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) is a multifunctional plasma glycoprotein involved in lipoprotein metabolism and a range of cell signalling phenomena. ApoE-deficient (apoE(-/-)) mice exhibit severe hypercholesterolaemia and are an excellent model of human atherosclerosis. ApoE somatic gene transfer and bone marrow transplantation in apoE(-/-) mice results in reversal of hypercholesterolaemia, inhibition of atherogenesis and regression of atherosclerotic plaque density. Replication defective adeno-associated virus vectors (rAAVs) are an attractive system currently in clinical trial for muscle-based heterologous gene therapy to express secreted recombinant plasma proteins. Here we have applied rAAV transduction of skeletal muscle to express wild-type (epsilon3) and a defective receptor-binding mutant (epsilon2) human apoE transgene in apoE(-/-) mice. In treated animals, apoE mRNA was present in transduced muscles and, although plasma levels of recombinant apoE fell below the detection levels of our ELISA (ie <10 ng/ml), circulating antibodies to human apoE and rAAV were induced. Up to 3 months after a single administration of rAAV/apoE3, a significant reduction in atherosclerotic plaque density in aortas of treated animals was observed (approximately 30%), indicating that low-level rAAV-mediated apoE3 expression from skeletal muscle can retard atherosclerotic progression in this well-defined genetic model.
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PMID:Inhibition of atherosclerosis in apolipoprotein-E-deficient mice following muscle transduction with adeno-associated virus vectors encoding human apolipoprotein-E. 1185 Jul 19

The allelic variation of Apolipoprotein E (ApoE) influences serum lipid levels. Postmenopausal estrogen replacement therapy (ERT) has favorable effects on the serum lipid profile. We examined the effect of ApoE genotype on lipid response to ERT in 692 community-dwelling women aged 60 and older. ApoE genotypes were categorized into three groups: ApoE 2 (E2/E2+E2/E3, n=94), ApoE 3 (E3/E3, n=430), and ApoE 4 (E3/E4+E4/E4, n=142). Compared to 497 women not using ERT, 169 women currently using ERT were younger (P=0.01), had lower levels of total cholesterol (TC; P=0.10) and low-density lipoprotein (P<0.001), higher levels of high-density lipoprotein (HDL; P<0.001) and triglycerides (TG; P=0.009), and were more likely to have had a surgical menopause (P<0.001). No significant differences in body mass index, alcohol intake, physical activity, or cigarette smoking were found between current ERT users and nonusers (P>0.10). There was a significant interaction between ApoE 2 and ERT for HDL levels: women with ApoE 2 using ERT had the highest HDL levels, and women with ApoE 2 not using ERT had the lowest HDL levels (P=0.015). The unfavorable effect of ApoE 4 genotype on lipoproteins is not altered by HRT, but ApoE 2 genotype modulates the HDL-ERT association in older women.
Atherosclerosis 2002 Mar
PMID:Apolipoprotein E genotype and response of lipid levels to postmenopausal estrogen use. 1188 34

We have previously shown that magnetic resonance microscopy (MRM) accurately quantifies atherosclerosis in Apolipoprotein E deficient (ApoE(-/-)) mice aged 36-84 weeks. The present study tests MRM in the quantification of aortic atherosclerosis over a broader range of lesion severity. Younger mice with less advanced disease were imaged in order to evaluate sensitivity, specificity and maximum practical resolution of MRM. Nineteen mice underwent in vivo MRM. Wall area measurements by MRM and light microscopy (LM) (n=43) were highly correlated (r=0.85, slope=0.88, P<0.0001). Wall areas by MRM ranged from 0.114 to 0.934 (median, 0.334) mm(2). A threshold of 0.35 mm(2), for the upper limit of normal, gave MRM positive predictive value (PPV) for detecting abnormally thickened arteries=89.5% and negative predictive value (NPV)=75%, referred to LM. Lesion shape assessed by LM and MRM were also well correlated (r=0.72, P<0.001). Increased wall area in atherosclerosis was found by MRM (P=0.01) and LM (P<0.0001) to be accommodated entirely by 'positive remodeling', confirming the importance of determining plaque size directly. MRM accurately quantifies mouse aortic atherosclerosis and will enhance studies in this important animal model.
Atherosclerosis 2002 Jun
PMID:Atherosclerotic lesions in genetically modified mice quantified in vivo by non-invasive high-resolution magnetic resonance microscopy. 1199 51

