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)

1. Nilvadipine (FK 235, FR 34235) suppressed ischemia (20 min)-reflow (20 min)-induced paw edema of mice (ED30:0.4 mg/kg i.v. and 2 mg/kg p.o.). Other calcium entry blockers of dihydropyridine-type also suppressed the edema, but 30-fold higher doses were required. 2. Oral dosing of nilvadipine suppressed carrageenan-induced paw edema (ED30:15 mg/kg in rats and 20 mg/kg in mice) at a potency corresponding to that of an anti-inflammatory drug, ibuprofen. Nifedipine, nicardipine and nimodipine resulted in a suppression of 30% only with 100 mg/kg oral dosing in rats. Nitrendipine, diltiazem and verapamil were without effect. 3. Nilvadipine inhibited superoxide radical (O-2production from xanthine oxidase (XOD) both with lactate dehydrogenase + NADH method and cytochrome c method (IC50:90 and 100 micrograms/ml, respectively). Nifedipine and nicardipine showed some inhibition, but the other calcium entry blockers failed to inhibit significantly even at 320 micrograms/ml. As uric acid formation was not reduced by the tested drugs, the inhibitory action might be due to their O-2scavenging effects. 4. Superoxide production of neutrophils from casein-induced peritoneal fluid in rats was most strongly inhibited by nilvadipine when the cells were stimulated by a calcium ionophore, A23187 (IC50:4 micrograms/ml). Inhibition by this drug when stimulated by f-methonyl-leucyl-phenylalanine and phorbol myristate acetate was less effective (IC50:20 and 30 micrograms/ml, respectively). Nifedipine and nicardipine inhibited neutrophil O-2production at higher concentrations (30-200 micrograms/ml) with all stimulants. Inhibitory actions by other drugs were weak. 5. Triggering of atherosclerosis depends largely on the oxidative stress on blood vessels after recently established concept.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by nilvadipine of ischemic and carrageenan paw edema as well as of superoxide radical production from neutrophils and xanthine oxidase. 165 7

A high performance liquid chromatographic system with chemiluminescence detection (HPLC-CL) was used for determining phospholipid hydroperoxides in human plasma low density lipoprotein (LDL). This system involved separation of phospholipids from LDL-total lipids with normal phase silica gel HPLC and post-column detection of hydroperoxide-dependent chemiluminescence produced by luminol oxidation during the reaction of hydroperoxide with cytochrome c-haeme. By using HPLC-CL, we could detect phosphatidylcholine hydroperoxide (PCOOH) in human plasma LDL, and the LDL-PCOOH concentration was significantly higher in patients with atherosclerosis and hyperlipidemia than that of healthy volunteers. The LDL-PCOOH level was proportional to the plasma total cholesterol concentration.
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PMID:Determination of lipid hydroperoxides in low density lipoprotein from human plasma using high performance liquid chromatography with chemiluminescence detection. 238 96

Heme proteins transport oxygen and facilitate redox reactions. Heme, however, may be dangerous, especially when free in biologic systems. For example, iron released from hemoglobin-derived heme can catalyze oxidative injury to neuronal cell membranes and may be a factor in post-traumatic damage to the central nervous system. We have shown that heme catalyzes the oxidation of low density lipoproteins which can damage vascular endothelial cells. The endothelium is susceptible to damage by oxidants generated by activated phagocytes, and this has been invoked as an important mechanism in a number of pathologies including the Adulte Respiratory Distress Syndrome (ARDS), acute tubular necrosis, reperfusion injury and atherosclerosis. Because of its highly hydrophobic nature, heme readily intercalates into endothelial membranes and potentiates oxidant-mediated damage. This injury is dependent on the iron content of heme and is completely blocked when concomitant hemopexin is added. Ferrohemoglobin, when added to cultured endothelial cells, is without deleterious effects, but if oxidized to ferrihemoglobin (methemoglobin), it greatly amplifies oxidant damage. Methemoglobin, but not ferrohemoglobin, releases its hemes which can then be incorporated into endothelial cells. Cultured endothelial cells, when exposed to methemoglobin but not ferrohemoglobin, cytochrome c or metmyoglobin, potentiate this oxidant injury. Stabilization of the methemoglobin by cyanide, haptoglobin or capture of the heme by hemopexin abrogates this effect. Paradoxically, more prolonged exposure of endothelium to heme or methemoglobin renders them remarkably resistant to oxidant challenge. Endothelium defends itself from heme by induction of the heme degrading enzyme heme oxygenase and the concomitant production of large amounts of the iron binding protein ferritin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Heme and the vasculature: an oxidative hazard that induces antioxidant defenses in the endothelium. 808 43

