Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

According to present knowledge, altered arterial reactivity associated with hypertension, atherosclerosis and hypercholesterolemia is related to impaired release of endothelial derived relaxing factor (EDRF). Impaired relaxation followed by enhanced vasoconstriction leads to a well known clinical entities such as unstable angina, acut myocardial infarction. Impairment of EDRF may also account for smooth muscle cell proliferation and migration. Aim of present study was to examine the endothelial dependent response during in vitro conditions in human femoral arteries taken from bypass operation and leg amputation. Examining the contractility, the effect was modulated with nifedipin, EDTA and pertussis toxin, respectively. Endothelium dependent relaxation to acethylcholin and histamine were markedly diminished, while those to calcium ionophore were maintained throughout the study. These results suggest that at least two or more receptor-coupled system may be involved in generation of EDRF. However, direct relaxation of femoral artery to nitrovasodilatators (nitroglycerine) were comparable between control and atherosclerotic artery. Another striking change in atherosclerotic artery was the increased sensitivity to the vasoconstrictions. To eluciadate to exact biochemical mechanism underlying the endothelial dysfunction may help to develop a new vasodilatator drug.
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PMID:[In vitro study of endothelium-dependent relaxation and contraction of human atherosclerotic femoral artery]. 934 May 78

The endothelium mediates a number of responses (relaxation or contraction) of arteries and veins from animals and humans. The endothelium-dependent relaxations are due to the release, by endothelial cells, of potent non-prostanoid vasodilator substances. Among these, the best characterized is endothelium-derived relaxing factor (EDRF), which is believed to be nitric oxide (NO). Nitric oxide is formed by the metabolism of L-arginine by the constitutive NO synthase of endothelial cells. In arterial smooth muscle, the relaxation evoked by EDRF is explained by the stimulation by NO of soluble guanylate cyclase that leads to the accumulation of cGMP. In a number of animal blood vessels and in human coronary arteries, the endothelial cells release a substance that causes hyperpolarization of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive (alpha 2-adrenoceptor activation, serotonin, aggregating platelets, leukotrienes) and insensitive (adenosine diphosphate (ADP), bradykinin) G proteins. In blood vessels from animals with regenerated and reperfused endothelium, and/or atherosclerosis, there is a selective loss of the pertussin toxin-sensitive mechanism of EDRF release, which favours the occurrence of vasospasm, thrombosis and cellular growth. The available information from isolated human blood vessels or obtained in situ concurs with the conclusions reached from studies with isolated animal tissues. In addition to relaxing factors, the endothelial cells can produce contracting factors (endothelium-derived contracting factors; EDCFs) which include superoxide anions, endoperoxides, thromboxane A2 and endothelin. From animal studies it can be concluded that the propensity to release EDCFs is maintained, or even augmented, in diseased blood vessels. The switch from a normally predominant release of EDRFs to that of EDCFs may play a crucial role in atherosclerosis.
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PMID:Endothelial dysfunction and atherosclerosis. 940 68

Low density lipoprotein (LDL) interactions with the endothelium are thought to play a major role in the development of atherosclerosis. The mechanism(s) involved are not fully understood, although several lines of evidence support the idea that oxidation of LDL increases its atherogenicity. In this study we report for the first time that native LDL (n-LDL) binding to the LDL receptor (100-700 mug/ml) triggers a rise in intracellular calcium which acts as a second messenger to induce vascular cell adhesion molecule-1 (VCAM-1) expression in human coronary artery (HCAEC) and pig aortic endothelial cells (PAEC) and VCAM-1 and E-selectin expression in human aortic (HAEC) endothelial cells. Preincubation of HCAEC with a monoclonal antibody (IgGC7) to the classical LDL receptor or pretreatment with pertussis toxin blocked the n-LDL-induced calcium transients. Preincubation of each of the endothelial cell lines with the calcium chelator 1,-2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetic acetomethyl ester (BAPTA/AM) prevented the expression of VCAM-1 and E-selectin. The increase in VCAM-1 by n-LDL results in increased monocyte binding to HCAEC which can be attenuated by inhibiting the intracellular calcium rise or by blocking the VCAM-1 binding sites. These studies in human and pig endothelial cells link calcium signaling conferred by n-LDL to mechanisms controlling the expression of endothelial cell adhesion molecules involved in atherogenesis.
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PMID:Native low density lipoprotein-induced calcium transients trigger VCAM-1 and E-selectin expression in cultured human vascular endothelial cells. 948 77

