Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A range of thromboxane A2 receptor blocking (TxRB) drugs, prostacyclin and aspirin have been assessed as inhibitors of human platelet deposition onto rabbit and human de-endothelialized arteries in vitro. Platelet deposition was quantified by measuring the radioactivity associated with de-endothelialized arteries following superfusion with 111indium-labelled human platelets reconstituted in blood. Using rabbit aorta, all of the compounds tested produced a similar maximum inhibition (approximately 70%) of platelet deposition; from scanning EM studies the residual deposition appeared to represent a monolayer of adhered platelets. The potency of the TxRB's for inhibiting deposition was GR32191 greater than or equal to GR36246 greater than SQ29,548 greater than ICI185282 greater than or equal to AH23848 much greater than BM13.177 consistent with their TxRB potency on human platelets. Using human umbilical arteries, the TxRB's achieved a smaller maximum inhibition of deposition (approximately 50%) than did prostacyclin or the fibrinogen receptor blocking peptide Gly-Arg-Gly-Asp-Ser (GRGDS) (60-75%). In addition, using human umbilical arteries, the structurally-related TxRB's GR32191 and GR36246 exhibited a greater than 1000-fold enhancement in potency as inhibitors of platelet deposition over that seen in the rabbit aorta. In preliminary experiments, GR32191 also displayed a similar high potency on human cerebral arteries. In contrast, the structurally unrelated compounds SQ29,548, ICI185282 and BM13.177 exhibited similar potencies on human umbilical arteries to those observed on the rabbit aorta; aspirin and prostacyclin also displayed similar potencies on the two preparations. The enhanced effect of GR32191 and GR36246 on human umbilical arteries therefore appears unrelated to their action as TxRB's on human platelets although the mechanism of this unique action is at present unknown. However, if these drugs exhibited a similar high potency for preventing mural thrombus formation in vivo in man, they may represent a major advance in the treatment of occlusive vascular disease.
 ...
PMID:Effect of GR32191 and other thromboxane receptor blocking drugs on human platelet deposition onto de-endothelialized arteries. 138 66

In Alzheimer's dementia (AD) the Primum Movens is Amyloid (AM) production on precapillaries: Dyshoric Angiopathy, and capillaries: Senile Plaques (SP) producing Blood-Brain-Barrier (BBB) disturbances, entry in the brain of toxic metals which displace the zinc. Cerebral AM alone may be asymptomatic. Clinical symptoms (Amnesia, Instrumental Disorders) appear when AM induces Neighbouring neuritic alterations: Paired Hellical Filaments (PHF) and Distant neuronal body lesions: Neurofibrillary Tangles (NFT). The AM is coded by a locus on the chromosome 21 and a duplication of this locus should be the etiology of cerebral AM in AD. In AD cerebral zinc decreases particularly in the hippocampus. The zinc-enzyme Superoxyde-Dismutase (SOD) is coded by a locus also on the chromosome 21 near AM and the plasma level of SOD is high in AD. Zinc deposits observed in capillary AM-SP, result probably from the excess of plasmatic SOD. Other metals: Iron, aluminium are also observed in the AM-SP and their excess in the brain may be related to the decrease of zinc by metal to metal displacement. The decrease of functional zinc in the brain may interfere in the pathogenesis of PHF-NFT by metalotoxicity, neighbouring and distant to AM. Without AM, NFT are produced also by metalotoxicity and therefore brain zinc displacement. a) by lead: Encephalopathia saturnica b) by many metals: Guam Encephalopathy c) by aluminium d) by BBB disturbances leading probably to an abnormal entry of metals in the brain (Dementia Pugilistica, viral encephalitides). NFT may be produced by the deficiency of the following zinc enzymes: 1. Those of DNA metabolism, indicating abnormal DNA and therefore abnormal protein synthesis: PHF-NFT. 2. Those of neuronal detoxication: SOD, Carbonic Anhydrase, Lactate Dehydrogenase leading to neuronal toxicity particularly in the hippocampus normally rich in SOD. 3. Of Glutamate (GLU) Dehydrogenase (GDH) resulting in an excitotoxic increase of GLU. 4. Those of the metabolism of neurotransmitters (NT): neuropeptides, Histamine, GABA, Acetylcholine. Therapeutic proposition: a zinc complex crossing the BBB should be useful a) to prevent that the AM produces PHF-NFT by Neighbouring and Distant metalotoxicity and DNA changes; b) to regularise zinc-enzymes of neuronal detoxification and of neurotransmitters metabolisms. Preliminary trials by zinc Aspartate give yet promising results.
 ...
PMID:[Alzheimer's dementia and zinc]. 170 60

