UMLS:C0042373 - FACTA Search

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Traditional risk factors for coronary artery disease (CAD) can only explain approximately two thirds of the observed clinical events. This has maintained interest in other nutritional and biochemical factors that might contribute to the underlying pathophysiology of vascular disease. Two such factors are dietary antioxidants and plasma homocysteine. Established risk factors such as hypertension, smoking and diabetes mellitus are all associated with increased oxidative stresses due to excess free radical activity in the vascular wall. This may facilitate the development of vascular disease because of (i) increased oxidation of low-density lipoprotein (LDL) particles which increases their propensity to deposition in the vascular wall, (ii) inactivation of endothelium-derived nitric oxide, and (iii) direct cytotoxicity to endothelial cells. Protective antioxidant molecules include vitamin C and vitamin E of which the latter is lipid soluble and is the primary antioxidant defence in circulating LDL particles. Epidemiological studies have suggested strongly that individuals who have high circulating concentrations or dietary intake of natural antioxidant vitamins are protected against vascular disease events (18). Furthermore, many studies have demonstrated a beneficial effect of natural and synthetic antioxidants on surrogate markers of vascular disease such as endothelial function and lipoprotein oxidation. However, large prospective randomized controlled intervention trials, mostly involving vitamin E (e.g. CHAOS, HOPE (22)), have failed to demonstrate any beneficial effect upon vascular mortality in high risk individuals. Possible reasons for these disappointing results include the pro-oxidant effects of high dose antioxidant supplements, particularly in patients with established vascular disease. Homocysteine is a sulphydryl-containing amino acid derived from the demethylation of dietary methionine. Epidemiological studies over 30 years have shown that increased concentrations of homocysteine are associated with vascular disease. This link is independent of other risk factors, is consistent across many studies and is strongly dose-related. Recently, evidence has accumulated to suggest that this link is also biologically plausible because homocysteine promotes oxidant injury to the vascular endothelium, impairs endothelium-dependent vasomotor regulation and may also alter the coagulant properties of the blood. Plasma homocysteine levels can be reduced by dietary supplements of folic acid and B vitamins. Studies are currently being undertaken to examine the impact of these vitamins in high risk patients and, thereby, establish a causative role for homocysteine in promoting vascular events.
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PMID:Coronary artery disease--free radical damage, antioxidant protection and the role of homocysteine. 1119 56

Experimental and epidemiological evidence suggests that activation of the reninangiotensin-aldosterone system and oxidative modification of low density lipoprotein cholesterol both play important roles in atherosclerosis. A substudy of the HOPE (Heart Outcomes Prevention Evaluation) trial, the SECURE trial (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E), evaluated the effects of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor, ramipril, and with vitamin E on atherosclerosis progression in high risk patients. A total of 732 patients were enrolled into the study. These patients were 55 years or older, had vascular disease or diabetes with at least one other cardiovascular risk factor, but did not have heart failure or low ejection fraction. Patients were randomly assigned according to a three-by-two factorial design to receive placebo, ramipril 2.5 mg/day or ramipril 10 mg/day and placebo or vitamin E 400 IU/day. Progression of atherosclerosis was evaluated by B-mode carotid ultrasonography. The primary outcome evaluated was the annualised progression slope of the mean maximum carotid intimal-medial thickness (IMT) across 12 pre-selected carotid arterial segments. The average follow-up was 4.5 years. The progression slope of the mean maximum IMT was 0.0217 +/- 0.04 mm/year in the placebo group, 0.018 +/- 0.44 mm/year in the ramipril 2.5 mg/day group and 0.0137 +/- 0.04 in the ramipril 10 mg/day group (P = 0.33 for the overall effect of ramipril and P = 0.028 for the comparison between patients receiving ramipril placebo and ramipril 10 mg/day). The reduction in atherosclerotic progression observed with ramipril remained significant after adjusting for systolic and diastolic blood pressure changes (P = 0.043) and after multivariate adjustment (P = 0.046). Administration of vitamin E 400 IU/day had no impact on atherosclerosis progression. The SECURE study is the first demonstration, in human subjects, of an effect of ACE inhibition on atherosclerotic progression. This benefit cannot be explained by the lowering of blood pressure alone. Vitamin E 400 IU/day had a neutral effect on the ultrasound measurements of atherosclerosis progression in the SECURE trial.
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PMID:Modifying the natural history of atherosclerosis: the SECURE trial. 1171 53