Mammalian endothelium acts as a mediator in arterial and venous relaxation and contraction. Endothelium-dependent relaxation is due to endothelial release of powerful, non-prostanoid vasodilatory substances. The best known of these is the endothelial factor EDRF identified as nitrous oxide (NO). It is the end result of the metabolism of L-arginine by the NO synthetase of endothelial cells. In arterial smooth muscle, the relaxation induced by EDRF is explained by NO stimulation of soluble guanylate cyclase, leading to accumulation of GMPc (cyclic guanosine monophosphate). In some animal vessels and in human coronary arteries, endothelial cells release a substance which induces hyperpolarisation of the cell membrane (endothelial derived hyperpolarising factor, EDHF). Release of EDRF by the cell membrane may be mediated by G proteins sensitive to pertussis toxin (activation of the alpha 2 adrenoreceptor, serotonin, platelet aggregation, leukotrienes) or non-sensitive G proteins (adenosine-diphosphate (ADP), bradykinin). In animal blood vessels where the endothelium is regenerated and reperfused, and/or atherosclerotic, a selective loss of the mechanism of EDRF release is observed, sensitive to pertussis toxin, which favors vasospasm, thrombosis and cellular proliferation. The available data on isolated or in situ human blood vessels concord with studies on isolated animal tissues. In addition to the relaxation factors, endothelial cells can also secrete contracting factors (endothelium derived contracting factors: EDCF); these include superoxide anions, endoperoxides, thromboxane A2 and endothelin. Animal studies indicate that the tendency to release EDCF is maintained or even increased in damaged vessels. The change from normally dominant EDRF release to EDCF release could play an important role in atherosclerosis.
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PMID:[Endothelial dysfunction and atherosclerosis]. 951 9

Vascular wound healing and such pathologies as atherosclerosis and restenosis are characterized by migration and proliferation of the smooth muscle cells of the media after denudation of the intima. To explore possible roles that alpha 2-adrenergic receptors (alpha 2-ARs) might have in these cellular responses, we characterized the alpha 2-ARs present in explant-derived cultures of rat aortic smooth muscle (RASM) cells. The results of immunofluorescence microscopy and reverse transcription followed by the polymerase chain reaction indicated that all three alpha 2-AR subtypes (alpha 2A, alpha 2B, and alpha 2C) were initially present. Mitogen-activated protein kinase activity in the RASM cells was stimulated fivefold over basal by the alpha 2-selective agonist dexmedetomidine (Dex) and was blocked by coincubation with the alpha 2-selective antagonist rauwolscine (RW) or by preincubation of the cells with the Gi/G(o)-protein inhibitor pertussis toxin. alpha 2-AR activation by Dex did not promote cell proliferation, as measured by the incorporation of [3H]thymidine. However, Dex significantly increased RASM cell migration, and antagonist blocked this effect. Incubation of RASM cells with Dex also produced a marked decrease in F-actin labeling, which again was prevented by coincubation with RW. The evidence clearly reveals the presence of functional alpha 2-ARs in RASM cells. The involvement of alpha 2-AR activation with cytoskeletal changes and cell migration is novel and indicates a potential role of these receptors in vascular wound healing and pathogenesis.
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PMID:Alpha 2-adrenergic receptors increase cell migration and decrease F-actin labeling in rat aortic smooth muscle cells. 953 96

The endothelium plays an obligatory role in a number of relaxations of isolated arteries. These endothelium-dependent relaxations are due to the release by the endothelial cells of potent vasodilator substances [endothelium-derived relaxing factors (EDRF)]. The best characterized EDRF is nitric oxide (NO). Nitric oxide is formed by the metabolism of L-arginine by the constitutive NO synthase of endothelial cells. In arterial smooth muscle, the relaxations evoked by EDRF are explained best by the stimulation by NO of soluble guanylate cyclase that leads to the accumulation of cyclic GMP. The endothelial cells also release an unidentified substance that causes hyperpolarization of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive (alpha2-adrenergic activation, serotonin, thrombin, aggregating platelets) and insensitive (adenosine diphosphate, bradykinin) G-proteins. In blood vessels from animals with regenerated endothelium, and/or atherosclerosis, there is a selective loss of the pertussis-toxin sensitive mechanism of EDRF-release which favors the occurrence of vasospasm, thrombosis and cellular growth.
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PMID:Endothelial dysfunction and vascular disease. 980 82

