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)

Excessive proliferation of vascular smooth muscle cells (VSMCs) is a critical element in the development of several vascular pathologies, particularly in atherosclerosis and in restenosis due to angioplasty. We have shown that butyrate, a powerful antiproliferative agent, a strong promoter of cell differentiation and an inducer of apoptosis inhibits VSMC proliferation at physiological concentrations with no cytotoxicity. In the present study, we have used cDNA array technology to unravel the molecular basis of the antiproliferative effect of butyrate on VSMCs. To assess the involvement of gene expression in butyrate-inhibited VSMC proliferation, proliferating VSMCs were exposed to 5 mmol/l butyrate 1 through 5 days after plating. Expression profiles of 1.176 genes representing different functional classes in untreated control and butyrate treated VSMCs were compared. A total of 111 genes exhibiting moderate (2.0-5.0 fold) to strong (> 5.0 fold) differential expression were identified. Analysis of these genes indicates that butyrate treatment mainly alters the expression of four different functional classes of genes, which include: 43 genes implicated in cell growth and differentiation, 13 genes related to stress response, 11 genes associated with vascular function and 8 genes normally present in neuronal cells. Examination of differentially expressed cell growth and differentiation related genes indicate that butyrate-inhibited VSMC proliferation appears to involve down-regulation of genes that encode several positive regulators of cell growth and up-regulation of some negative regulators of growth or differentiation inducers. Some of the down-regulated genes include proliferating cell nuclear antigen (PCNA), retinoblastoma susceptibility related protein p130 (pRb), cell division control protein 2 homolog (cdc2), cyclin B1, cell division control protein 20 homolog (p55cdc), high mobility group (HMG) 1 and 2 and several others. Whereas the up-regulated genes include cyclin D1, p21WAF1, p141NK4B/p15INK5B, Clusterin, inhibitor of DNA binding 1 (ID1) and others. On the other hand, butyrate-responsive stress-related genes include some of the members of heat shock protein (HSP), glutathione-s-transferase (GST), glutathione peroxidase (GSH-PXs) and cytochrome P450 (CYP) families. Additionally, several genes related to vascular and neuronal function are also responsive to butyrate treatment. Although involvement of genes that encode stress response, vascular and neuronal functional proteins in cell proliferation is not clear, cDNA expression array data appear to suggest that they may play a role in the regulation of cell proliferation. However, cDNA expression profiles indicate that butyrate-inhibited VSMC proliferation involves combined action of a proportionally large number of both positive and negative regulators of growth, which ultimately causes growth arrest of VSMCs. Furthermore, these butyrate-induced differential gene expression changes are not only consistent with the antiproliferative effect of butyrate but are also in agreement with the roles that these gene products play in cell proliferation.
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PMID:Gene expression profile of butyrate-inhibited vascular smooth muscle cell proliferation. 1467 79

Recent studies on cultured aortic endothelial cells (AECs) from atherosclerosis-susceptible (SUS) and -resistant (RES) strains of Japanese quail suggest that differences in atherosclerosis susceptibility between RES and SUS may be due to differences in endothelial heme oxygenase (HO) and antioxidant components. We have now investigated the effects of oxidant-induced injury on HO and glutathione (GSH) in AECs from SUS and RES quail. We report that cultured AECs from SUS and RES birds differ in their response to oxidative stress. AECs from the SUS strain cells are more susceptible than those from the RES strain to oxidative stress induced by tert-butylhydroperoxide, as judged by lower HO activity, HO-1 expression, ferritin and GSH levels. Aortic endothelial cells from SUS birds also showed higher levels of catalytic iron, TBARS production and LDH release compared with RES cells, indicating that SUS AECs are more susceptible to oxidative stress than cells from the resistant strain. Furthermore, independently of genetic status, AECs from old birds have higher TBARS and lower levels of HSP70 induction than AECs from younger birds, suggesting that aging is associated with a decreased ability of AECs to respond to oxidative stress, and this may be relevant to the permissive effect of aging on the process of atherogenesis. Our results indicate that genetic factors and endogenous antioxidant systems in the blood vessel wall may be important in determining the susceptibility of vascular cells to oxidative stress and atherosclerotic plaque formation.
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PMID:Effects of oxidant-induced injury on heme oxygenase and glutathione in cultured aortic endothelial cells from atherosclerosis-susceptible and -resistant Japanese quail. 1467 83

