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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oxidation of low density lipoprotein (LDL) is a key event in the development and progression of atherosclerosis because it generates molecular epitopes that are more atherogenic than parent LDL. We found previously that patients with carotid atherosclerosis have a significantly higher titer of autoantibodies against oxidatively modified LDL than normal subjects. The aim of this study is to correlate biological markers of in vivo LDL oxidation with the degree of carotid stenosis and of plaque ulceration (PU) in a series of patients undergoing carotid endoarteriectomy (CEA). Ninety-four consecutive patients (68M and 26F, aged 67.3 +/- 8.2 years) who underwent CEA at our institution between June 1993 and January 1994 were included in the study. The degree of carotid stenosis and the presence and extent of PU were correlated with the level of autoantibodies (IgG) against oxidatively modified LDL (Cu++-oxidized [oxLDL] or malondialdehyde derivatized LDL [MDA-LDL]), that consistently mirrors the occurrence of oxidative modifications in vivo. A statistically significant correlation (r = 0.23, p = 0.039) was found between the degree of carotid stenosis and antiMDA-LDL specific ratio (a parameter that describes the specificity of LDL towards other proteins as target for oxidative modification). A statistically significant correlation was also found between the PU score and antioxLDL IgG (r = 0.32, p = 0.011), antiMDA-LDL IgG (r = 0.25, p = 0.045) and antiMDA-LDL IgG specific ratio (r = 0.38, p = 0.002). None of the classical biochemical parameters (total, LDL and HDL cholesterol and triglycerides) correlated with the above-mentioned plaque characteristics. The results shown, support the use of biological markers of in vivo LDL oxidation (antioxidatively modified LDL autoantibody titers) to evaluate the clinical setting of high-risk carotid atherosclerosis both in screening and in follow-up studies.
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PMID:In search of biological markers of high-risk carotid artery atherosclerotic plaque: enhanced LDL oxidation. 945 89

Oxidative modifications of low-density lipoproteins (LDL) ("oxidation hypothesis") appears to be the pathophysiologic mechanism implicated in early atherogenesis. Oxidized LDL (ox-LDL) may also induce several pro-atherogenic mechanisms, such as the regulation of vascular tone, by interfering with nitric oxide, the stimulation of cytokines and chemotactic factors (MCP-1, M-CSF, VCAM-1, etc.) and transcription factors (AP1 and NFk beta). These phenomena complicate the spectrum of direct and indirect actions of ox-LDL. The immunogenicity of ox-LDL was used to generate monoclonal antibodies against many epitopes of ox-LDL, such as malondialdehyde-lysine (MDA-2) or 4-hydroxynonenal-lysine (NA59). These antibodies showed the occurrence of ox-LDL in vivo. Another issue is the role of the humoral and cellular immune system in atherogenesis, in particular whether the immune response to ox-LDL enhances or reduces early atherogenesis. Moreover, the induction of autoantibodies against ox-LDL and the recognition by "natural" antibodies, and the use of the those antigens to screen human sera may serve as a marker of atherosclerosis. In this review, we have stressed the importance of methodologic approach in the assessment of LDL-oxidation and the fact that lipoprotein (a) may also undergo oxidative modifications. Several clinical conditions are associated with increased rate of LDL-oxidation. Recently, we have observed the presence of LDL oxidation-specific epitopes in human fetal aortas. Antioxidants studies in primary prevention of atherosclerosis have produced contradictory results. This may be explained in part by the selection of patients who had advanced lesions and were often smokers. New trails suggest that antioxidants be administered early in children. Lastly, antioxidant studies in the secondary prevention of coronary heart disease (CHAOS, WACS, and HOPE) show clear evidence of the benefits of antioxidants in reducing new cardiovascular events.
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PMID:Low density lipoprotein oxidation and atherogenesis: from experimental models to clinical studies. 947 66