The Heart Protection Study (HPS), with over 20,500 subjects, is the largest trial of statin therapy ever conducted. It provides important and definitive new information on women, the elderly, diabetics, and people with low baseline cholesterol pre-treatment and those with prior occlusive non-coronary vascular disease. It is a prospective double blind randomised controlled trial with a 2 x 2 factorial design investigating prolonged use (>5 years) of simvastatin 40 mg and a cocktail of antioxidant vitamins (650 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene). The HPS specifically included patients with high risk for coronary heart disease (CHD) but characteristics that excluded them from participation in previous statin trials. Simvastatin 40 mg treatment showed benefit across all patient groups regardless of age, gender or baseline cholesterol value and proved safe and well tolerated. Results show a 12% reduction in total mortality, a 17% reduction in vascular mortality, a 24% reduction in CHD events, a 27% reduction in all strokes and a 16% reduction in non-coronary revascularisations. Among high-risk patients in this western population (with a minimum total cholesterol [TC] > or = 3.5 mmol/l at entry) there appears to be no threshold cholesterol value below which statin therapy is not associated with benefit; even among those with pre-treatment cholesterol levels below current national recommended targets. Over the 5.5 year study period patients and their doctors were encouraged to add an active non-study statin to the study regimen if they wished to do so. Thus the trial eventually had only two-thirds complying with the original intention-to-treat design. Nevertheless, results were highly significant for the study statin--simvastatin 40 mg once daily. Preliminary results of the HPS are negative for the antioxidant vitamin cocktail but provide reassurance that vitamins do no harm.
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PMID:The MRC/BHF Heart Protection Study: preliminary results. 1183 37

Although hyperhomocysteinemia has been recognized as an independent risk factor for atherosclerosis, its mechanism(s) are not well understood. Because chemotaxis and accumulation of leukocytes such as monocytes and T cells have been demonstrated to be critical events in the initiation and development of atherosclerosis, we investigated the effect of homocysteine (HCY) on U937 monocytic cells- and Jurkat T-cell-human aortic endothelial cell (HAEC) interactions under inflammatory cytokine-stimulated conditions. When HAEC were pretreated with HCY followed by stimulation with IL-1 beta, U937 and Jurkat T-cell adhesion to HAEC increased in a dose-dependent manner. The significant increase in U937 cell adhesion to HAEC was also observed when U937 cells were treated with HCY or when both cell types were treated with HCY. We also demonstrated that HCY increases endothelial surface expression and mRNA level of adhesion molecules, VCAM-1 and E-selectin. Attenuation of Jurkat T-cell and U937 cell adhesion to HAEC by monoclonal antibodies directed to specific adhesion molecules demonstrated that both VCAM-1 and E-selectin are involved in Jurkat T-cell adhesion, and VCAM-1 in U937 cell adhesion. Supplementation of HAEC with vitamin E was effective in preventing HCY-stimulated Jurkat T-cell adhesion and VCAM-1 and E-selectin expression in HAEC. These results indicate that HCY-mediated leukocyte-endothelial cell interaction is one potential mechanism by which homocysteinemia may lead to the development of atherosclerosis under inflammatory conditions. Dietary antioxidants such as vitamin E may attenuate HCY-stimulated activation of the endothelium and may help reduce the risk of vascular disease associated with hyperhomocysteinemia.
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PMID:Homocysteine increases monocyte and T-cell adhesion to human aortic endothelial cells. 1188 19

Advanced glycation end products (AGEs) are believed to play an important role in the development of angiopathy in diabetes mellitus. Previous reports suggested a correlation between accumulation of AGEs and production of vascular endothelial growth factor (VEGF) in human diabetic retina. However, the mechanisms involved were not revealed. In this study, we investigated the transcriptional regulation of the expression of vascular endothelial growth factor (VEGF) by AGEs, and possible involvement of reactive oxygen species (ROS) in the induction. We employed an AGE of bovine serum albumin (BSA) prepared by an incubation of BSA with D-glucose for 40 weeks and N(epsilon)-(carboxymethyl)lysine (CML), a major AGE. The expression of VEGF was induced by CML-BSA in RAW264.7 mouse macrophage-like cells. CML-BSA stimulated the DNA-binding activity of activator protein-1 (AP-1). Promoter assay showed that the induction of VEGF was dependent on AP-1. The activity of Ras/Raf-1/MEK/ERK1/2 was involved in the CML-BSA-stimulated signaling pathways to activate the AP-1 transcription with a peak at 1 h. AGE-BSA also induced VEGF mediated by AP-1, however, there was a difference of effect between AGE-BSA and CML-BSA in the activation of AP-1. AGE-BSA-stimulated AP-1 activity showed a peak at 5 h, which paralleled the formation of ROS. Reduction of AGE-BSA with NaBH(4) or addition of vitamin E attenuated the AGE-BSA-stimulated signaling pathways leading to the same pattern as for CML-BSA-stimulated signals. These results suggest an important role for AGEs in stimulation of the development of angiogenesis observed in diabetic complications, and that ROS accelerates the AGE-stimulated VEGF expression.
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PMID:Reactive oxygen species accelerate production of vascular endothelial growth factor by advanced glycation end products in RAW264.7 mouse macrophages. 1193 95