The cardinal lesions of Alzheimer's disease are neurofibrillary tangles, senile neuritic plaques, and vascular amyloid, the latter generally involving cortical arteries and small arterioles. All three lesions are composed of amyloid-like, beta-pleated sheet fibrils. Recently, a 4,200-dalton peptide has been isolated from extraparenchymal meningeal vessels, neuritic plaques, and neurofibrillary tangles. The assumption of N-terminal homogeneity in vascular amyloid has been used as an argument for a neuronal (versus blood) origin of the peptide. However, intracortical microvessels from Alzheimer's disease have not been previously isolated. The present studies describe the isolation of a microvessel fraction from Alzheimer's disease and control fresh autopsy human brain. Alzheimer's disease isolated brain microvessels that were extensively laden with amyloid and control microvessels were solubilized in 90% formic acid and analyzed by urea sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The arteriole fraction from the Alzheimer's subject with extensive amyloid angiopathy contained a unique 4,200-dalton peptide, whereas the arterioles or capillaries isolated from two controls and two Alzheimer's disease subjects without angiopathy did not. This peptide was purified by HPLC and amino acid composition analysis showed the peptide is nearly identical to the 4,200-dalton peptide recently isolated from neuritic plaques or from neurofibrillary tangles. Sequence analysis revealed N-terminal heterogeneity. The N-terminal sequence was: Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr, which is identical to the N-terminal sequence of the 4,200-dalton peptide isolated previously from extraparenchymal meningeal vessels and neuritic plaques.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Amyloid angiopathy of Alzheimer's disease: amino acid composition and partial sequence of a 4,200-dalton peptide isolated from cortical microvessels. 331 95

Elevated homocysteine (Hcy) levels are observed in two apparently unrelated diseases: neural-tube defects (NTD) and premature vascular disease. Defective human methionine synthase (MS) could result in elevated Hcy levels. We sequenced the coding region of MS in 8 hyperhomocysteinaemic patients (4 NTD patients and 4 patients with pregnancies complicated by spiral arterial disease, SAD). We identified only one mutation resulting in an amino acid substitution: an A-->G transition at bp 2756, converting an aspartic acid (D919) into a glycine (G). We screened genomic DNA for the presence of this mutation in 56 NTD patients, 69 mothers of children with NTD, 108 SAD patients and 364 controls. There was no increased prevalence of the GG and AG genotypes in NTD patients, their mothers or SAD patients. The D919G mutation does not seem to be a risk factor for NTD or vascular disease. We then examined the mean Hcy levels for each MS genotype. There was no correlation between GG- or AG-genotype and Hcy levels. The D919G mutation is thus a fairly prevalent, and probably benign polymorphism. This study, though limited, provides no evidence for a major involvement of MS in the aetiology of homocysteine-related diseases such as NTD or vascular disease.
 ...
PMID:Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease. 932 29