Iron-derived reactive oxygen species are implicated in the pathogenesis of various vascular disorders including atherosclerosis, vasculitis, and reperfusion injury. The present studies examine whether heme, when liganded to physiologically relevant proteins as in hemoglobin, can provide potentially damaging iron to intact endothelium. We demonstrate that reduced ferrohemoglobin, while relatively innocuous to cultured endothelial cells, when oxidized to ferrihemoglobin (methemoglobin), greatly amplifies oxidant (H2O2)-mediated endothelial-cell injury. Drawing upon our previous observation that free heme similarly primes endothelium for oxidant damage, we posited that methemoglobin, but not ferrohemoglobin, releases its hemes that can then be incorporated into endothelial cells. In support, cultured endothelial cells exposed to methemoglobin--in contrast to exposure to ferrohemoglobin, cytochrome c, or metmyoglobin--rapidly increased their heme oxygenase mRNA and enzyme activity, thereby supporting heme uptake; ferritin production was also markedly increased after such exposure, thus attesting to eventual incorporation of Fe. These cellular methemoglobin effects were inhibited by the heme-scavenging protein hemopexin and by haptoglobin or cyanide, agents that strengthen the liganding between heme and globin. If the endothelium is exposed to methemoglobin for a more prolonged period (16 hr), it accumulates large amounts of ferritin; concomitantly, and presumably associated with iron sequestration by this protein, the endothelium converts from hypersusceptible to hyperresistant to oxidative damage. We conclude that when oxidation of hemoglobin facilitates release of its heme groups, catalytically active iron is provided to neighboring tissue environments. The effect of this relinquished heme on the vasculature is determined both by extracellular factors--i.e., plasma proteins, such as haptoglobin and hemopexin--as well as intracellular factors, including heme oxygenase and ferritin. Acutely, if both extra- and intracellular defenses are overwhelmed, cellular toxicity arises; chronically, when ferritin is induced, resistance to oxidative injury may supervene.
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PMID:Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. 841 93

We investigated the effects of aging, a cardiovascular risk factor, on vascular function with regard to endothelial nitric oxide synthase (eNOS), superoxide dismutase (SOD), and endothelin (ET-1) in aorta and femoral artery of the rat. Concentration-response curves to acetylcholine, calcium ionophore A23187, norepinephrine, ET-1, big endothelin, sodium nitroprusside, and exogenous SOD were obtained. Expression of eNOS mRNA was analyzed by reverse-transcription polymerase chain reaction, SOD activity was assessed using a chemiluminescence-based cytochrome c assay, and ET-1 plasma concentrations were measured by radioimmunoassay. In aorta of old rats, relaxations to acetylcholine and calcium ionophore A23187, basal NO release, and expression of eNOS mRNA in aortic endothelial cells were reduced (P<.05). In femoral arteries, relaxations to acetylcholine were preserved, whereas basal release of NO was attenuated (P<.05). Aging selectively increased contractions to norepinephrine and functional endothelin converting enzyme activity and attenuated contractions to ET-1 in aortas but not femoral arteries. Vascular SOD activity was higher in the femoral artery (P<.05) and unaffected by aging. Plasma ET-1 levels increased and plasma SOD activity decreased with age (P<.05). Aging was associated with an anatomic heterogeneity of endothelial dysfunction, functional endothelin converting enzyme activity, and vascular SOD activity. Vascular function was impaired in the aorta but not the femoral artery, which may be related to lower eNOS mRNA expression and SOD activity. These data suggest differential regulation of the vascular aging process that may contribute to the anatomic heterogeneity of atherosclerosis.
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PMID:Anatomic heterogeneity of vascular aging: role of nitric oxide and endothelin. 933 78