There exists much evidence suggesting a major role for the oxidized low density lipoprotein (LDL) and VLDL particles in the pathogenesis of atherosclerosis. Although obesity is characterized by dyslipidemia, less is known about the oxidation capacity of lipoproteins in obese subjects. We measured the oxidizability in vitro in 21 premenopausal women with a BMI of 36.7+/-5.4 and compared them to 18 age-matched controls (BMI 21.9+/-1.8). The oxidizability of the non-HDL fraction is evaluated by measuring the fluorescence and thiobarbituric acid reactive substances (TBARS; MDA nM/mg non-HDL) at different time intervals of incubation. TBARS formation increased linearly with the increase of lipids both in non-obese and obese subjects. TBARS, measured every 30 min, increased in non-obese controls up to a maximum of 59.6 at 180' in contrast to a maximum of 77.1 at 180' (P < 0.001) in obese, but healthy, normocholesterolemic subjects. At each measurement the TBARS were significantly higher (P < 0.01-0.001) in obese subjects. Also the lag-time (period from zero to the start of the particle oxidation process) was significantly lower (92.5 vs. 123.4; P < 0.001) in obese subjects, when compared to lean controls. BMI correlates significantly with TBARS formation and its log transformed values (maximum P < 0.001). The lag-time was negatively related (n=39 total group, r=- 0.57, P < 0.001) to body weight and BMI. A significant relationship exists between TBARS formation (up to r=0.59) and triglyceride levels and a negative relationship exists with HDL-cholesterol levels. In vitro oxidizability of non-HDL lipoproteins is significantly increased in obese, non-diabetic subjects and related to increased body weight and triglyceride levels. Further studies are necessary to explore the underlying mechanisms for this phenomenon.
Atherosclerosis 1998 Apr
PMID:The in vitro oxidizability of lipoprotein particles in obese and non-obese subjects. 969 40

Body iron status has been implicated in atherosclerotic cardiovascular disease. The main hypothesis was that high iron status was associated with increased oxidation of LDL. The associations of serum ferritin (a marker of iron status) and dietary iron intake with the susceptibility of LDL to in vitro oxidation (lag phase) and autoantibodies against MDA-modified LDL (two markers of oxidation stress) were examined among 281 men and 192 women with a mean age of 59 years (S.D. = 5) who participated in the Atherosclerosis Risk in Communities (ARIC) Study visit 2 in 1990 through 1992. Lag phase duration and the autoantibodies against MDA-modified LDL were weakly correlated with each other (r = 0.19, P = 0.001 in men; r = 0.15, P = 0.03 in women). In linear regression analysis adjusting for age, field center, blood storage time, and carotid atherosclerosis case-control status, there was no association between ferritin level and the lag-phase, or between ferritin level and autoantibodies against MDA-modified LDL in either sex. Further adjustment for traditional cardiovascular risk factors (smoking, vitamin supplement use, body mass index, LDL cholesterol, hypertension and diabetes) did not alter these null results. Ferritin was significantly and positively correlated with body mass index in both sexes (r = 0.21 among men and r = 0.22 among women) and with the waist-to-hip ratio among women (r = 0.26). In addition, among women, ferritin was positively correlated with orosomucoid (r = 0.24) and with sialic acid (r = 0.19). Dietary iron was not associated with the parameters of LDL oxidation or with ferritin level. These findings do not support a role of body iron stores in promoting oxidation of LDL.
Atherosclerosis 1998 Jul
PMID:Lack of association between ferritin level and measures of LDL oxidation: the ARIC study. Atherosclerosis Risk in Communities. 969 7

Antibodies against oxidized low density lipoproteins (Ox-LDLs) have been proposed to be independent predictors of atherosclerosis development. The main aims of the current study were to (1) compare antibody titers to Ox-LDL in patients with heterozygous familial hypercholesterolemia (n=51) with those in matched controls (n=45) and (2) analyze whether the antibody titers were related to the extent of atherosclerosis, as assessed cross-sectionally and prospectively by ultrasonography in the 2 study groups. Antibody titers were determined with a solid-phase ELISA, and plates were coated with the antigens Ox-LDL or malondialdehyde-treated LDL (MDA-LDL) as well as with the postcoat only (5% dry milk powder). Antibody titers were expressed as absorbance [(value in patient serum minus that in postcoat) divided by (Internal Standard Serum minus postcoat)]. There were no significant differences in antibody titers against Ox-LDL or MDA-LDL between the group of patients with familial hypercholesterolemia and the controls. In cross-sectional comparisons, no significant associations were observed between the intima-media thickness of the carotid or femoral arteries and antibody titers against Ox-LDL or between plaque occurrence and these titers. Patients with a history of myocardial infarction had significantly lower IgM titers against Ox-LDL compared with patients without a history of myocardial infarction and with controls. In conclusion, mean values for antibody titers against Ox-LDL were not increased in the patient group compared with a healthy control group, and no positive, significant relationship was observed between antibody titers and the extent of atherosclerosis, as measured by ultrasound, in the carotid or femoral arteries. Taken together, these findings indicate that the relationship between the autoimmune response to Ox-LDL and the extent of atherosclerosis is more complex than previously anticipated.
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PMID:Antibody titers against oxidized LDL are not elevated in patients with familial hypercholesterolemia. 971 26

