UMLS:C0004153 - FACTA Search

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

Oxidation of low density lipoprotein (LDL) may be instrumental in the development of atherosclerosis. We have examined the effect of the angiotensin converting enzyme (ACE) inhibitors captopril and quinaprilat and the -SH containing compound N-acetylcysteine on LDL oxidation. Oxidation of isolated human LDL was initiated with CuCl2. Conjugated diene formation (monitored spectrophotometrically at 234 nm) gave a measure of LDL oxidation. Captopril inhibited LDL oxidation but quinaprilat did not. The lag phase to the rapid increase in absorbance at 234 nm determined was 109 (65-157) min median and range for control samples and rose to 209 (168-305) min with captopril 10 microM, a ratio of 2.1:1 for drug to control (P = 0.01). N-acetylcysteine had a similar effect to captopril (drug to control lag time ratio 2.0:1, with NAC 10 microM), i.e. suggesting resistance to oxidation was due to the -SH group of both drugs. Captopril may have a potentially anti-atherosclerotic property not shared by other ACE inhibitors.
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PMID:Effects of ACE inhibitors on oxidation of human low density lipoprotein. 814 19

Atherosclerotic lesions are found opposite vascular flow dividers at sites of low shear stress and oscillatory flow. Since endothelial proinflammatory genes prominent in lesions are regulated by oxidation-sensitive transcriptional control mechanisms, we examined the redox state of cultured human umbilical vein endothelial cells after either oscillatory or steady laminar fluid shear stress. Endothelial oxidative stress was assessed by measuring activity of the superoxide (O2.- )-producing NADH oxidase (a major source of reactive oxygen species in vascular cells), intracellular O2.- levels, induction of the redox-sensitive gene heme oxygenase-1 (HO-1), and abundance of Cu/Zn superoxide dismutase (Cu/Zn SOD), an antioxidant defense enzyme whose level of expression adapts to changes in oxidative stress. When cells were exposed to oscillatory shear (+/-5 dyne/cm2, 1 Hz) for 1, 5, and 24 hours, NADH oxidase activity and the amount of HO-1 progressively increased up to 174+/-16% (P<0.05) and 505+/-111% (P<0.05) versus static conditions, respectively, whereas levels of Cu/Zn SOD remained unchanged. This upregulation of HO-1 was completely blocked by the antioxidant N-acetylcysteine (NAC, 20 mmol/L). In contrast, steady laminar shear (5 dyne/cm2) induced NADH oxidase activity and NAC-sensitive HO-1 mRNA expression only at 1 and 5 hours, a transient response that returned toward baseline at 24 hours. Levels of Cu/Zn SOD mRNA and protein were increased after 24 hours of steady laminar shear. Furthermore, intracellular O2.-, as measured by dihydroethidium fluorescence, was higher in cells exposed to oscillatory than to laminar shear. These data are consistent with the hypothesis that continuous oscillatory shear causes a sustained activation of pro-oxidant processes resulting in redox-sensitive gene expression in human endothelial cells. Steady laminar shear stress initially activates these processes but appears to induce compensatory antioxidant defenses. We speculate that differences in endothelial redox state, orchestrated by different regimens of shear stress, may contribute to the focal nature of atherosclerosis.
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PMID:Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. 962 62

We investigated the ability of NAC to inhibit in vitro LDL oxidation, and the effects of the timing of NAC addition, repeated additions of NAC, and the presence of preoxidized LDL, on the oxidation reaction. NAC inhibited in vitro LDL oxidation induced by copper sulfate, 2,2'-azobis(2-amidinopropane) dihydrochloride, and UV light, and protected LDL against depletion of antioxidant vitamins. Glutathione was similarly effective against copper-mediated LDL oxidation. NAC's effectiveness was inversely related to the timing of its addition. Sequential NAC additions prolonged the lag phase more effectively than initial addition of the same total dose. NAC reduced CD formation during the oxidation of native LDL by oxidized LDL. NAC's effectiveness as an inhibitor of in vitro LDL oxidation is dependent on the temporal sequence of the oxidation reaction, sequential additions, and the presence of previously oxidized LDL.
Atherosclerosis 1998 Jun
PMID:Temporal and kinetic determinants of the inhibition of LDL oxidation by N-acetylcysteine (NAC). 969 Sep 15