Amyloid beta-peptide (Abeta) fibril deposition on cerebral vessels produces cerebral amyloid angiopathy that appears in the majority of Alzheimer's disease patients. An early onset of a cerebral amyloid angiopathy variant called hereditary cerebral hemorrhage with amyloidosis of the Dutch type is caused by a point mutation in Abeta yielding Abeta(Glu22-->Gln). The present study addresses the effect of amyloid fibrils from both wild-type and mutated Abeta on vascular cells, as well as the putative protective role of antioxidants on amyloid angiopathy. For this purpose, we studied the cytotoxicity induced by Abeta(1-40 Glu22-->Gln) and Abeta(1-40 wild-type) fibrils on human venule endothelial cells and rat aorta smooth muscle cells. We observed that Abeta(Glu22-->Gln) fibrils are more toxic for vascular cells than the wild-type fibrils. We also evaluated the cytotoxicity of Abeta fibrils bound with acetylcholinesterase (AChE), a common component of amyloid deposits. Abeta(1-40 wild-type)-AChE fibrillar complexes, similar to neuronal cells, resulted in an increased toxicity on vascular cells. Previous reports showing that antioxidants are able to reduce the toxicity of Abeta fibrils on neuronal cells prompted us to test the effect of vitamin E, vitamin C, and 17beta-estradiol on vascular damage induced by Abeta(wild-type) and Abeta(Glu22-->Gln). Our data indicate that vitamin E attenuated significantly the Abeta-mediated cytotoxicity on vascular cells, although 17beta-estradiol and vitamin C failed to inhibit the cytotoxicity induced by Abeta fibrils.
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PMID:Vitamin E but not 17beta-estradiol protects against vascular toxicity induced by beta-amyloid wild type and the Dutch amyloid variant. 1194 11

The Heart Outcomes Prevention Evaluation (HOPE) study was designed to test the hypotheses that two preventive intervention strategies, namely angiotensin-converting enzyme (ACE) inhibition or vitamin E, would improve morbidity and mortality in patients at high risk of cardiovascular events compared with placebo. This review addresses the ACE inhibitor (ACE-I) (ramipril) arm of the study, both on the trial population as a whole, and on the large diabetic subgroup. Patients were included in the study who were considered to be at high risk of future fatal or non-fatal cardiovascular events, by virtue of their age (>55 years), existing or previous cardiovascular disease, or diabetes. Diabetics had at least one other risk factor, either known vascular disease or other factors such as cigarette smoking, high cholesterol or hypertension. Ramipril or placebo was added to concomitant medication, which included, in a substantial proportion of patients, antihypertensive drugs (excluding ACE-I), lipid-lowering agents or aspirin. As a result, despite a history of hypertension in nearly 50% of patients, blood pressure (BP) at baseline was normal and the reduction in BP attributable to ramipril modest (a fall of 3-4 mmHg systolic BP and 1-2 mmHg diastolic). The trial was stopped early on the advice of the Data Monitoring Committee because of convincing evidence of the benefit of ramipril treatment on the combined primary endpoint of cardiovascular death, non-fatal myocardial infarct (MI) and non-fatal stroke (14% vs. 17.8% on ramipril and placebo, respectively; relative risk reduction 22%, p<0.001). This comprised a risk reduction of 32% for stroke, 20% for MI, 26% for cardiovascular death and 16% for all-cause mortality, as well as a reduction in the risk of several other endpoints including heart failure and revascularisation procedures. The results among the 3577 diabetic subjects were even more striking, with a reduction of 25% in the combined primary endpoint. This reduction in the combined endpoint and in particular the reduction in MI far exceeded that which would be expected from the modest fall in BP. Furthermore, a multiple regression analysis of the diabetic subgroup showed similar relative risk reductions even after allowing for the effects of the fall in BP. Possible explanations for the non BP-mediated benefits of ramipril include reduction of angiotensin II-induced intimal and vascular smooth muscle proliferation and possible plaque stabilisation. The HOPE study results show that it is both safe and beneficial to lower BP that is already within the 'normal' range, particularly in patients with known vascular risk factors. This should greatly extend the use of ACE-I to a wider group of patients - not only those with left ventricular dysfunction, hypertension or diabetic microalbuminuria, but to the sort of high-risk patients who are currently given prophylactic treatment with aspirin.
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PMID:The HOPE Study (Heart Outcomes Prevention Evaluation). 1196 89

