglyceridemia are similar across regions of Europe, and homogeneous in healthy young subjects with and without a family history of early myocardial infarction. This suggests that the influence of apolipoprotein E on myocardial infarction risk may be acting through mechanisms other than through effects on postprandial triglyceridemia.
Atherosclerosis 1999 Aug
PMID:Effect of apo E phenotype on plasma postprandial triglyceride levels in young male adults with and without a familial history of myocardial infarction: the EARS II study. European Atherosclerosis Research Study. 1048 67


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