Obesity is accompanied by a high incidence of atherosclerosis, arterial hypertension and non-insulin dependent diabetes mellitus in the pathogenesis of which is associated with oxygen-derived free radicals. The aim of the study was to compare blood oxidation status in obese women without coexisting diseases and in healthy women with normal body mass index (BMI). Studies were performed in 29 premenopausal obese (BMI 35.79 +/- 4.62 kg/m2) and 31 lean (BMI 22.29 +/- 1.05 kg/m2) women. Plasma lipid profile, activities of antioxidant enzymes: copper/zinc (Cu/ZnSOD) and manganese-containing superoxide dismutase (MnSOD) and glutathione peroxidase (GSH-Px), as well as concentrations of malondialdehyde (MDA)--a product of lipid peroxidation, were examined. In obese women there were significantly higher concentrations of total cholesterol (5.02 +/- 0.83 vs. 4.15 +/- 0.43 mmol/l; p < 0.05), LDL-cholesterol (3.12 +/- 0.90 vs. 2.35 +/- 0.42 mmol/l; p < 0.05) and triglycerides (1.72 +/- 0.85 vs. 1.02 +/- 0.18 mmol/l; p < 0.01), while HDL-cholesterol level was lower (1.01 +/- 0.16 vs. 1.25 +/- 0.2 mmol/l; p < 0.05). Moreover, in comparison to the control group, obese women showed increased activities of plasma MnSOD (6.72 +/- 1.43 vs. 4.99 +/- 0.58 NU/ml; p < 0.05) and erythrocyte GSH-Px (35.38 +/- 10.31 vs. 19.15 +/- 7.12 mumol NADPH2/g Hb/min; p < 0.001), and concentrations of plasma MDA (2.93 +/- 0.53 vs. 2.16 +/- 0.31 mumol/l; p < 0.05) and erythrocyte MDA (2.24 +/- 0.30 vs. 1.59 +/- 0.36 mumol/g Hb; p < < 0.001). There were no differences between the two groups in activities of plasma and erythrocyte Cu/ZnSOD. In conclusion, the results demonstrate disturbances in oxidation status in premenopausal obese women with abnormal lipid profile, which may indicate the association between oxygen-derived free radicals and the increase in the incidence of obesity-related diseases.
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PMID:[Assessment of blood superoxide dismutase, glutathione peroxidase activity and malondialdehyde concentration as oxidation status parameters in obese women]. 1468 7

An imbalance between oxidative damage and antioxidative protection in association with the pathophysiology of atherosclerosis has been suggested. The aim of our study was to investigate the relationship between plasma lipids, the antioxidant system and oxidative damage in Thai patients with stable coronary artery disease (CAD). Sixty-one patients (40 males, 21 females), who were angiographically defined as having CAD and were clinically stable, participated in this study. Thirty-two healthy subjects (20 males, 12 females) served as normal controls. The investigation included the measurements of plasma lipid profiles and plasma total antioxidative status (TAS) such as plasma vitamin E erythrocyte glutathione (GSH) and glutathione peroxidase (GPx), as well as malondialdehyde (MDA) and total plasma total protein thiols (P-SH). In patients with CAD, erythrocyte GSH and GPx were significantly lower than those found in controls. However plasma TAS and vitamin E were not significantly different between groups. Patients with CAD also had higher MDA and lower P-SH levels than the controls, which represents the oxidative damage products of lipid and proteins. Multiple regression analysis revealed negative correlations between GSH and cholesterol, GSH and low density lipoprotein (LDL), vitamin E and MDA, as well as P-SH and MDA. This study demonstrated the status of oxidative stress in patients with stable CAD. Since oxidative stress is the imbalance between the total oxidants and antioxidants in the body, any single oxidant/antioxidant parameter may not reflect the overall oxidative stress system. Thus, in patients with CAD, diets with various types of antioxidants may be more beneficial in increasing antioxidant activity than any particular antioxidant supplementation.
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PMID:The correlation between markers of oxidative stress and risk factors of coronary artery disease in Thai patients. 1472 57

