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)

Oxidation of low density lipoprotein (LDL) has been shown to occur in the artery wall of atherosclerotic lesions in both animal models and human arteries. The oxidant(s) responsible for initiating this process are under intensive investigation and 15-lipoxygenase has been suggested in this context. Another possibility is that nitric oxide and superoxide, generated by cells present in the artery wall, react together to form peroxynitrite which decomposes to form the highly reactive hydroxyl radical. In the present study we have modelled the simultaneous generation of superoxide and nitric oxide by using the sydnonimine, SIN-1 and have investigated its effects on LDL. SIN-1 liberates both superoxide and nitric oxide during autooxidation resulting in the formation of hydroxyl radicals. We have demonstrated that superoxide generated by SIN-1 is not available to take part in a dismutation reaction since it reacts preferentially with nitric oxide. It follows, therefore, that during the autooxidation of SIN-1 little or no superoxide, or perhydroxyl radical will be available to initiate lipid peroxidation. We have shown that SIN-1 is capable of initiating the peroxidation of LDL and also converts the lipoprotein to a more negatively charged form. The SIN-1-dependent peroxidation of LDL is completely inhibited by superoxide dismutase which scavenges superoxide. Neither sodium nitroprusside or S-nitroso-N-acetyl penicillamine, which only produce nitric oxide, are able to modify LDL. These results are consistent with the hypothesis that a product of superoxide and nitric oxide could oxidize lipoproteins in the artery wall and so contribute to the pathogenesis of atherosclerosis in vivo.
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PMID:The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. 133 19

In canine and porcine coronary arteries, experimental atherosclerosis (induced by endothelial denudation followed by a high-cholesterol diet) potentiates the vasoconstrictor effects of histamine, serotonin, and ergonovine. In isolated human atherosclerotic coronary arteries, only hypersensitivity to histamine has been demonstrated. This discrepancy could be due to several factors. First, the atherosclerotic lesions in human vessels are different from those observed in the animal, since experimental atherosclerosis often corresponds only to the early stage of the disease in humans. Second, the human atherosclerotic coronary arteries were isolated mainly from patients with cardiac failure, a condition that alters the responses of coronary smooth muscle to vasoactive amines. With regard to endothelium-dependent vasodilators, marked attenuations of the relaxations to substance P, bradykinin, and the Ca2+ ionophore A23187 have been described in isolated human atherosclerotic arteries. Acetylcholine elicits variable responses in these preparations and even if the arteries are devoid of atherosclerotic lesions, it often fails to relax them. In addition to this endothelial dysfunction, severely atherosclerotic human coronary vessels exhibit a slightly decreased responsiveness to nitroglycerin and SIN-1 but not to forskolin. Another abnormality of the smooth muscle is a marked attenuated beta-adrenergic relaxation. Thus, atherosclerosis of human coronary vessels induces not only marked alterations in endothelium-dependent responses but also modifies the sensitivity to several endothelium-independent vasodilators.
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PMID:Atherosclerosis and responses of human isolated coronary arteries to endothelium-dependent and -independent vasodilators. 248 97

The recent discovery of endothelium-derived relaxation factor (EDRF) has altered the traditional classification of vasodilators used in angina pectoris and heart failure. If a vasodilator induces release of EDRF from the epithelium it is classified as endothelium-dependent, if not it is independent. Sodium nitroprusside and SIN-1 (active metabolite of molsidomine) are the main independent vasodilators since the endothelium relaxation factor appears to be principally a nitric oxide radical in these synthetic vasodilators. In contrast, calcium-channel blockers and a good number of endogenous chemical mediators (acetylcholine, bradykinin, serotonin, etc.) are endothelium-dependent. Furthermore, simple increase in blood flow through the large vessels can result in endothelium-dependent vasodilation (flow rate-dependence) the extent of which depends on the drug examined. The fact that the pharmacologic response of a vasodilator can be altered under certain pathologic conditions (atherosclerosis, hypertension, diabetes, etc.) further increases the importance of the role of the vascular endothelium in the action of vasodilators since endothelial modulation may then be completely diverted to secretion of endothelium-derived contracting factors (EDCFS).
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PMID:[Vasodilator agents and the vascular endothelium]. 262 13