Humic acid (HA) has been implicated as an etiologic factor in the vasculopathy of Blackfoot disease. In this study, the ability of HA to induce apoptosis was studied in cultured human umbilical vein endothelial cells. Treatment of endothelial cells with a variety of concentrations of HA (50-200 microg/ml) resulted in dose- and time-dependent sequences of events marked by apoptosis as shown by loss of cell viability, chromatin condensation, and internucleosomal DNA fragmentation. Antioxidants (superoxide dismutase, vitamin C, and vitamin E) and Ca(2+) chelator (BAPTA) effectively suppressed HA-induced DNA fragmentation (apoptosis). Further studies have shown that HA induced dramatic Ca(2+)-dependent caspase activation (2, 3, 6, 8, and 9). In contrast, negligible caspase-1 activation was observed. The increase in HA-induced apoptosis correlated with a reduction in Bcl-2, a potent cell death inhibitor, and an increase in Bax protein levels, which heterodimerizes with and thereby inhibits Bcl-2. Both of the antioxidants vitamin C and vitamin E prevented the dysregulation of Bcl-2 and Bax in HA-treated endothelial cells. Furthermore, the increase in p53 protein levels correlated with an increase in HA-induced apoptosis. We concluded that both Ca(2+) and oxidative stress were mediators of apoptosis caused by HA and the induction of apoptotic cell death on endothelial cells may be important to the etiology of HA-induced vascular disorder of Blackfoot disease.
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PMID:Humic acid induces apoptosis in human endothelial cells. 1212 61

Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of cultured human brain pericytes. In this study, we aimed to identify inhibitors of A beta-induced toxicity in human brain pericytes. The toxic effect of HCHWA-D A beta(1-40) on human brain pericytes was inhibited by co-incubation with catalase, but not with superoxide dismutase, glutathione or vitamin E analogue Trolox. Catalase interacts with A beta, both in cell cultures and in cell-free assays, and has a prominent effect on the amount and conformational state of A beta binding to the cell surface of human brain pericytes. This activity of catalase is likely based on its ability to bind and slowly degrade A beta and not by its usual capacity to convert hydrogen peroxide. Our data confirm that assembly of A beta at the cell surface of human brain pericytes is a crucial step in A beta-induced cellular degeneration of human brain pericytes. Inhibition of fibril formation at the cell surface could be an important factor in therapy aimed at reducing cerebral amyloid angiopathy.
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PMID:Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro. 1236 10

Oxidative modifications of low-density lipoprotein (LDL) have been proposed to play a critical role in atherogenesis. To test the role of proposed antioxidants in inhibiting LDL oxidation and vascular disease, it is important to identify the biologically relevant sources of oxidative stress in the human arterial wall. Mass spectrometric (MS) quantification of oxidized amino acids in proteins was used as a "molecular fingerprint" to identify the pathways that inflict oxidative damage in vivo. For example, myeloperoxidase is expressed in macrophages in human atherosclerotic lesions, and immunohistochemical studies suggest that it might be a pathway for LDL oxidation. We found that hypochlorous acid, tyrosyl radical, and reactive nitrogen species generated by myeloperoxidase each yielded a unique pattern of protein oxidation products in vitro. MS analysis of human atherosclerotic tissue revealed a similar pattern of oxidation products. This strategy has pinpointed myeloperoxidase as a pathway that promotes LDL oxidation in the human artery wall. It is noteworthy that vitamin E fails to inhibit LDL oxidation by myeloperoxidase in vitro. Because the utility of an antioxidant depends critically on the nature of the oxidant that inflicts tissue damage, interventions that specifically inhibit physiologically relevant pathways would be logical candidates for clinical trials of antioxidants. Such a rational approach to therapy is likely to accelerate progress against oxidative stress and coronary artery disease.
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PMID:Oxidative stress: new approaches to diagnosis and prognosis in atherosclerosis. 1264 39

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