It has been reported that oxidized LDL (oxLDL) are involved in the pathogenesis of atherosclerosis, and that macrophages as well as other cells of the arterial wall can oxidize LDL in vitro, depending on the balance between intracellular prooxidant generation and antioxidant defense efficiency. Because of their possible beneficial role in the prevention of atherosclerosis and other oxidative stress-associated diseases, phenolic compounds naturally occurring in vegetables, fruits, and beverages are receiving increased attention. In the present work, we investigated the mechanisms underlying the protective effect exerted by extra virgin olive oil biophenols, namely, protocatechuic acid and oleuropein, on LDL oxidation mediated by murine J774 A.1 macrophage-like cells. The biophenols were added to the cells with LDL and left in the medium during the entire experimental period, or for a period of 2 h and then removed from the medium before the addition of LDL. The effect of biophenols alone was also tested. In both experimental procedures, these antioxidants had the following effects: 1). completely prevented the J774 A.1-mediated oxidation of LDL; 2). counteracted the time-dependent variations in intracellular redox balance, inhibiting the production of O(2)(.-) and H(2)O(2) and the decrease in glutathione (GSH) content; 3). restored glutathione reductase (GR) and peroxidase (GPx) activities; and 4). restored the mRNA expression of gamma-glutamylcisteine synthetase (gammaGCS), GR, and GPx to control values. More importantly, we observed significant overtranscription and increased activities of two antioxidative enzymes, GPx and GR, compared with controls when the biophenols were present in the medium for 2 h and then removed before LDL exposure, or when the cells were exposed to the antioxidants alone for up to 24 h. Our findings suggest that the activation of mRNA transcription of GSH-related enzymes represents an important mechanism in phenolic antioxidative action.
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PMID:Extra virgin olive oil biophenols inhibit cell-mediated oxidation of LDL by increasing the mRNA transcription of glutathione-related enzymes. 1505 26

Recent data indicate that the oxidative stress plays an important role in the pathogenesis of diabetes and its complications such as retinopathy, nephropathy and accelerated atherosclerosis. In diabetic retinopathy, it was demonstrated a selective loss of pericytes accompanied by capillary basement membrane thickening, increased permeability and neovascularization. This study was designed to investigate the role of diabetic conditions such as high glucose, AGE-Lysine, and angiotensin II in the modulation of antioxidant enzymes activities, glutathione level and reactive oxygen species (ROS) production in pericytes. The activity of antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) was measured spectrophotometrically. The production of ROS was detected by spectrofluorimetry and fluorescence microscopy after loading the cells with 2'-7' dichlorofluoresceine diacetate; as positive control H2O2 was used. Intracellular calcium was determined using Fura 2 AM assay. The results showed that the cells cultured in high glucose alone, do not exhibit major changes in the antioxidant enzyme activities. The presence of AGE-Lys or Ang II induced the increase of SOD activity. Their combination decreased significantly GPx activity and GSH level. A three times increase in ROS production and a significant impairment of intracellular calcium homeostasis was detected in cells cultured in the presence of the three pro-diabetic agents used. In conclusion, our data indicate that diabetic conditions induce in pericytes: (i) an increase of ROS and SOD activity, (ii) a decrease in GPx activity and GSH level, (iii) a major perturbation of the intracellular calcium homeostasis. The data may explain the structural and functional abnormalities of pericytes characteristic for diabetic retinopathy.
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PMID:Changes in oxidative balance in rat pericytes exposed to diabetic conditions. 1509 Feb 67

Imbalance between production and scavenging of superoxide anion results in hypertension by the inactivation of nitric oxide, and the increased oxidative stress from the resultant peroxynitrite that is produced promotes inflammatory processes such as atherosclerosis. Induction of phase 2 proteins promotes oxidant scavenging. We hypothesized that intake of dietary phase 2 protein inducers would ameliorate both hypertension and atherosclerotic changes in the spontaneously hypertensive stroke-prone rat. For 5 days/week for 14 weeks, we fed rats 200 mg/day of dried broccoli sprouts that contained glucoraphanin, which is metabolized into the phase 2 protein-inducer sulforaphane (Group A), sprouts in which most of the glucoraphanin was destroyed (Group B), or no sprouts (Group C). After 14 weeks of treatment, no significant differences were seen between rats in Groups B and C. Rats in Group A had significantly decreased oxidative stress in cardiovascular and kidney tissues, as shown by increased glutathione (GSH) content and decreased oxidized GSH, decreased protein nitrosylation, as well as increased GSH reductase and GSH peroxidase activities. Decreased oxidative stress correlated with better endothelial-dependent relaxation of the aorta and significantly lower (20 mm Hg) blood pressure. Tissues from Groups B and C had considerable numbers of infiltrating activated macrophages, indicative of inflammation, whereas animals in Group A had few detectable infiltrating macrophages. There is interest in dietary phase 2 protein inducers as means of reducing cancer incidence. We conclude that a diet containing phase 2 protein inducers also reduces the risk of developing cardiovascular problems of hypertension and atherosclerosis.
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PMID:Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system. 1510 25