Laminar shear stress activates NADPH oxidase in vascular endothelial cells (ECs), and the generated superoxide radicals (O2(-.) are known to be involved in intercellular adhesion molecule (ICAM)-1 expression. In this study, the role of a glycosphingolipid (GSL), lactosylceramide (LacCer), as a second messenger in the shear-induced O2(-.) generation and ICAM-1 expression was examined. It is known that glucosylceramide synthase (GlcT-1) catalyzes the synthesis of glucosylceramide (GlcCer) from ceramide, and subsequently lactosylceramide synthase (GalT-2) synthesizes LacCer from GlcCer. We observed that exposing cultured human umbilical vein ECs (HUVECs) to fluid shear stress (20 dyn/cm(2) for 30 min) activated GalT-2. Shear stress also increased EC O2(-.) generation, that peaked at 30 min, and surface ICAM-1 protein expression at 6 h post-shear. EC preincubation with the antioxidant N-acetylcysteine (NAC; 20 mM for 2 h) completely abolished the shear-induced O2(-.) production and significantly inhibited ICAM-1 expression. EC preincubation with D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of the GSL glycosyltransferases GlcT-1 and GalT-2, abrogated the shear-induced activation of GalT-2. D-PDMP also abolished the shear-induced O2(-.) production and ICAM-1 expression. We conclude that laminar shear stress activates GalT-2 to produce LacCer. In turn, LacCer activates NADPH oxidase, which produces O2(-.), and O2(-.) mediates the shear-induced increase in ICAM-1 expression. Thus, LacCer may play an important role in hemodynamic force-induced pathological conditions, such as atherosclerosis and ischemia/reperfusion injury.
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PMID:Lactosylceramide mediates shear-induced endothelial superoxide production and intercellular adhesion molecule-1 expression. 1174 Jan 54

We examined the mechanism of action of lysophosphatidylcholine (lyso-PC), which is suggested to be involved in the pathogenesis of atherosclerosis and inflamatory disorders, and its interaction with well-known vasoactive compounds such as hydrogen peroxide (H2O2), thromboxane A2 (TX-A2), serotonin (5-HT), angiotensin II (Ang-II), endothelin-1 (ET-1), or urotensin II (U-II) on VSMC proliferation. Growth-arrested rabbit VSMCs were incubated with given concentrations of lyso-PC with H202, TX-A2, 5-HT, Ang-II, ET-1, or U-II. [3H]Thymidine incorporation into DNA was measured as an index of VSMC proliferation. Lyso-PC induced a maximal effect on [3H]thymidine incorporation at a concentration of 15 microM (156%), and its effect was significantly inhibited by the phospholipase C inhibitor U73122 (10 microM), the intracellular antioxidant NAC (400 microM), and the NADPH oxidase inhibitor diphenylene iodonium (1 microM), but not by the MAPK kinase inhibitor (10 microM). H2O2, TX-A2, 5-HT, Ang-II, ET-1, or U-II also stimulated [3H]thymidine incorporation in a dose-dependent manner. A non-mitogenic concentration of lyso-PC (5 microM) significantly potentiated the effect of low concentrations of H2O2 (0.1 microM, 110 to 222%), TX-A2 (5 microM, 120 to 202%), 5-HT (5 microM, 182 to 259%), Ang-II (0.5 microM, 167 to 304%), ET-1 (0.01 microM, 139 to 297%), or U-II (0.025 microM, 120 to 332%) on [3H]thymidine incorporation. The results suggest that lyso-PC acts synergistically with the vasoactive compounds H2O2, TX-A2, 5-HT, Ang-II, ET-1, or U-II in inducing VSMC proliferation, which may play an important role in the progression of atherosclerosis.
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PMID:Lysophosphatidylcholine potentiates the mitogenic effect of various vasoactive compounds on rabbit aortic smooth muscle cells. 1222 16

