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

Homocysteine metabolism is increasingly implicated in a diverse group of clinical disorders, including atheromatous vascular disease. We studied the disposition of homocysteine via the trans-sulphuration pathway, plasma glutathione peroxidase (GPx) activity and plasma levels of the sulphated hormone dehydro-epiandrosterone sulphate (DHEAS) in six vitamin B(12)-deficient human subjects before and after 2 weeks of vitamin B(12) repletion, both in the fasting state and following an oral methionine load (0.1 g/kg body weight). Fasting plasma total homocysteine concentrations fell (P=0.03) and total cysteine concentrations rose significantly (P=0.048) after treatment for 2 weeks with vitamin B(12) injections. The magnitude of the mean fall in the fasting concentration of homocysteine (38.8 micromol/l) was similar to the mean rise in cysteine levels (36.0 micromol/l) following vitamin B(12) therapy. Circulating levels of homocysteine were increased at 4 h after a methionine load when compared with fasting levels, both before and after vitamin B(12) repletion (P=0.003 for both). Total cysteinyl-glycine was lower post-methionine than in the fasting state following vitamin B(12) therapy (P=0.007). Fasting plasma GPx fell significantly after 2 weeks of vitamin B(12) therapy (P=0.05). The change in plasma GPx between the fasting state and 4 h after methionine loading was significantly different pre- and post-vitamin B(12) therapy (P=0.05). The present study provides indirect support to the hypothesis that defects in the trans-sulphuration and remethylation of homocysteine produce hyperhomocysteinaemia in vitamin B(12) deficiency in human subjects. Elevated homocysteine levels directly or indirectly may up-regulate GPx. Sulphation status, as measured by plasma DHEAS, was unchanged.
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PMID:Homocysteine and thiol metabolites in vitamin B12 deficiency. 1111 25

The crystal structure of human cystatin C, a protein with amyloidogenic properties and a potent inhibitor of cysteine proteases, reveals how the protein refolds to produce very tight two-fold symmetric dimers while retaining the secondary structure of the monomeric form. The dimerization occurs through three-dimensional domain swapping, a mechanism for forming oligomeric proteins. The reconstituted monomer-like domains are similar to chicken cystatin except for one inhibitory loop that unfolds to form the 'open interface' of the dimer. The structure explains the tendency of human cystatin C to dimerize and suggests a mechanism for its aggregation in the brain arteries of elderly people with amyloid angiopathy. A more severe 'conformational disease' is associated with the L68Q mutant of human cystatin C, which causes massive amyloidosis, cerebral hemorrhage and death in young adults. The structure of the three-dimensional domain-swapped dimers shows how the L68Q mutation destabilizes the monomers and makes the partially unfolded intermediate less unstable. Higher aggregates may arise through the three-dimensional domain-swapping mechanism occurring in an open-ended fashion in which partially unfolded molecules are linked into infinite chains.
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PMID:Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. 1127 39

Chronic exposure to arsenite is associated with vascular disease, such as arteriosclerosis. However, the cellular mechanisms for vascular disease in response to arsenic are not well known. The present study has demonstrated that arsenite not arsenate decreased the Fas ligand (FasL) expression on ECV304 cells through reactive oxygen species. Incubation of ECV304 cells with arsenite decreased the FasL expression and increased the intracellular peroxide levels. In addition, hydrogen peroxide was found to suppress FasL expression in a dose-dependent manner. The antioxidant, N-acetyl-cysteine, blocked the suppression of FasL expression in response to arsenite. These data suggested that arsenite initiates endothelium dysfunction, at least partly, by suppressing the FasL expression through activating reactive oxygen species sensitive endothelial cell signaling.
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PMID:Suppression of Fas ligand expression on endothelial cells by arsenite through reactive oxygen species. 1151 1

Hyperglycemia-induced oxidative stress may play a key role in the pathogenesis of diabetic vascular disease. The purpose of this study was to determine the effects of glucose on levels of glutathione (a major intracellular antioxidant), the expression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione de novo synthesis), and DNA damage in human vascular smooth muscle cells in vitro. High glucose conditions and buthionine sulphoximine, an inhibitor of gamma-glutamylcysteine synthetase, reduced intracellular glutathione levels in vascular smooth muscle cells. This reduction was accompanied by a decrease in the mRNA expression of both subunits of gamma-glutamylcysteine synthetase as well as an increase in DNA damage. In high glucose conditions, incubation of the vascular smooth muscle cells with alpha-lipoic acid and L-cystine restored glutathione levels. We suggest that the decrease in GSH levels seen in high glucose conditions is mediated by the availability of cysteine (rate-limiting substrate in de novo glutathione synthesis) and the gene expression of the gamma-glutamylcysteine synthetase enzyme. Glutathione depletion is associated with an increase in DNA damage, which can be reduced when glutathione levels are restored.
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PMID:Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions. 1170 92

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.
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PMID:NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL. 1170 20

Hereditary cystathioninuria (MIM 219500) is presumed to be caused by deficiency of the activity of cystathionine gamma-lyase (cystathionase; CTH EC 4.4.1.1), which is normally required for the conversion of methionine into cysteine. To date, no mutations have been described among patients with cystathioninuria. From genomic DNA, we sequenced CTH in four unrelated probands with cystathioninuria. We found two nonsense mutations, namely exon 8 c.940-941delCT and exon 11 c.1220delC, and two missense mutations, namely exon 2 c.356C>T (T67I) and exon 7 c.874C>G (Q240E). All affected subjects were either simple homozygotes or compound heterozygotes. A common non-synonymous single nucleotide polymorphism in exon 12, namely c.1364G>T (S403I), was also identified and characterized in four ethnic groups. The reagents described in this report make the molecular diagnosis of cystathioninuria possible, allowing for studies of phenotype-genotype correlation. Also, the availability of a common non-synonymous SNP can allow for testing of association of the CTH gene with biochemical traits affected by trans-sulfuration, such as plasma concentrations of homocysteine or even cystathionine itself, in addition to more downstream clinical phenotypes, such as vascular disease.
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PMID:Genomic basis of cystathioninuria (MIM 219500) revealed by multiple mutations in cystathionine gamma-lyase (CTH). 1257 42

Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-kappaB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.
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PMID:Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2. 1274 10

Translation initiation, the rate-limiting step in protein synthesis, is a key event in vascular smooth muscle cell growth, a major component of vascular disease. Translation initiation is regulated by interaction between PHAS-I and the eukaryotic initiation factor 4E (eIF4E). Although angiotensin II (Ang II)-induced vascular smooth muscle cell hypertrophy requires the generation of reactive oxygen species (ROS), the ROS sensitivity of these events and their upstream activators remain unclear. Here, we investigated the role of ROS in the regulation of PHAS-I phosphorylation on Thr-70 and Ser-65, an event required for the release of eIF4E from PHAS-I. Ang II-induced Ser-65 phosphorylation was ROS-dependent as assessed by pretreatment with ebselen (3.6 +/- 0.2 versus 1.1 +/- 0.2), diphenylene iodonium (3.6 +/- 0.2 versus 1.0 +/- 0.1), and N-acetyl cysteine (3.6 +/- 0.2 versus 1.2 +/- 0.1), but Ang II-stimulated phosphorylation of Thr-70 was ROS-insensitive. Although phosphatidylinositol 3-kinase pathway inhibition by LY294004 blocked both Ser-65 and Thr-70 phosphorylation (3.8 +/- 0.1 versus 0.8 +/- 0.1 and 3.2 +/- 0.2 versus 1.0 +/- 0.01, respectively), protein phosphatase 2A inhibition by okadaic acid selectively increased (3.3 +/- 0.1 versus 5.2 +/- 0.1) and p38 mitogen-activated protein kinase inhibition by SB203580 selectively decreased (3.8 +/- 0.1 versus 1.4 +/- 0.3) Ser-65 phosphorylation. Dominant negative Akt adenovirus also inhibited only Ser-65 phosphorylation (3.7 +/- 0.1 versus 1.0 +/- 0.03). These results demonstrate a unique differential ROS sensitivity of two separate residues on PHAS-I, which seems to be explained by the selective involvement of distinct signaling pathways in the regulation of these phosphorylation events.
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PMID:Reactive oxygen species sensitivity of angiotensin II-dependent translation initiation in vascular smooth muscle cells. 1286 Sep 93

Mild hyperhomocysteinemia (HHcy) is a risk factor for vascular disease and is closely associated with endothelial dysfunction. Oxidative stress and decreased nitric oxide (NO) bioavailability were reported in HHcy-induced vascular injury; however, the exact relationship is not understood. We thus directly determine the production of reactive oxygen species (ROS) and NO in cultured endothelial cells (HUVECs) to demonstrate the correlated variation between ROS and NO induced by Hcy (homocysteine), Cys (cysteine), another thiol compound, and Met (methionine), precursor of HHcy in animal study. HUVECs were treated with Hcy, Cys, or Met for 0.5 or 22-24 h; ROS generation was detected by DCF fluorescence with flow cytometry and NO by chemiluminescence. In non-cytotoxic (<1.0 mM) concentration ranges, Met exerted no effects on either ROS production or NO concentration, Cys decreased ROS production and increased NO in both short-term (0.5 h) and long-term (22-24 h) treatments; Hcy, however, induced a biphasic effect on ROS production, i.e., inhibitory at 0.5 h but stimulatory at 24 h. The maximal stimulation by Hcy (0.25 mM) was significantly reduced by co-incubation (12 h) with estrogen (1 microM). Hcy caused an early (0.5 h) increase of medium NO which was absent in long-term Hcy treatment. The oxidative stress caused by long-term Hcy incubation could be ameliorated by estrogen, consistent with earlier in vivo observations that estrogen prevents HHcy-induced injury.
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PMID:Homocysteine altered ROS generation and NO accumulation in endothelial cells. 1467 82

Plasma homocyst(e)ine level is a strong independent risk factor for vascular disease. The spelling of homocyst(e)ine reflects that what is measured, and what constitutes the risk factor; it includes homocysteine, homocystine (the dimer of homocysteine) and mixed cysteine-homocysteine disulfide. Homocyst(e)ine levels above 10.2 micro mol/L are associated with a doubling of coronary risk, and levels above 20 micro mol/L are associated with a 9.9-fold increase in risk compared with levels below 9 micro mol/L. The mechanisms by which homocyst(e)ine promotes vascular disease include increased thrombosis, consumption of nitric oxide, endothelial injury, and reduced thrombolysis. Homocyst(e)ine is an independent predictor of carotid atherosclerosis. Vitamin therapy with folate, pyridoxine (vitamin B(6)), and cyanocobalamin (vitamin B(12)) reduces blood levels of homocyst(e)ine, improves endothelial function, reduces levels of fibrinogen and lipoprotein(a), improves thrombolysis, and in uncontrolled clinical observation, leads to regression of carotid plaque. These lines of evidence support a causal relationship between homocyst(e)ine and atherosclerosis, and suggest that in patients with vascular disease, an appropriate target level for therapy may be below 9 or 10 micro mol/L. Randomized controlled studies are under way to determine whether vitamin therapy is effective in secondary prevention of myocardial infarction and stroke.
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PMID:Patients with atherosclerotic vascular disease: how low should plasma homocyst(e)ine levels go? 1472 38


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