Pistacia lentiscus var. Chia (Anacardiaceae) grows almost exclusively on Chios Island, Greece, and gives a resinous exudate resin used for culinary purposes by Mediterranean people. We investigated the molecular mechanisms through which total polar extract of the resin inhibits oxidized low-density lipoprotein (oxLDL) cytotoxic effect on peripheral blood mononuclear cell (PBMC). Cells exposed to oxLDL underwent apoptosis and necrosis, dependent on the duration of exposure. When culturing cells with oxLDL and the polar extract concurrently, we observed inhibition of both the phenomena. Because under oxidative stress the pro-oxidant systems outbalance the antioxidant, potentially producing oxidative damage and ultimately leading to cell death, we measured the levels of intracellular antioxidant glutathione (GSH). Additionally, we measured CD36 expression, a class B scavenger receptor, on CD14-positive cells, as CD36 has been identified as the oxLDL receptor in macrophages and may play a pivotal role in atherosclerotic foam cell formation. oxLDL decreased GSH levels and upregulated CD36 expression. P. lentiscus extract restored GSH levels and downregulated CD36 expression, even at the mRNA level. In order to find out the biologically drastic constituents of the resin's polar extract, fractions derived from RP-HPLC analysis were examined for their antioxidant effect on oxidatively stressed PBMC. The triterpenoid fraction revealed remarkable increase in intracellular GSH. We suggest GSH restoration and downregulation of CD36 mRNA expression as the pathways via which P. lentiscus triterpenes exert antioxidant/antiatherogenic effect. Additionally, our results provide strong evidence of the resin's antiatherogenic effect; therefore it is credited with beneficial health aspects.
Atherosclerosis 2004 Jun
PMID:Antiatherogenic effect of Pistacia lentiscus via GSH restoration and downregulation of CD36 mRNA expression. 1513 59

A strong association between elevated plasma low-density-lipoprotein (LDL) and the development of cardiovascular diseases (CVD) has been established. Oxidation of LDL (Ox-LDL) promotes vascular dysfunction, enhances the production and release of inflammatory mediators such as reactive oxygen species and contribute to the initiation and progression of atherosclerosis. In addition, Ox-LDL enhances the production and release of tumor necrosis factor (TNF-alpha), interleukin (IL)-6, arachidonic acid metabolites and nitric oxide (NO) that are responsible for various human pathologies including cancer. Organosulfur compounds (OSC) from alliaceae modulate the glutathione (GSH) redox cycle and inhibits NFkappa-B activation in human T cells. Furthermore, OSC bioactivities include antioxidant, antibacterial, anticarcinogenic, antiatherogenic, immunostimulatory, and liver protection potential.
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PMID:Organosulfur compounds from alliaceae in the prevention of human pathologies. 1516 29

Little is known about the vascular metabolic status of glutathione (GSH), which is crucial in cell antioxidant protection, in experimental conditions like high-fat diet-induced atherosclerosis. This issue was, therefore, investigated in two groups of seven rabbits fed a 0.5% cholesterol-, 5% lard- and 5% peanut oil-enriched diet for 18 and 80 days, which, respectively, raised the plasma values of total cholesterol by factors of about 12 and 37, and those of triglycerides by factors of 3 and 13; rabbits fed a standard diet for the same periods served as controls. Total GSH and the activities of the GSH level-maintaining enzymes glutathione reductase (GSSG-Red), gamma-glutamylcysteine synthetase (gamma-GCS) and gamma-glutamyl transpeptidase (gamma-GT) were specifically assessed in the aortic tissue, which was also assayed for fluorescent damage products of lipid peroxidation (FDPL). Sudan red staining of the aortic intima surface was also performed in two other groups of six controls and six fat-fed rabbits. After 18 days of fat feeding, a significant decrement of aortic GSSG-Red activity, associated with gamma-GCS activation, increased GSH levels and normal gamma-GT activity, was observed; FDPL were only moderately enhanced, and atherosclerotic lesions did not occur. After 80 days of atherogenic diet, aortic GSH content was significantly decreased in concomitance with a marked depression of gamma-GT activity, while GSSG-Red and gamma-GCS activities were not significantly changed with respect to 18 days of fat feeding; FDPL underwent further considerable augmentation, and extensive Sudan red-stained atherosclerotic lesions were evident. Thus, short-term fat feeding induces gamma-GCS-dependent GSH biosynthesis of the rabbit aorta; prolonged high-fat intake and hyperlipidemic burden result instead in vascular gamma-GT dysfunction with GSH depletion, eventually favoring oxidative atherogenic effects.
Atherosclerosis 2004 Mar
PMID:Aortic glutathione metabolic status: time-dependent alterations in fat-fed rabbits. 1517 20


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