Apolipoprotein E (apo E), a genetic determinant of plasma lipid levels and coronary heart disease (CHD) needs to be investigated in Asian Indians since they have a propensity to develop dyslipidemia and accelerated atherosclerosis. We studied apo E phenotypes and plasma lipid levels in 52 Northern Indian male patients (aged 38-71 years) with angiographically proven CHD, and compared them to 50 healthy blood donors taken as the control group. High levels of Lp(a), (p < 0.05), and a definite trend towards lower levels of HDL-C (p < 0.05), was observed in the CHD patients as compared to the control subjects. The frequency of apo E allele epsilon3 was 0.86 and 0.862, and epsilon4 allele was 0.12 and 0.08 in the patients and controls, respectively. However, a lower frequency of the E2 allele was observed in the patient group (E2 = 0.02) as compared to the controls (epsilon2 = 0.06) (p = ns). In individuals with apo E3/E3 phenotype, significantly lower HDL-C levels was observed in the CHD patients as compared to the control subjects (p < 0.05). A positive correlation was observed between apo E phenotypes and Lp(a) levels in the CHD subjects as compared to the controls (p < 0.05), the level being significantly high in CHD subjects with at least one E4 allele. To conclude, in this sample of Northern Indian subjects with CHD, there is a significant correlation between apo E3/E3 phenotype and low levels of HDL-C as compared to the control subjects. Further, apo E phenotype is positively correlated with high Lp(a) levels in the CHD subjects having at least one E4 allele. However, these relationships need to be explored in a larger sample of subjects.
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PMID:Apolipoprotein E polymorphism in Northern Indian patients with coronary heart disease: phenotype distribution and relation to serum lipids and lipoproteins. 1203 Mar 85

Monocyte chemoattractant protein-1 (MCP-1), which binds to C-C chemokine receptor 2, has been implicated as the primary source of monocyte chemoattractant function in the early stages of atherosclerosis. Recently, propagermanium, a drug used clinically for the treatment of chronic hepatitis in Japan, has been shown to inhibit C-C chemokine receptor 2 function and suppress monocyte/macrophage infiltration in vitro and in vivo. Given the importance of monocyte infiltration in atherogenesis, the inhibition of it by propagermanium might prevent atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were fed an atherogenic high cholesterol diet with or without 0.005% propagermanium for 8 or 12 weeks. Although the plasma lipid levels were unchanged by the drug treatment, atherosclerotic lesion area in the aortic root was reduced by 50% in the drug-treated apoE-KO mice compared with the nontreated apoE-KO mice after 8 weeks of cholesterol feeding (0.62+/-0.12 versus 1.27+/-0.07 mm2, respectively; P<0.01). Moreover, the accumulation of macrophages in the lesions was markedly reduced in the drug-treated group (macrophage positive area, 0.23+/-0.06 mm2 [drug-treated group] versus 0.67+/-0.07 mm2 [control group]; P<0.01). After 12 weeks of cholesterol feeding, atherosclerotic lesion formation in the aortic root and in the descending thoracic aorta was significantly reduced in the drug-treated group. Inhibition of macrophage infiltration by propagermanium prevented the formation of atherosclerotic lesions in apoE-KO mice. This drug may serve as a therapeutic tool for the treatment of atherosclerosis.
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PMID:Propagermanium reduces atherosclerosis in apolipoprotein E knockout mice via inhibition of macrophage infiltration. 1206 6

A better understanding of atherogenesis at the level of gene expression could lead to the identification of new therapeutic strategies for vascular diseases. With DNA array technology, it is possible to identify multiple, simultaneous changes in gene expression in small tissue samples from atherosclerotic arteries. We analyzed gene expression in normal arteries and in immunohistologically characterized human advanced atherosclerotic lesions using an array of 18376 cDNA fragments. The array method was first validated by detecting a group of genes (n=17) that were already known to be connected to atherogenesis. These genes included e.g. Apolipoprotein E, CD68, TIMP and phospholipase D. Next we detected 75 differentially expressed genes that were previously not connected to atherogenesis. A subgroup of genes involved in cell signaling and proliferation was selected for further analyzes with in situ hybridization and RT-PCR which confirmed array results by showing induction in advanced lesions of Janus kinase 1 (JAK-1) which is an important signaling molecule in activated macrophages; VEGF receptor-2 which mediates angiogenic and vasculoprotective effects of VEGF; and an unknown gene, which mapped on chromosome 19. It is concluded that DNA array technology enables fast screening of gene expression in small samples of atherosclerotic lesions. The technique will be useful for the identification of new factors, such as JAK-1 and VEGF receptor-2, which may play an important role in atherogenesis.
Atherosclerosis 2002 Nov
PMID:Changes in gene expression in atherosclerotic plaques analyzed using DNA array. 1220 67