We and others previously showed that immunization of rabbits with different forms of oxidized low density lipoprotein (LDL) significantly reduced atherogenesis. We now investigated the effect of continued immunization on atherosclerosis in LDL receptor-deficient (LDLR-/-) mice to determine whether a similar reduction of atherosclerosis occurred in murine models and whether this was due to humoral immune responses, ie, formation of high titers of antibodies to oxidation-specific epitopes. Three groups of LDLR-/- mice were repeatedly immunized with homologous malondialdehyde-modified LDL (MDA-LDL), native LDL, or phosphate-buffered saline (PBS) for 7 weeks. Extensive hypercholesterolemia and accelerated atherogenesis were then induced by feeding a cholesterol-rich diet for 17 weeks, during which immunizations were continued. Binding of immunoglobulin (Ig) M and IgG antibodies, as well as IgG1 and IgG2a isotypes, to several epitopes of oxidized LDL were followed throughout the study. After 24 weeks of intervention, atherosclerosis in the aortic origin was significantly reduced by 46.3% and 36.9% in mice immunized with MDA-LDL and native LDL, respectively, compared with PBS (133 558 and 157 141 versus 248 867 microm2 per section, respectively). However, the humoral immune response to oxidative neoepitopes in the MDA-LDL group was very different from that of the LDL or PBS group. IgG antibody binding to MDA-LDL and other epitopes of oxidized LDL, such as oxidized phospholipid (cardiolipin), oxidized cholesterol, or oxidized cholesteryl linoleate, but not native LDL, increased markedly in mice immunized with MDA-LDL, but not in mice immunized with native LDL or PBS. In the MDA-LDL group, both T helper cell (Th)2-dependent IgG1 antibody and Th1-dependent IgG2a antibody binding to oxidative neoepitopes increased significantly over time. The fact that mice immunized with both MDA-LDL and native LDL had a significant reduction in atherosclerosis, whereas only the MDA-LDL group developed very high titers of antibodies to oxidation-specific epitopes, suggests that the antiatherogenic effect of immunization is not primarily dependent on very high titers of antibodies to oxidation-specific epitopes but is more likely to result from the activation of cellular immune responses.
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PMID:Immunization of LDL receptor-deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. 984 92

The anti-atherogenic and cholesterol-lowering drug probucol (0.5-1%) or quercetin (1%), a natural antioxidant, was given to cholesterol-fed (1.5%) mice for a period of 6 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for a period of 8 weeks to investigate the oxidative changes in plasma and lipoproteins. Oxidation was measured as the total amount of malondialdehyde (nmol MDA/g protein) by a very specific MDA-HPLC method. A large and significant increase in MDA was seen in LDL from probucol treated WHHL rabbits (1778.7+/-585.5 nmol/g vs. 394.4+/-144.5 nmol/g, P < 0.001) and cholesterol-fed mice (579.7 + 47.3 nmol/g vs. 408.1+/-85.8 nmol/g, P < 0.05) as compared to controls while LDL cholesterol was lowered (WHHL rabbits: P < 0.05; mice: P < 0.01). In WHHL rabbits VLDL oxidation was determined additionally, and also revealed a large increase in the probucol group (2102.7+/-1156.1 nmol/g vs. 455.0+/-207.8 nmol/g, P< 0.01). In contrast, the oxidation of plasma and HDL from probucol treated animals was not statistically significantly increased, implying that probucol mediates a selective oxidation of atherogenic cholesterol-transporting lipoproteins. Quercetin treated animals did not show increased oxidation of LDL (and VLDL in rabbits) and cholesterol levels were not decreased. Furthermore, no protective antioxidant effect of quercetin was seen. In conclusion, the results suggest that a prooxidant mechanism rather than antioxidative effects influences lipoprotein metabolism in these animals. It is hypothesized that the oxidation of lipoproteins might be a physiological mechanism performed by macrophages or other cells for uptake and degradation (by macrophages and liver) of excessive amounts of LDL or VLDL and that probucol oxidizes atherogenic lipoproteins and thereby leads to a decrease in cholesterol levels.
Atherosclerosis 1999 Jan
PMID:Probucol selectively increases oxidation of atherogenic lipoproteins in cholesterol-fed mice and in Watanabe heritable hyperlipidemic rabbits. 992 May 18