F2-Isoprostanes are novel bioactive prostaglandin F2-like compounds produced by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. F2-Isoprostanes are initially formed in situ on phospholipids and subsequently released. Quantification of the F2-isoprostanes has been found to represent a valuable and reliable marker of lipid peroxidation. Oxidative modification of low-density lipoprotein (LDL) is a key process for the recognition of LDL by the scavenger receptors on macrophages. The oxidative mechanism responsible for the modification of LDL in vivo remains unclear, but an attractive candidate is the powerful oxidant peroxynitrite, which can be formed by reaction of nitric oxide and superoxide in the vessel wall. To further explore the potential role of peroxynitrite in the oxidative modification of plasma lipids, we investigated whether incubation of LDL and plasma with peroxynitrite or SIN-1, which decomposes to form nitric oxide and superoxide, catalyzes the formation of F2-isoprostanes. Incubation of LDL with peroxynitrite (0.125 to 1 mmol/L) or SIN-1 (0.5 and 1 mmol/L) induced a concentration-dependent increase in the formation of F2-isoprostanes, reaching a maximum of 5.5 +/- 2.05-fold (SEM) and 18.2 +/- 4.0-fold above control values, respectively. The increase of F2-isoprostanes induced by SIN-1 was essentially completely inhibited by superoxide dismutase. Incubation of plasma with peroxynitrite or SIN-1 yielded similar results. These results indicate that peroxynitrite can induce the formation of F2-isoprostanes in lipoproteins. Since F2-isoprostanes can exert potent biological activity such as vasoconstriction, they may contribute to the vascular pathobiology associated with atherosclerosis.
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PMID:Formation of F2-isoprostanes during oxidation of human low-density lipoprotein and plasma by peroxynitrite. 761 20

Leukocyte adhesion to vascular endothelium is a crucial step in the early stages of atherosclerosis, which may be mediated by the interaction of adhesion molecules expressed on the surfaces of both cell types. In this study, we investigated the effects of nitric oxide (NO) on the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). ICAM-1 and VCAM-1 protein and mRNA expression were determined by cellular ELISA and Northern blot analysis, respectively. Both ICAM-1 and VCAM-1 expression were increased markedly by interleukin-1 beta (IL-1 beta). This IL-1 beta-mediated induction of ICAM-1 and VCAM-1 expression was significantly inhibited in the presence of a NO donor 3-morpholino-sydnonimine (SIN-1) in a dose-dependent manner. The inhibitory effect of SIN-1 was abolished in the presence of a NO scavenger haemoglobin, while addition of 8-bromo-cGMP showed no significant effect on IL-1 beta-induced ICAM-1 or VCAM-1 expression. Northern blot analysis showed that IL-1 beta markedly increased ICAM-1 and VCAM-1 mRNA expression, while SIN-1 decreased the accumulation of these transcripts induced by IL-1 beta. These results suggest that NO could prevent the focal adhesion and accumulation of leukocytes through the inhibition of ICAM-1 and VCAM-1 expression in endothelial cells.
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PMID:Nitric oxide attenuates adhesion molecule expression in human endothelial cells. 904 77

Intimal thickening in arteries is considered as a site of predilection for atherosclerosis. We investigated whether oral application of the nitric oxide (NO) donors SPM-5185 (N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethylester, 10 mg/kg body weight/b.i.d.) and molsidomine (pro-drug of 3-morpholino-sydnonimine (SIN-1), 10 mg/kg body weight/day) can retard intimal thickening and changes in vascular reactivity induced by a silicone collar positioned around the carotid artery of rabbits. Intimal thickening was significantly inhibited by SPM-5185 (cross-sectional area 18 +/- 6 vs. 44 +/- 10 x 10(-3) mm2; P < 0.05), but not by molsidomine (28 +/- 6 vs. 35 +/- 9 x 10(-3) mm2), which is a donor of both NO and superoxide anions. In organ chamber studies collaring was associated with a decreased sensitivity to acetylcholine (ACh). SPM-5185 evoked a tendency towards normalization of the pD2 of ACh in collared arteries. We also investigated whether chronic nitric oxide (NO) treatment affected vascular reactivity and fatty streak development in the rabbit aorta. During 16 weeks rabbits received 150 g/day of a standard diet, or diets with 0.3% cholesterol, with 0.02% molsidomine (10 mg/kg body weight/day) or with the combination. The NO donor enhanced the area of fatty streaks, without affecting hypercholesterolemia. Moreover, it desensitized the smooth muscle cells of the rabbit aorta to vasodilators acting via the cytoplasmic guanylate cyclase and suppressed the capacity of the endothelial cells to release NO in response to muscarinic receptor stimulation. This suggested that chronic exposure to large quantities of NO caused a negative feedback, with selective decreases of both the endothelial capacity to generate NO and the responsiveness to vasodilators operating via cyclic GMP. In conclusion, we demonstrated that exogenous NO can decrease intimal hyperplasia in vivo. However, prolonged in vivo treatment with a donor of NO enhanced atherosclerosis in hypercholesterolemic rabbits.
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PMID:The effect of chronic treatment with NO donors during intimal thickening and fatty streak formation. 926 3

