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)

Monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, is thought to play a major role in atherosclerosis, but whether its atherogenic effects involve the direct modulation of vascular smooth muscle cell (SMC) functions remains unclear. This study examined the effects of MCP-1 on the migration of cultured A7r5 SMCs and the signaling pathways involved. Addition of recombinant MCP-1 stimulated SMC migration in modified Boyden chambers coated with type I collagen in a concentration-dependent manner, with 10(-9) M being maximally effective. Using untreated A7r5 cells, two MCP-1 receptors, CCR2 and CCR4, were detected and MCP-1 secretion was significantly increased by stimulation with platelet-derived growth factor. MCP-1-stimulated A7r5 migration was completely blocked by the NAD(P)H oxidase inhibitor, diphenylene iodonium (DPI), and dose-dependently inhibited by polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), suggesting a role for reactive oxygen species (ROS) in this process. During MCP-1 stimulation, ROS production increased rapidly, then gradually decayed over 60 min, and this effect was markedly decreased by pretreatment with DPI or PEG-SOD. Interestingly, U0126 and PD98059, which inhibit activation of extracellular signal-regulated kinases 1/2 (ERK 1/2), significantly inhibited MCP-1-activated ROS generation. Furthermore, transfection of an active mutant of MEK1 (ERK 1/2 kinase) markedly increased superoxide production in rat aortic smooth muscle cells, as detected by dihydroethydium staining, suggesting that ERK 1/2 activation stimulates ROS generation. ERK 1/2 activation was increased for at least 30 min in cells incubated with MCP-1, and this effect was abolished by U0126 or DPI pretreatment. These results demonstrate that MCP-1 is a chemoattractant for SMCs and that MCP-1-stimulated migration requires both ROS production and ERK 1/2 activation in a positive activation loop, which may contribute to the atherogenic effects of MCP-1.
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PMID:Reactive oxygen species and ERK 1/2 mediate monocyte chemotactic protein-1-stimulated smooth muscle cell migration. 1591 91

The mechanisms of neointimal formation in cuff-injury models are still uncertain. To examine whether extracellular superoxide dismutase (EC-SOD) can reduce neointimal formation in a cuff-injury model, adenoviruses expressing EC-SOD (AxCAEC-SOD) or Escherichia coli beta-galactosidase (AxCALacZ) was injected between the cuff and the adventitia of rat femoral arteries. As a result, EC-SOD protein was effectively produced in the adventitia, as assessed by immunohistochemical staining. In comparison with cuff-treated control arteries and AxCALacZ-transfected arteries, neointimal formation was significantly reduced in AxCAEC-SOD-transfected arteries. Furthermore, proliferating smooth muscle cells in neointima and media were reduced by EC-SOD treatment. Similarly, augmented iNOS expression, apoptosis and collagen content in the vascular wall were also reduced by EC-SOD treatment. Reactive oxygen species (ROS) generation in tissue was reduced by EC-SOD expression, as assessed by dihydroethidium staining and coelenterazine chemiluminescence. These results suggest that ROS, especially superoxide anions at an adventitia, are responsible for neointimal formation in a cuff-injury model.
Atherosclerosis 2005 Jul
PMID:Extracellular superoxide dismutase overexpression reduces cuff-induced arterial neointimal formation. 1593 54