There is currently much interest in the possibility that dietary antioxidants may confer protection from certain diseases, such as atherosclerosis and cancer. The importance of alpha-tocopherol (vitamin E) as a biological antioxidant is widely recognized. However, pro-oxidant properties of alpha-tocopherol have been observed in chemical systems, and it has been reported that the vitamin can induce tumor formation and act as a complete tumor promotor in laboratory animals. In the present communication, we find that alpha-tocopherol can act as a potent DNA-damaging agent in the presence of copper(II) ions, using a simplified, in vitro model. alpha-Tocopherol was found to promote copper-dependent reactive oxygen species formation from molecular oxygen, resulting in DNA base oxidation and backbone cleavage. Neither alpha-tocopherol nor Cu(II) alone induced DNA damage. Bathocuproine, a Cu(I)-specific chelator, and catalase inhibited the DNA damage, whereas free hydroxyl radical scavengers did not. The order of DNA cleavage sites was thymine, cytosine > guanine residues. Examinations using an oxygen electrode and cytochrome c indicate that molecular oxygen was consumed in the reaction of alpha-tocopherol and Cu(II) and that superoxide was formed. Stoichiometry studies showed that two Cu(II) ions could be reduced by each alpha-tocopherol molecule. Electron spin resonance spin-trapping investigations were then used to demonstrate that hydrogen peroxide interacts with Cu(I) to generate the reactive species responsible for DNA damage, which is either the hydroxyl radical or a species of similar reactivity. These findings may be of relevance to the tumorigenic properties of the vitamin reported in the literature. However, further studies are required to establish the significance of these reactions under in vivo conditions.
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PMID:Alpha-tocopherol induces oxidative damage to DNA in the presence of copper(II) ions. 970 46

In patients with diabetes, non-enzymatic glycation of low-density lipoprotein (LDL) has been suggested to be involved in the development of atherosclerosis. alpha-Dicarbonyl compounds were identified as intermediates in the non-enzymatic glycation and increased levels were reported in patients with diabetes. We studied the effect of the alpha-dicarbonyl compound methylglyoxal (MG) on the physicochemical and biological properties of LDL. MG dose-dependently modifies LDL, as indicated by the formation of fluorescent products and the increase of a net negative charge. MG (10 mmol/l) induced major modifications of arginine residues (up to 85%) and minor lysine modifications (less than 6%). MG-LDL preparations generated small amounts of superoxide anion radicals as measured by the reduction of cytochrome c, but this was not accompanied by peroxidation of the polyunsaturated fatty acids of MG-LDL. MG-LDL showed diminished recognition and uptake by the human LDL receptor in cultured cells and a markedly increased plasma clearance rate in vivo in rats. The reduced association and degradation of 125I-oxidised LDL by murine macrophages indicates recognition of MG-LDL by a scavenger receptor. Surprisingly, MG-LDL caused significantly less cholesteryl ester synthesis in murine macrophages, as compared to native LDL and oxidised or acetylated LDL. Highly modified MG-LDL did not induce activation of human endothelial cells, as measured by the expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1.
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PMID:Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein. 979 11