Inhibitors of platelet glycoprotein (GP) IIb-IIIa have been demonstrated to be effective in controlling acute cardiac complications in patients presenting with acute ischemic coronary syndromes (AICS). Since patients with atherosclerotic coronary vascular disease may present with AICS on multiple occasions, it is important to have documented evidence that novel antithrombotic agents are nonimmunogenic and thus safe for repeated administration. Eptifibatide (Integrilin) is a cyclic heptapeptide inhibitor that contains a modified lysine-glycine-aspartic acid sequence that recognizes the binding site of platelet GP IIb-IIIa, resulting in potent and selective inhibition of its binding to fibrinogen. An enzyme-linked immunosorbent assay sensitive to all classes of immunoglobulins was developed to test the immunogenicity of eptifibatide in humans. In two clinical studies, Integrilin to Minimize and Prevent Acute Coronary Thrombosis (IMPACT) and IMPACT II, samples were obtained from 414 patients undergoing coronary angioplasty to determine anti-eptifibatide antibodies at baseline and 30 days after treatment. In a separate clinical pharmacology study, 28 healthy volunteers received 2 infusions of eptifibatide 28 days apart and were monitored at baseline (immediately before the first infusion), at 28 days (immediately before the second infusion), and at 42, 56, 84, and 112 days after enrollment to monitor for an anamnestic anti-eptifibatide response. Eptifibatide administration did not result in an antibody response in any of the 3 studies, even after repeated administration. Eptifibatide represents a potent, specific inhibitor of the platelet GP IIb-IIIa complex that has not been observed to be immunogenic in clinical studies and is thus safe for repeated administration. This finding suggests that small, peptide-based therapeutic agents, which are becoming increasingly common, may be used in humans without inciting an immune response.
 ...
PMID:Nonimmunogenicity of eptifibatide, a cyclic heptapeptide inhibitor of platelet glycoprotein IIb-IIIa. 1009 Apr 30

Among patients undergoing maintenance hemodialysis, a decreased high-density lipoprotein cholesterol (HDL-C) concentration is among the most common abnormalities of lipid metabolism and apparently is an independent risk factor for vascular disease. A common missense mutation of cholesteryl ester transfer protein gene, D442G (Asp 442 to Gly), increases HDL-C levels through the reduced activity of cholesteryl ester transfer from HDL to VLDL, but the mutation also may lead to reduced activity of reverse cholesterol transport. To investigate the effect of the D442G polymorphism on atherosclerotic complications in dialysis patients, the genotype and allele frequency of the polymorphism were determined in 414 unselected dialysis patients and 220 control subjects, and postprandial serum lipid levels were measured in the dialysis patients. A similar genotype distribution was found between hemodialysis patients and healthy control subjects, and in dialysis patients with and without vascular disease. Serum levels of total cholesterol and HDL-C did not differ between patients with and without the mutation and in patients with and without vascular disease. However, patients with sub-median HDL-C levels (<45 mg/dl) had an independent odds ratio of 1.8 for vascular disease (95% confidence interval, 1.04 to 3.2; P < 0.05). In this low-HDL-C subgroup, patients with the D442G mutation had a significantly higher prevalence of vascular disease than those with no mutation (54.5% versus 24.4%; P < 0.05), and an independent odds ratio of 4.9 (95% confidence interval, 1.05 to 22.65; P < 0.05). In conclusion, the D442G mutation is an independent risk factor for atherosclerotic complications in dialysis patients with HDL-C levels below 45 mg/dl.
 ...
PMID:A cholesteryl ester transfer protein gene mutation and vascular disease in dialysis patients. 1021 28

A new lipoprotein lipase-like gene has been cloned from endothelial cells through a subtraction methodology aimed at characterizing genes that are expressed with in vitro differentiation of this cell type. The conceptual endothelial cell-derived lipase protein contains 500 amino acids, including an 18-amino acid hydrophobic signal sequence, and is 44% identical to lipoprotein lipase and 41% identical to hepatic lipase. Comparison of primary sequence to that of lipoprotein and hepatic lipase reveals conservation of the serine, aspartic acid, and histidine catalytic residues as well as the 10 cysteine residues involved in disulfide bond formation. Expression was identified in cultured human umbilical vein endothelial cells, human coronary artery endothelial cells, and murine endothelial-like yolk sac cells by Northern blot. In addition, Northern blot and in situ hybridization analysis revealed expression of the endothelial-derived lipase in placenta, liver, lung, ovary, thyroid gland, and testis. A c-Myc-tagged protein secreted from transfected COS7 cells had phospholipase A1 activity but no triglyceride lipase activity. Its tissue-restricted pattern of expression and its ability to be expressed by endothelial cells, suggests that endothelial cell-derived lipase may have unique functions in lipoprotein metabolism and in vascular disease.
 ...
PMID:Cloning of a unique lipase from endothelial cells extends the lipase gene family. 1031 35