Increased oxidative stress (SOX) has been reported in continuous ambulatory peritoneal dialysis (CAPD) patients, but its influence on beta-chemokine levels and progression of atherosclerosis remains unknown. We determined three distinct SOX markers: Cu/Zn superoxide dismutase (Cu/Zn SOD), total peroxide and autoantibodies against oxidized LDL (OxLDL-Ab); high sensitivity C-reactive protein (hs CRP); beta-chemokines: monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory proteins (CCL3 and CCL4) and regulated upon activation, normal T cell expressed and secreted (CCL5) and the intima-media thickness (IMT) values in CAPD patients both with and without cardiovascular disease (CVD) and healthy controls. CAPD patients both with and without CVD had significantly increased IMT (p<0.001 and <0.01), Cu/Zn SOD (both p<0.001) and CCL2 levels (p<0.001 and <0.01, respectively) as compared to controls. CCL4 (p<0.01) and hs CRP (p<0.05) were increased only in patients with CVD, whereas there were no differences in the total peroxide, OxLDL-Ab and CCL3 levels between patients and controls. CCL5 concentrations were significantly decreased in both patients subgroup (both p<0.001) versus controls. Multivariate analysis showed that age (p<0.001), male sex (p<0.01), CCL4 and CCL2 levels (both p<0.05) were the independent variables linked to IMT values. Our data suggest a possible role of enhanced beta-chemokine levels in the carotid atherosclerosis in patients treated with CAPD, in addition to age and male sex.
Atherosclerosis 2006 May
PMID:Carotid atherosclerosis is associated with enhanced beta-chemokine levels in patients on continuous ambulatory peritoneal dialysis. 1609 64

Since alterations of tryptophan metabolism have been reported in diabetes and atherosclerosis, it was thought of interest to investigate any role of cloricromene through the influence on the oxidative metabolism of the amino acid by using diabetic/hyperlipidemic rabbits. Male 4-month-old New Zealand white rabbits, fed a diet enriched with 1% cholesterol and 10% corn oil, were made diabetic with alloxan. During the hyperlipidemic diet, a group of rabbits was treated with cloricromene (10 mg/kg/day subcutaneously plus 1.5 mg/kg/day intravenously, for 5 weeks). The other group received saline. Normometabolic New Zealand rabbits fed standard diet, treated or not with cloricromene, were used as control. The specific activities of liver tryptophan 2,3-dioxygenase and small intestine indole 2,3-dioxygenase were not significantly changed by the drug treatment. Also the specific activities of other enzymes of the kynurenine pathway in the liver and kidneys, specifically kynurenine 3-monooxygenase, kynureninase and kynurenine-oxoglutarate transaminase, did not show any significant difference in both tissues between the two groups of rabbits. On the contrary, 3-hydroxyanthranilate 3,4-dioxygenase activity in the liver of diabetic/hyperlipidemic rabbits and control rabbits treated with cloricromene showed a slight increase in comparison with untreated animals. Conversely, the specific activity of the enzyme in kidneys was not affected by the drug treatment in diabetic/hyperlipidemic animals but was reduced in controls. Aminocarboxymuconate-semialdehyde decarboxylase specific activity remained unchanged in the liver following cloricromene treatment, instead the specific activity of the enzyme in the kidneys of the diabetic/hyperlipidemic rabbits was significantly increased by the drug, with a value more than double in comparison to untreated animals. The activity of the scavenger enzyme Cu/Zn superoxide dismutase (Cu/Zn SOD) in the small intestine was also determined and found significantly increased of about twice as much in the group of diabetic/hyperlipidemic rabbits treated with cloricromene. In conclusion, in diabetic/hyperlipidemic rabbits, cloricromene appeared to influence the enzymes involved in the last steps of tryptophan oxidative metabolism through the kynurenine pathway. This, together with the antioxidant action through the activation of Cu/Zn SOD, might deserve further investigation for evaluating any link between the observed experimental findings at the level of the kynurenine pathway and the clinical effect of the drug.
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PMID:Cloricromene effect on the enzyme activities of the tryptophan-nicotinic acid pathway in diabetic/hyperlipidemic rabbits. 1612 32