Reactive oxygen species (ROS) are known to induce apoptotic cell death in various cell types. In the vessel wall, ROS can be formed by macrophages within the atherosclerotic plaque or can act on the endothelium after adhesion of monocytes or leucocytes. Moreover, ROS are endogenously synthesized by endothelial and vascular smooth muscle cells by NAD(P)H oxidase. Enhanced ROS production is a very early hallmark in the atherogenic process, suggesting a link between ROS and apoptosis. In endothelial cells, the endogenous generation of ROS is induced by different pro-inflammatory and pro-atherosclerotic factors such as Ang II, oxLDL or TNFalpha, which all promote the execution of programmed cell death. ROS synthesis is thereby causally involved in apoptosis induction, because antioxidants prevent endothelial cell death. The pro-apoptotic effects of endogenous ROS in endothelial cells mechanistically seems to involve the disturbance of mitochondrial membrane permeability followed by cytochrome c release, which finally activates the executioner caspases. In contrast to the pro-apoptotic capacity of ROS in endothelial cells, in vascular smooth muscle cells emerging evidence suggests that endogenous ROS synthesis promotes cell proliferation and hypertrophy and does not affect cell survival. However, high concentrations of exogenous ROS can also stimulate smooth muscle cell apoptosis as shown for other cell types probably via activation of p53. Taken together, the double-edged effects of endogenously derived ROS in endothelial cells versus VSMC may provide a mechanistic clue to the anti-atherosclerotic effects of antioxidants shown in experimental studies, given that the promotion of endothelial survival in combination with inhibition of VSMC proliferation blocks two very important steps in the pathogenesis of atherosclerosis.
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PMID:Reactive oxygen species and vascular cell apoptosis in response to angiotensin II and pro-atherosclerotic factors. 1082 88

The broad significance of apoptosis in the cardiovascular system only began to be recognized more widely recently. Apoptotic cell death is a normal component of postnatal morphogenesis of the human cardiac conduction system and may also be involved in the pathogenesis of a variety of cardiovascular diseases, including heart failure, myocardial infarction and atherosclerosis. Recently, it has become evident that mitochondria play important role in the signaling machinery of apoptotic cell death by releasing several apoptotic factors such as cytochrome c, apoptosis-inducing factor and procaspases. Furthermore, calcium signals have been identified as one of the major signals that converge on mitochondria to trigger the mitochondrion-dependent pathway of the apoptotic cell death. Calcium signals are also important in the physiological control of mitochondrial energy metabolism and it has not yet been explored how Ca(2+) turns from a signal for life to a signal for death. Since large elevations of cytosolic [Ca(2+)] ([Ca(2+)](c)) occur during each heartbeat in cardiac myocytes and these [Ca(2+)](c) signals may efficiently propagate to the mitochondria, the Ca(2+)-dependent mitochondrial pathways of apoptosis can be particularly important in the heart. This review is concerned with the role of mitochondrial Ca(2+) signaling in the control of cardiac apoptosis.
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PMID:Mitochondrial ca(2+) signaling and cardiac apoptosis. 1135 Nov 29

Apoptotic cell death following injury of vascular endothelium is assumed to play an important role in the pathogenesis of atherosclerosis. In this report, we demonstrate that high density lipoproteins (HDL), a major anti-atherogenic lipoprotein fraction, protect endothelial cells against growth factor deprivation-induced apoptosis. HDL blocked the mitochondrial pathway of apoptosis by inhibiting dissipation of mitochondrial potential (Deltapsi(m)), generation of reactive oxygen species, and release of cytochrome c into the cytoplasm. As a consequence, HDL prevented activation of caspases 9 and 3 and apoptotic alterations of the plasma membrane such as increase of permeability and translocation of phosphatidylserine. Treatment of endothelial cells with HDL induced activation of the protein kinase Akt, an ubiquitous transducer of anti-apoptotic signals, and led to phosphorylation of BAD, a major Akt substrate. Suppression of Akt activity both by wortmannin and LY-294002 or by a dominant negative Akt mutant abolished the anti-apoptotic effect of HDL. Two bioactive lysosphingolipids present in HDL particles, sphingosylphosphorylcholine and lysosulfatide, fully mimicked the survival effect of HDL by blocking the mitochondrial pathway of apoptosis and potently activating Akt. In conclusion, the present study identifies HDL as a carrier of endogenous endothelial survival factors and suggests that inhibition of endothelial apoptosis by HDL-associated lysosphingolipids may represent an important and novel aspect of the anti-atherogenic activity of HDL.
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PMID:Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids. 1143 65

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