Epidemiological and pathogenetic evidences suggest a strong association between vascular risk factors and sporadic Alzheimer's disease (sAD). In agreement with the vascular hypothesis of AD, the role of various candidate genes for atherosclerosis has been investigated, leading to conflicting results. In order to clarify the significance of angiotensin-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism in a group of patients with sAD, we conducted a case-control study including 149 cases and 149 age and sex matched controls. All subjects were genotyped for ACE and Apolipoprotein E (APOE). There were no significant differences in ACE genotype or allele frequencies between cases and controls, even after stratification for APOE4 carrier status. Our data suggest that the ACE I/D polymorphism is not associated to genetic susceptibility in sAD patients.
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PMID:Lack of association between angiotensin converting enzyme polymorphism and sporadic Alzheimer's disease. 1245 19

Monocyte chemoattractant protein-1 (MCP-1) has been shown to play an essential role in the pathogenesis of arteriosclerosis and other vascular diseases, such as restenosis after arterial injury, by recruiting monocytes into the arterial wall. We devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (7ND), which lacks the amino-terminal amino acids 2 to 8 of the human MCP-1 gene, into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene suppressed inflammatory and proliferative changes and arteriosclerosis formation induced by the chronic inhibition of nitric oxide synthesis in rats. 7ND gene transfection also inhibited the initiation, progression, and destabilization of atherosclerosis in Apolipoprotein E-knockout mice. Moreover, the strategy reduced restenosis after balloon injury in rabbits, rats, and monkeys, or neointimal formation after stent implantation in monkeys. This new strategy may be a useful and feasible gene therapy against atherosclerosis and restenosis after angioplasty.
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PMID:Gene therapy targeting monocyte chemoattractant protein-1 for vascular disease. 1256 May 86

Interleukin (IL)-10 is an anti-inflammatory cytokine that may play a protective role in atherosclerosis. The aim of this study was to assess the effect of IL-10 deficiency in the apolipoprotein E knockout mouse. Apolipoprotein E deficient (E-/-) and IL-10 deficient (-/-) mice were crossed to generate E-/- x IL-10-/- double knockout mice. By 16 wk, cholesterol and triglycerides were similar in double and single knockouts but the lack of IL-10 led to increased low-density lipoprotein cholesterol whereas very-low-density lipoprotein was reduced. In parallel, T-helper 1 responses and lesion size were dramatically increased in double knockout compared with E-/- controls. At 48 wk, matrix metalloproteinases and tissue factor activities were increased in lesions of double-knockout mice. Furthermore, markers of systemic coagulation were increased, and vascular thrombosis in response to i.v. thrombin occurred more frequently in E-/- x IL-10-/- than in E-/- mice. Our findings suggest that IL-10 deficiency plays a deleterious role in atherosclerosis. The early phase of lesion development was increased, and the proteolytic and procoagulant activity was elevated in advanced lesions. These data show that IL-10 may reduce atherogenesis and improve the stability of plaques.
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PMID:Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. 1276 35

Oxidative stress is involved in the pathogenesis of atherosclerosis, and angiotensin II (AT-II) induces oxidative stress and enhances atherogenesis. Aldosterone, which has an important role in the pathology of heart failure, has recently been implicated as a mediator of AT-II biologic activities. In this study, we analyzed whether administration of the selective aldosterone blocker eplerenone to atherosclerotic apolipoprotein E-deficient (E0) mice would affect their oxidative status and atherogenesis. Apolipoprotein E-deficient mice were administered chow containing eplerenone (200 mg/kg/day) for 3 months. Blood pressure, serum and macrophage oxidative status, and aortic atherosclerotic lesion area were evaluated in mice treated with eplerenone compared with untreated mice. Eplerenone administration significantly decreased systolic and diastolic blood pressure by 12% and 11%, respectively, compared with untreated mice. Serum susceptibility to lipid peroxidation decreased by as much as 26%, and serum paraoxonase activity increased by 28% in eplerenone-treated mice compared with untreated mice. Peritoneal macrophages from eplerenone-treated mice contained reduced levels of lipid peroxides, and their macrophage oxidation of low-density lipoprotein (LDL) and superoxide ion release were significantly reduced (by 17% and 43%, respectively), compared to untreated mice. Daily injections of AT-II (0.1 mL, 10(-)7M) during the final 3 weeks of the study in eplerenone-treated mice substantially attenuated the eplerenone-mediated reduction in macrophage superoxide release and LDL oxidation. Finally, the atherosclerotic lesion area in aortas of eplerenone-treated mice was significantly reduced (by 35%) versus untreated mice, and this effect was reversed by AT-II. Administration of the selective aldosterone blocker eplerenone significantly reduced oxidative stress and atherosclerosis progression in E0 mice. These data suggest that aldosterone could have a significant pro-oxidative role in the pathogenesis of atherosclerosis.
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PMID:Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apolipoprotein E-deficient mice. 1277 76


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