Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein E fulfills fundamental functions in lipid transport and neural tissue repair after injury.(6,8) Its three most common isoforms (E2, E3, and E4) are critical determinants of diverse human diseases, including major cardiovascular and neurodegenerative disorders.(8,14) Apolipoprotein E4 is associated with an increased risk for Alzheimer's disease(3,5) and poor clinical outcome after head injury or stroke.(11,16) The precise role of apolipoprotein E4 in these conditions remains unknown. To characterize the effects of human apolipoprotein E isoforms in vivo, we analysed transgenic Apoe knockout mice that express apolipoprotein E3 or E4 or both in the brain. Hemizygous and homozygous apolipoprotein E3 mice were protected against age-related and excitotoxin-induced neurodegeneration, whereas apolipoprotein E4 mice were not. Apolipoprotein E3/E4 bigenic mice were as susceptible to neurodegeneration as apolipoprotein E4 singly-transgenic mice. At eight months of age neurodegeneration was more severe in homozygous than in hemizygous apolipoprotein E4 mice consistent with a dose effect. Thus, apolipoprotein E4 is not only less neuroprotective than apolipoprotein E3 but also acts as a dominant negative factor that interferes with the beneficial function of apolipoprotein E3. The inhibition of this apolipoprotein E4 activity may be critical for the prevention and treatment of neurodegeneration in APOE varepsilon4 carriers.
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PMID:Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease. 1079 51

The mechanism linking the APOE4 gene with increased susceptibility for Alzheimer's disease (AD) and poorer outcomes following closed head injury and stroke is unknown. One potential link is activation of the innate immune system in the CNS. Our previously published data demonstrated that apolipoprotein E regulates production of nitric oxide, a critical cytoactive factor released by immune active macrophages. To determine if immune regulation is different in the presence of apolipoprotein E4 compared to apolipoprotein E3, we have measured NO production by peritoneal and CNS macrophages (microglia) cultured from transgenic mice that only express the human apoE4 or apoE3 protein isoform. Significantly more NO was produced in APOE4 mice compared to APOE3 transgenic mice that only express human apoE3 protein. Similarly, monocyte derived macrophages from humans carrying APOE4 gene alleles also produce significantly greater NO than those individuals with APOE3. The mechanism for this isoform-specific difference in NO production is not known and multiple sites in the NO production pathway may be affected. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein are not significantly different between the APOE3 and APOE4 mice, suggesting that induction of iNOS is not a primary cause of the increased NO production in APOE4 animals. One alternative regulatory mechanism that demonstrates isoform specificity is arginine transport, which is greater in microglia from APOE4 transgenic mice compared to microglia from APOE3 mice. Increased transport is consistent with an increased production of NO and may reflect a direct or indirect effect of the APOE genotype on microglial arginine uptake and microglial activation in general. Overall, greater NO production in APOE4 carriers where characteristically high levels of oxidative/nitrosative stress are found in diseases such as AD provides a mechanism that potentially explains the genetic association between APOE4 and human diseases.
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PMID:APOE and the regulation of microglial nitric oxide production: a link between genetic risk and oxidative stress. 1239 81

The clinical significance of the apolipoprotein E genotype in patients with hypertension has been a subject of debate. We enrolled 94 patients with hypertension and 102 healthy controls in this study and determined their plasma levels of triglyceride, total cholesterol, high- and low-density lipoprotein-cholesterol, apolipoprotein AI, and apolipoprotein B. The apolipoprotein E genotypes were identified by polymerase chain reaction, restriction fragment length polymorphism, and polyacrylamide gel electrophoresis. Apolipoprotein E3/4 genotype and set membership, vertical bar on horizontal stroke 4 allele frequencies in the hypertensive group were higher than in controls. In hypertensive patients with apolipoprotein E3/4 and E4/4 genotypes, systolic blood pressure was significantly higher than in those with apolipoprotein E2/3 or E3/3 genotypes. Meanwhile, the plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and apolipoprotein B were higher in hypertensive patients with the.4 allele than the set membership, vertical bar on horizontal stroke 2 or set membership, vertical bar on horizontal stroke 3 allele. The echographic measurements of carotid artery intimal-medial thickness showed increasing values from set membership, vertical bar on horizontal stroke 2 to set membership, vertical bar on horizontal stroke 4 allele carriers in the hypertensive group. Analysis of variance showed that the carotid intimal-medial thickness was significantly greater in hypertensive patients with set membership, vertical bar on horizontal stroke 4 alleles compared with set membership, vertical bar on horizontal stroke 2 or set membership, vertical bar on horizontal stroke 3 alleles. Our data show an association between apolipoprotein E genotype and hypertension and support the hypothesis that the apolipoprotein set membership, vertical bar on horizontal stroke 4 allele is a susceptibility locus for systolic hypertension and carotid artery atherosclerosis.
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PMID:Association of apolipoprotein E gene polymorphism with essential hypertension and its complications. 1262 8