Oxidative modification of low density lipoprotein (LDL) plays an important role in atherogenesis. Inducible type nitric oxide synthase (iNOS) has been shown to be expressed in vascular smooth muscle cells (VSMC) of atherosclerotic arteries. Nitric oxide (NO) donors have been shown to inhibit metal ion- or cell-mediated oxidation of LDL. To elucidate whether NO produced by iNOS in VSMC inhibit oxidation of LDL, we investigated the effect of NO donors and iNOS-induction in VSMC on oxidation of LDL. NO donor, S-Nitroso-n-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1) (0.1-1.0 mmol/l) dose-dependently reduced copper-induced oxidation of LDL as demonstrated by the inhibition of electrophoretic mobilities on agarose gels and the formation of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes. Moreover, treatment with IL-1beta (5-50 ng/ml) reduced the increases in electrophoretic mobilities on agarose gels and TBARS formation in association with increases in NO production. In addition, inhibition of NO production by NG-monomethyl-L-arginine monoacetate reduced the inhibitory effect of IL-1beta on LDL oxidation. These results indicate that NO release via iNOS action induced by cytokines in VSMC may play protective roles in oxidative modification of LDL during the atherosclerosis process.
Atherosclerosis 1998 Jan
PMID:Inhibitory effect of inducible type nitric oxide synthase on oxidative modification of low density lipoprotein by vascular smooth muscle cells. 954 31

Generalized atherosclerosis and coronary artery disease (CAD) are associated with endothelial dysfunction and during acute myocardial ischemia platelet activation has been reported. Activated platelets exert activated fibrinogen receptors (GP IIb/IIIa) and express CD 62p being regarded as reliable marker for platelet activation. Patients with angiographically proven CAD performed a bicycle exercise test until the onset of angina or ST-segment depression. We studied the ischemia-induced alterations in fibrinogen binding to activated platelet GP IIb/IIIa receptors and CD 62p expression. Therefore, the basal fibrinogen binding to GP IIb/IIIa and CD 62p expression and the thrombin-concentration for half-maximal platelet activation before and after exercise testing were determined. Additionally, inhibition of thrombin-induced platelet activation by increasing concentrations of the prostacyclin-analog iloprost and the NO-donor SIN-1 was examined. In patients with CAD, a significantly reduced basal activation and a highly significant reduction in sensitivity towards thrombin was measured. The thrombin-induced expression of GP IIb/IIIa and CD 62p was significantly diminished in patients with CAD after physical exercise and their platelets were significantly more sensitive towards the inhibitory effects of iloprost and SIN-1. These data demonstrate a significant reduction in platelet activation in response to physical exercise in patients with CAD and advanced atherosclerosis. Despite exercise induced myocardial ischemia as evidenced by angina and ECG-changes, the platelets are not generally activated, as it could be expected. Thus, patients with myocardial ischemia experienced a reduced platelet activity and enhanced sensitivity towards prostacyclin (PGI2) and nitric oxide, probably due to an augmented release of endogenous platelet inhibitory mediators.
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PMID:Increased platelet sensitivity toward platelet inhibitors during physical exercise in patients with coronary artery disease. 995 Feb 58

Cigarette smoking is a well-known risk factor for atherosclerosis, but the mechanism of the adverse biological effect of smoking remains to be established. Cigarette smoke contains high concentrations of free radicals and oxidants. We show here that cigarette smoke extracts (CSE), prepared by bubbling the gas phase of smoke into phosphate-buffered saline, could convert tyrosine to 3-nitrotyrosine. The tyrosine nitration terminated 6 h after incubating tyrosine with CSE at 37 degrees C. These results indicate that the active oxidants in CSE are peroxynitrite-generating species like 3-morpholinosydnonimine (SIN-1), suggesting that they modify plasma lipoproteins and contribute to the pathogenesis of atherosclerosis.
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PMID:Peroxynitrite-generating species: good candidate oxidants in aqueous extracts of cigarette smoke. 1087 94

Peroxynitrite-mediated oxidation may be an important physiological mechanism for oxidation of low density lipoprotein (LDL), however, the molecular basis for the interaction of peroxynitrite oxidized LDL (OxLDL) with scavenger receptors such as CD36, has not been characterized. In this study, we compared the biochemical characteristics and receptor binding of LDL that was oxidized using: (1) Cu2+, a standard method of oxidizing LDL in vitro; and (2) 3-morpholinosydnonimine (SIN-1), a source of peroxynitrite. Both methods of oxidation caused an increase in electrophoretic migration of LDL, but greater mobility was observed with Cu2+-OxLDL. In addition, greater fragmentation of apolipoprotein B was observed following Cu2+ oxidation than after SIN-1 oxidation. The levels of lipid peroxides and thiobarbituric acid reactive substances were similar after 20 h of oxidation by both methods, although the time-course was distinct. Cu2+ and SIN-1-OxLDL bound specifically to the macrophage scavenger receptor CD36 with high affinity. Binding of the 20 h SIN-1 treated LDL to CD36 was comparable to a 4 h Cu2+ modified LDL. The binding of Cu2+ and SIN-1-OxLDL to CD36 was similar under different biochemical conditions and modifications of the receptor, suggesting that OxLDL particles, generated by either method, bind to the same domain of CD36. The results demonstrate that SIN-1 produced an oxidized LDL particle that binds specifically to CD36 and suggests that peroxynitrite OxLDL may represent a more physiologically relevant model than Cu2+-OxLDL for studying the interactions of OxLDL with cells and lipoprotein receptors in vitro.
Atherosclerosis 2001 Mar
PMID:Characterization of peroxynitrite-oxidized low density lipoprotein binding to human CD36. 1122 22


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