Cardiovascular diseases (CVD), being mostly a clinical manifestation of atherosclerosis, are the main cause of mortality in patients with chronic renal failure (CRF). It is now generally accepted that the first step in atherosclerosis is endothelial dysfunction. Recently, oxidative stress (SOX) has been implicated as an important etiologic factor in atherosclerosis and vascular dysfunction both in general and uremic populations. The aim of the present study was to establish the effect of two different method of dialysis therapy: hemodialysis (HD) and continuous peritoneal dialysis (CAPD) on the markers of SOX: lipid peroxides, Cu/Zn superoxide dismutase (Cu/Zn SOD) and autoantibodies against oxidized LDL (OxLDL-Ab), and endothelial injury: antigen of the von Willebrand factor (vWF : Ag), soluble thrombomodulin (TM) and tissue factor pathway inhibitor (TFPI) in 43 patients with CRF. Compared with the control subjects, patients with CRF showed a significant increase in plasma concentrations of Cu/Zn SOD, which was more elevated in HD than in CAPD group. The lipid peroxide levels were increased only in the post-HD samples, whereas OxLDL-Ab were more elevated in HD than in CAPD group. Markers of endothelial injury were significantly higher in dialyzed patients relative to controls, and were positively correlated themselves as well as with Cu/Zn SOD levels. The patients on HD and CAPD are exposed to increased SOX as well as to endothelial injury. The association between Cu/Zn SOD and the endothelial injury markers suggests the possible effect of oxidative stress on endothelial dysfunction in CRF patients.
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PMID:[Method of dialysis therapy and selected markers of oxidative stress and endothelial injury in patients with chronic renal failure]. 1613 May 97

Exclusively synthesized by normal neutrophil and monocyte precursor cells, myeloperoxidase (MPO) functions not only in host defense by mediating efficient microbial killing but also can contribute to progressive tissue damage in chronic inflammatory states such as atherosclerosis. The biosynthetic precursor, apoproMPO, is processed slowly in the ER, undergoing cotranslational N-glycosylation, transient interactions with the molecular chaperones calreticulin and calnexin, and heme incorporation to generate enzymatically active proMPO that is competent for export into the Golgi. After exiting the Golgi the propeptide is removed prior to final proteolytic processing in azurophil granules, resulting in formation of a symmetric MPO homodimer linked by a disulfide bond. Some proMPO escapes granule targeting and becomes constitutively secreted to the extracellular environment. Although the precise mechanism is unknown, the pro-segment is required for normal processing and targeting, as propeptide-deleted MPO precursor is either degraded or constitutively secreted. Characterizing the molecular consequences of naturally occurring mutations that cause inherited MPO deficiency provides unique insight into the structural determinants of MPO involved in biosynthesis, processing and targeting.
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PMID:Biosynthesis, processing, and sorting of human myeloperoxidase. 1618 32

Endothelial dysfunction is an early sign of atherosclerosis. Patients with risk factors for atherosclerosis (e.g., hypertension, hyperlipidemia and diabetes mellitus) often show endothelial dysfunction at early stages of atherosclerosis before cardiovascular complications develop. Clinical studies and basic researches are revealing that calcium antagonists not only protect the endothelium through their hypotensive action but also improve the endothelial function through the stimulation of NO production. Regarding the mechanism for this kind of action by nifedipine (a calcium antagonist), it seems likely that the drug stimulates SOD expression in endothelial cells through enhanced VEGF expression by vascular smooth muscle cells, and thus reduces oxidative stress, leading to increased NO production.
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PMID:[Calcium antagonists and endothelial function]. 1619 12