Inflammatory processes in the arterial wall are important in atherogenesis. The present review discusses the development of DiNAC as a potential new treatment modality for atherosclerosis related diseases. DiNAC, N,N'-diacetyl-L-cystine, is the disulphide dimer of N-acetyl cysteine, NAC. It was selected as an immunomodulating drug candidate due to its ability to modify contact sensitivity/delayed type hypersensitivity (CS/DTH) reactions in vivo. Initial structure-activity relationship (SAR) studies indicated that an intact disulfide bridge was essential for this effect. Antioxidants, like probucol and some close analogs with two sulphurs in close proximity (but not disulphides), were also found to have similar effects on CS/DTH reactions. These antioxidants have antiatherosclerotic effects, while structurally related compounds without sulphurs do not. Therefore, it was hypothesized that DiNAC might also possess antiatherosclerotic effects. This was investigated in WHHL rabbits and mice. In both species, DiNAC had antiatherosclerotic activity similar to that of probucol. The effect of DiNAC was not due to an alteration of lipid metabolism. Impaired endothelium mediated relaxation is known to be associated with atherosclerosis. DiNAC was shown to reverse this process in WHHL rabbits with advanced atherosclerosis, probably due to an action on the vessel wall itself that is not related to the extent of atherosclerosis or to plasma lipid levels. Preliminary data from a clinical investigation in hypercholesterolemic subjects suggest that DiNAC is likely to have similar effects also in patients. Taken together, these findings suggest immunomodulation to be a potential new therapy for atherosclerosis related diseases. DiNAC may represent a new treatment modality for such diseases.
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PMID:The antiatherogenic effect of DiNAC: experimental findings supporting immunomodulation as a new treatment for atherosclerosis related diseases. 1284 63

Smooth muscle cell migration in response to platelet-derived growth factor (PDGF) is a key event in several vascular pathologies, including atherosclerosis and restenosis. PDGF increases intracellular levels of reactive oxygen species (ROS) in vascular smooth muscle cells (VSMCs), but the ROS sensitivity of migration and of the signaling pathways leading to migration are largely unknown. In VSMCs, PDGF dose-dependently increased migration compared with nonstimulated cells, with a maximum increase at 10 ng/mL. Pretreatment with the antioxidant N-acetyl-cysteine, the flavin-containing enzyme inhibitor diphenylene iodonium, or the glutathione peroxidase mimetic ebselen significantly attenuated migration (PDGF alone, 5.0+/-1.1-fold; NAC, 1.8+/-0.2-fold; diphenylene iodonium, 1.4+/-0.3-fold migration; and ebselen, 2.0+/-0.5-fold migration), as did overexpression of catalase. Pretreatment of VSMCs with the Src inhibitor PP1 or dominant-negative Rac adenovirus significantly inhibited migration, but only Src activation was attenuated by ROS inhibitors. Phosphorylation of the Src- and Rac-effector p21-activated protein kinase (PAK) 1 on Thr423 (the phosphoinositide-dependent kinase-1 [PDK1] site) was attenuated by ROS inhibition, and infection of VSMCs with dominant-negative PAK1 adenovirus attenuated migration. Moreover, kinase-inactive K111N-PDK1 inhibited PAK1 phosphorylation on Thr423, and both K111N-PDK1 and Y9F-PDK1 significantly inhibited VSMC migration. PDK1 tyrosine phosphorylation was also ROS dependent. These data indicate that PDGF-induced VSMC migration is ROS dependent and identify the Src/PDK1/PAK1 signaling pathway as an important ROS-sensitive mediator of migration. Such information is critical to understanding the role of ROS in vascular diseases in which migration of VSMCs is an important component.
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PMID:Phosphoinositide-dependent kinase 1 and p21-activated protein kinase mediate reactive oxygen species-dependent regulation of platelet-derived growth factor-induced smooth muscle cell migration. 1505 30

The class B scavenger receptor, CD36, binds to oxidized LDL (OxLDL), is present in atherosclerotic lesions, and is upregulated by OxLDL or AcLDL. Previously we have shown that RRR-alpha-tocopherol (AT) enrichment of human monocyte-derived macrophages inhibited OxLDL or AcLDL induced CD36 expression. The mechanism by which AT inhibited CD36 expression is not known. In the present study, we explored the mechanism by which AT decreases CD36 expression in human macrophages. Macrophages were enriched with AT (100 microM) or N-acetyl cysteine (NAC, 6 mM) overnight and then incubated with oxLDL or AcLDL for 48 h. The effect of protein kinase C inhibitors, and tyrosine kinase inhibitors on OxLDL or AcLDL-induced CD36 expression was quantitated by flow cytometry. Protein kinase C inhibitors or NAC had no effect while there was a significant inhibition with tyrosine kinase inhibitors (P < 0.01). OxLDL or AcLDL significantly increased tyrosine kinase activity which was significantly inhibited by pre-incubation with AT or with tyrosine kinase inhibitors. Western blotting revealed an increase in Tyk2 as well as phosphotyk2 with OxLDL or AcLDL. Immunoprecipitation of CD36 followed by Western blotting with Tyk2 antibodies revealed that Tyk2 was associated with CD36. In conclusion, this study demonstrates an additional direct cellular effect of AT, i.e. inhibition of CD36 expression via inhibition of tyrosine kinase (Tyk2).
Atherosclerosis 2004 Aug
PMID:RRR-alpha-tocopherol decreases the expression of the major scavenger receptor, CD36, in human macrophages via inhibition of tyrosine kinase (Tyk2). 1526 76