Recent study demonstrated high susceptibility of plasma LDL to lipid peroxidative modification in patients with variant angina. Oxidized stress state, especially oxidized LDL, may induce coronary artery spasm by its impairing effect of endothelium-dependent arterial relaxation, but precise mechanisms remain unclear. Study subjects included 93 patients who underwent coronary angiographic examination: 12 patients with coronary artery spasm provoked by ergonovine without organic stenosis (group I), 11 patients who did not demonstrate coronary artery spasm or organic stenosis (group II) and 70 patients with organic coronary artery stenosis (group III). Levels of plasma HDL-cholesterol and apoA-I in group I were similar to those in III but were significantly lower than those in II, although the other plasma lipid parameters were not different among the three groups. The levels of TBARS in plasma and HDL were significantly higher in group I than in II or III (2.94+/-1.56 vs. 1.91+/-0.35 or 2.23+/-0.89 nmol MDA/ml and 1.23+/-1.00 vs. 0.54+/-0.37 or 0.70+/-0.63 nmol MDA/mg protein; P < 0.05), although the levels of TBARS in LDL were not significantly different. In the monitoring curve of diene production during copper-induced lipid peroxidation of HDL, its propagation slope was steeper and levels of maximum diene absorbance was higher in group I as compared with that in II or III, but not found in those of LDL. These results suggested that high susceptibility of HDL to lipid peroxidative modification in group I may contribute to the genesis of coronary artery spasm, and oxidized HDL rather than oxidized LDL is more likely to be related to coronary artery spasm.
Atherosclerosis 1999 Jan
PMID:Possible role of high susceptibility of high-density lipoprotein to lipid peroxidative modification and oxidized high-density lipoprotein in genesis of coronary artery spasm. 992 May 19

The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Potent synthetic antioxidants are currently being tested, but they are not necessarily safe for human use. We here characterize the antioxidant activity of IRFI005, the active metabolite of Raxofelast (IRFI0016) that is a novel synthetic analog of vitamin E under clinical development, and demonstrate that it prevents oxidative modification of LDL. IFI005 inhibited the oxidative modification of LDL, measured through the generation of MDA, electrophoretic mobility and apo B100 fluorescence. During the oxidation process IRF1005 was consumed with the formation of the benzoquinone oxidation product. The powerful antioxidant activity of IRFI005 is at least in part mediated by a chain breaking mechanism as it is an efficient peroxyl radical scavenger with a rate constant k(IRFI005 + LOO(o)) of 1.8 X 10(6) M(-1)s(-1). 4. IRFI005 substantially preserved LDL-associated antioxidants, alpha-tocopherol and carotenoids, and when co-incubated with physiologic levels of ascorbate provoked a synergistic inhibition of LDL oxidation. Also the co-incubation of IRFI005 with Trolox caused a synergistic effect, and a lag phase in the formation of the trolox-benzoquinone oxidation product. A synergistic inhibition of lipid peroxidation was also demonstrated by co-incubating IRFI005 and alpha-tocopherol incorporated in linoleic acid micelles. These data strongly suggest that IRFI005 can operate by a recycling mechanism similar to the vitamin E/ascorbate sysem.
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PMID:Protection of low density lipoprotein oxidation by the antioxidant agent IRFI005, a new synthetic hydrophilic vitamin E analogue. 1023 29

The effect of oxidative modification of high-density lipoprotein (HDL) was assessed by incubation of normal HDL (obtained from Rhesus monkeys fed a stock diet) with 5 microM CuSO4 at 37 degrees C for 12 h/24 h. The physicochemical properties of oxidized-HDL (Ox-HDL) were found to be affected in terms of lipid peroxidation, as observed by the increased level of thiobarbituric acid reactive substances (nmol MDA/mg HDL protein). The biological properties of HDL were altered, since a decrease in the efflux of free cholesterol into the medium was found in the presence of Ox-HDL24h compared with normal HDL (N-HDL). The binding, uptake and degradation of 125I-LDL by macrophages increased in the presence of Ox-HDL24h. The activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione-peroxidase) was reduced in monocytes in the presence of Ox-HDL. However, in the presence of N-HDL, the levels of antioxidant enzymes were maintained at a higher level than in the control (in the absence of HDL) monocytes. Furthermore, the number of monocytes adhered to aortic endothelium were found to be increased in the presence of Ox-HDL. These findings suggest that HDL is susceptible to oxidative modification. Since the parameters selected in the present study are involved in the pathogenesis of atherosclerosis, it can be postulated that the in vivo protection of HDL in atherosclerosis can be reversed in the circumstances in which HDL undergoes oxidative modification like low-density lipoprotein (LDL).
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PMID:The role of oxidized HDL in monocyte/macrophage functions in the pathogenesis of atherosclerosis in Rhesus monkeys. 1040 Jan 66


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