Epidemiological studies have shown that there is a positive correlation between the incidence of coronary heart disease (CHD) and the blood cholesterol level. To study the effect of plant derived triterpene, lupeol and its ester lupeol linoleate, on blood lipid status and oxidant stress in heart and hemolysate, male albino Wistar rats were fed high cholesterol diet (normal rat chow supplemented with 4% cholesterol and 1% cholic acid; HCD) for 30 days. A significant increase (p<0.05) in plasma total cholesterol (4.22 fold) and triglycerides (1.7 fold) was observed in HCD fed rats, along with elevated LDL (3.56 fold) and VLDL (1.99 fold) cholesterol and decreased HDL cholesterol (34.14%). Treatment with lupeol and its derivative normalized the lipid profile. The significant increase (p<0.05) in lipid peroxidation (LPO) was paralleled by significantly diminished (p<0.05) activities of antioxidant enzymes (SOD, CAT and GPx) and decreased (p<0.05) concentration of antioxidant molecules (GSH, Vit C and Vit E) in cardiac tissue and hemolysate of HCD fed rats. The oxidative tissue injury in hypercholesterolemic rats was substantiated by the increase in cardiac marker, serum CPK and the drop in its activity in the heart tissue. Lupeol and lupeol linoleate treatment decreased the LPO levels and increased enzymatic and nonenzymatic antioxidants. CPK activity in the treated group was comparable with that of the control. These observations highlight the beneficial effects of the triterpene, lupeol and its linoleate ester derivative, in ameliorating the lipidemic-oxidative abnormalities in the early stage of hypercholesterolemic atherosclerosis.
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PMID:Role of lupeol and lupeol linoleate on lipemic-oxidative stress in experimental hypercholesterolemia. 1621 77

In this study the effects of stable and intermittent high glucose concentrations on ICAM-1, VCAM-1 and E-selectin production, PKC activity and PKCbetaI, betaII and delta isoforms expression in cultured HUVEC have been examined. In stable high glucose ICAM-1, VCAM-1 and E-selectin concentration and mRNA expression increased, and this effect was even more evident in intermittent high glucose. PKC activity increased in fluctuating glucose compared to stable high glucose, due to an over-expression of betaI, betaII and delta isoforms. ICAM-1, VCAM-1 and E-selectin, after the adding of total PKC inhibitor bisindolylmaleimide-I (BIMI-I) and LY379196, a specific inhibitor of PKCbeta, were equally reduced. 8-Hydroxydeoxyguanosine (8-OHdG), a sensitive indicator of oxidative damage to DNA, increased in stable and even more in intermittent high glucose and was reduced by both BIMI-I and LY379196. However, when thenoyltrifluoroacetone (TTFA), an inhibitor of mitochondrial complex II and the SOD mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP) were added, all adhesion molecules, any PKC isoforms expression and 8-hydroxydeoxyguanosine were normalized in both constant and oscillating glucose. In conclusion intermittent high glucose induces a greater expression of the adhesion molecules than stable high glucose; this effect seems to be related to an activation of PKCbeta, but completely dependent from mitochondrial free radicals over-production.
Atherosclerosis 2005 Dec
PMID:Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production. 1628 92

Matrix metalloproteinases (MMPs)/their inhibitors (TIMPs) system and elevated oxidative stress (SOX) have been implicated as important factors in atherosclerosis and vascular remodeling. The aim of the present study was to investigate whether MMPs/TIMPs system is associated with SOX in hemodialyzed (HD) patients. We compared the serum levels of metalloproteinases and their inhibitors, markers of SOX, inflammation and atherosclerosis between HD patients (n=40) with and without cardiovascular disease (CVD) and controls (n=20). Cu/Zn superoxide dismutase (Cu/Zn SOD) were elevated (all p<0.001), whereas total lipid peroxide levels were similar in HD patients and controls. The autoantibodies against oxidized LDL (OxLDL-Ab) levels were increased only in patients with CVD (p<0.05). Intima media thickness (IMT) in both CVD and in patients without CVD significantly exceeded those in the control (p<0.001 and p<0.01, respectively). Serum pre-HD values of MMP-2, TIMP-1 and TIMP-2 were significantly increased in HD patients, especially in the CVD group (all p<0.001), and they were associated with those of Cu/Zn SOD, IMT and CVD prevalence. Multiple regression analysis showed that MMP-2, Cu/Zn SOD levels and age independently and significantly predicted elevated IMT in HD patients. Our results suggest the association between SOX and the MMPs/TIMPs system in HD patients, which could represent one of the mechanisms involved in the progression of atherosclerosis in this population.
Atherosclerosis 2007 Jan
PMID:Serum matrix metalloproteinase-2 and increased oxidative stress are associated with carotid atherosclerosis in hemodialyzed patients. 1651 Jan 49


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