Thiazolidinediones (TZDs), which were known as novel insulin-sensitizing antidiabetic agents, have been reported to inhibit the acceleration of atherosclerotic lesions. Macrophages play important roles in the development of atherosclerosis. We previously reported that oxidized low-density lipoprotein (Ox-LDL) induces macrophage proliferation through ERK1/2-dependent GM-CSF production. In the present study, we investigated the effects of two TZDs, troglitazone and ciglitazone on Ox-LDL-induced macrophage proliferation. Troglitazone significantly inhibited Ox-LDL-induced increases in [(3)H]thymidine incorporation into and proliferation of mouse peritoneal macrophages, whereas ciglitazone had no effects. Troglitazone and ciglitazone both significantly induced PPARgamma activity, suggesting that the inhibitory effect of troglitazone was not mediated by PPARgamma. Ox-LDL-induced production of GM-CSF was significantly inhibited by troglitazone, but not by ciglitazone. Troglitazone inhibited Ox-LDL-induced production of intracellular reactive oxygen species, whereas ciglitazone had no effect. The antioxidant reagents NAC and NMPG each inhibited phosphorylation of ERK1/2, whereas troglitazone and ciglitazone had no effects. However, troglitazone, NAC and NMPG all inhibited nuclear translocation of ERK1/2. In conclusion, troglitazone inhibited Ox-LDL-induced GM-CSF production by suppressing nuclear translocation of ERK1/2, thereby inhibiting macrophage proliferation. This suppression of macrophage proliferation by troglitazone may, at least in part, explain its antiatherogenic effects.
Atherosclerosis 2007 Mar
PMID:Troglitazone inhibits oxidized low-density lipoprotein-induced macrophage proliferation: impact of the suppression of nuclear translocation of ERK1/2. 1672 45

Mercury, cadmium, and other heavy metals have a high affinity for sulfhydryl (-SH) groups, inactivating numerous enzymatic reactions, amino acids, and sulfur-containing antioxidants (NAC, ALA, GSH), with subsequent decreased oxidant defense and increased oxidative stress. Both bind to metallothionein and substitute for zinc, copper, and other trace metals reducing the effectiveness of metalloenzymes. Mercury induces mitochondrial dysfunction with reduction in ATP, depletion of glutathione, and increased lipid peroxidation; increased oxidative stress is common. Selenium antagonizes mercury toxicity. The overall vascular effects of mercury include oxidative stress, inflammation, thrombosis, vascular smooth muscle dysfunction, endothelial dysfunction, dyslipidemia, immune dysfunction, and mitochondrial dysfunction. The clinical consequences of mercury toxicity include hypertension, CHD, MI, increased carotid IMT and obstruction, CVA, generalized atherosclerosis, and renal dysfunction with proteinuria. Pathological, biochemical, and functional medicine correlations are significant and logical. Mercury diminishes the protective effect of fish and omega-3 fatty acids. Mercury, cadmium, and other heavy metals inactivate COMT, which increases serum and urinary epinephrine, norepinephrine, and dopamine. This effect will increase blood pressure and may be a clinical clue to heavy metal toxicity. Cadmium concentrates in the kidney, particularly inducing proteinuria and renal dysfunction; it is associated with hypertension, but less so with CHD. Renal cadmium reduces CYP4A11 and PPARs, which may be related to hypertension, sodium retention, glucose intolerance, dyslipidemia, and zinc deficiency. Dietary calcium may mitigate some of the toxicity of cadmium. Heavy metal toxicity, especially mercury and cadmium, should be evaluated in any patient with hypertension, CHD, or other vascular disease. Specific testing for acute and chronic toxicity and total body burden using hair, toenail, urine, serum, etc. with baseline and provoked evaluation should be done.
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PMID:The role of mercury and cadmium heavy metals in vascular disease, hypertension, coronary heart disease, and myocardial infarction. 1740 90

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