Elevation in plasma homocysteine concentration has been associated with vascular disease and neural tube defects. Methionine synthase is a vitamin B(12)-dependent enzyme that catalyses the remethylation of homocysteine to methionine. Therefore, defects in this enzyme may result in elevated homocysteine levels. One relatively common polymorphism in the methionine synthase gene (D919G) is an A to G transition at bp 2,756, which converts an aspartic acid residue believed to be part of a helix involved in co-factor binding to a glycine. We have investigated the effect of this polymorphism on plasma homocysteine levels in a working male population (n = 607) in which we previously described the relationship of the C677T "thermolabile" methylenetetrahydrofolate reductase (MTHFR) polymorphism with homocysteine levels. We found that the methionine synthase D919G polymorphism is significantly (P = 0.03) associated with homocysteine concentration, and the DD genotype contributes to a moderate increase in homocysteine levels across the homocysteine distribution (OR = 1.58, DD genotype in the upper half of the homocysteine distribution, P = 0.006). Unlike thermolabile MTHFR, the homocysteine-elevating effects of the methionine synthase polymorphism are independent of folate and B(12) levels; however, the DD genotype has a larger homocysteine-elevating effect in individuals with low B(6) levels. This polymorphism may, therefore, make a moderate, but significant, contribution to clinical conditions that are associated with elevated homocysteine.
 ...
PMID:Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteine concentrations. 1052 Feb 12

Several mutations in the amyloid precursor protein (APP) gene have been found to associate with pathologic deposition of the beta-amyloid peptide (Abeta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of Abeta40 in plaques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of Abeta, thus differing from familial Alzheimer's disease mutations, which occur outside the Abeta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral amyloid angiopathy-related hemorrhage found no other instances of this mutation. These results suggest a novel site within Abeta that may promote its deposition and toxicity.
 ...
PMID:Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. 1140 17

Amyloid beta-protein (Abeta) assembly into toxic oligomeric and fibrillar structures is a seminal event in Alzheimer's disease, therefore blocking this process could have significant therapeutic benefit. A rigorous mechanistic understanding of Abeta assembly would facilitate the targeting and design of fibrillogenesis inhibitors. Prior studies have shown that Abeta fibrillogenesis involves conformational changes leading to the formation of extended beta-sheets and that an alpha-helix-containing intermediate may be involved. However, the significance of this intermediate has been a matter of debate. We report here that the formation of an oligomeric, alpha-helix-containing assembly is a key step in Abeta fibrillogenesis. The generality of this phenomenon was supported by conformational studies of 18 different Abeta peptides, including wild-type Abeta(1-40) and Abeta(1-42), biologically relevant truncated and chemically modified Abeta peptides, and Abeta peptides causing familial forms of cerebral amyloid angiopathy. Without exception, fibrillogenesis of these peptides involved an oligomeric alpha-helix-containing intermediate and the kinetics of formation of the intermediate and of fibrils was temporally correlated. The kinetics varied depending on amino acid sequence and the extent of peptide N- and C-terminal truncation. The pH dependence of helix formation suggested that Asp and His exerted significant control over this process and over fibrillogenesis in general. Consistent with this idea, Abeta peptides containing Asp-->Asn or His-->Gln substitutions showed altered fibrillogenesis kinetics. These data emphasize the importance of the dynamic interplay between Abeta monomer conformation and oligomerization state in controlling fibrillogenesis kinetics.
 ...
PMID:Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis. 1158 Feb 53


1 2 3 Next >>