We examined the mechanism of action of lysophosphatidylcholine (LPC), which is suggested to be involved in the pathogenesis of atherosclerosis and inflammatory disorders, in HL-60 leukaemia cells. Extracellular 1-palmitoyl LPC increased the intracellular Ca2+ concentration in association with production of inositol phosphate. These actions of LPC were markedly inhibited by treatment of the cells with pertussis toxin and U73122, a phospholipase C inhibitor. The lipid-induced stimulation of the phospholipase C/Ca2+ system was also attenuated in the dibutyryl cAMP-induced differentiated (neutrophil-like) cells, in which phospholipase C activation induced by NaF or formyl-Met-Leu-Phe was enhanced. In contrast with the stimulatory action of 1-palmitoyl LPC, 1-stearoyl LPC was inhibitory for the phospholipase C/Ca2+ system stimulated by NaF as well as by 1-palmitoyl LPC or other Ca2+-mobilizing agonists. In a cell-free system, only an inhibitory effect on phospholipase C activity was observed even by 1-palmitoyl LPC; 1-stearoyl LPC was more inhibitive than 1-palmitoyl LPC. Taken together, these results suggest that atherogenic and inflammatory LPC exerts both stimulatory and inhibitory actions on the phospholipase C/Ca2+ system depending on the species of fatty acid residue of the lipid; the stimulatory effect is possibly mediated through G-protein-coupled receptors; the inhibitory effect might be caused by dysfunction of the components involved in the enzyme system owing to the amphiphilic nature of the lipid. 1-Palmitoyl LPC prefers the former receptor stimulation at least in intact cells, but 1-stearoyl LPC preferentially exerts the latter inhibitory action.
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PMID:Stimulatory and inhibitory actions of lysophosphatidylcholine, depending on its fatty acid residue, on the phospholipase C/Ca2+ system in HL-60 leukaemia cells. 982 Aug 28

Mechanical forces related to pressure and flow are important for the etiology of atherosclerosis and hypertension. We hypothesized the presence of mechanosensors that were solely sensitive to pure atmospheric pressure in the absence of shear and tensile stresses. A pressure-loading apparatus was set up to examine the effects of atmospheric pressure on human aortic smooth muscle cells (HASMC). Pressure application of 140 to 180 mmHg produced DNA synthesis in a pressure-dependent manner. In contrast, pressure of 120 mmHg or less produced no significant change. Both extracellular signal-regulated kinase and c-Jun N-terminal kinase activities, but not p38 activity, were stimulated by pressures of more than 160 mmHg. Pertussis toxin (PTx) completely inhibited the pressure-induced increase of DNA synthesis under the high pressure of 200 mmHg. These data suggest that HASMC have a mechanosensing cellular switch for DNA synthesis which is sensitive to pure atmospheric pressure, and that the molecular switch is activated by pressure of more than 140 mmHg. The activation mechanism consists of PTx-sensitive and -insensitive pathways, and the former is activated by high pure pressure.
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PMID:Threshold-dependent DNA synthesis by pure pressure in human aortic smooth muscle cells: Gialpha-dependent and -independent pathways. 1006 49

Oxidized low-density lipoproteins (oxLDL) have been shown to play a crucial role in atherosclerosis, but the underlying molecular mechanisms have not been fully understood. The present study showed that oxLDL strongly evoked phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) in rat vascular smooth muscle cells (VSMCs) in concentration- and time-dependent manners, reaching the maximal activation at 100 microg/mL within 5 minutes. The results from immunofluorescence staining also revealed that p38 MAPK was activated by oxLDL in 5 minutes, and the activated p38 MAPK was translocated from cytoplasm to nucleus of VSMCs in 15 minutes. Activation of p38 MAPK by oxLDL was apparently not mediated by their classical scavenger receptors and was not affected by tyrosine kinase inhibitors. However, activation of p38 MAPK was effectively blocked by pretreatment with pertussis toxin and was significantly reduced by phospholipase C inhibitor U-73122. OxLDL also inhibited forskolin-stimulated cAMP accumulation and increased inositol phosphate formation. More interestingly, inhibition of p38 MAPK by its specific inhibitor SB203580 significantly blocked oxLDL-induced cytotoxicity (increased leakage of cytoplasmic lactate dehydrogenase to the culture medium, reduced [3H]thymidine incorporation, and attenuated mitochondrial metabolism of tetrazolium salt, (3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-s ulfophenyl)- 2H-tetrazolium), MTS) in VSMCs, and pretreatment with pertussis toxin also inhibited oxLDL-induced cytotoxicity. Taken together, our data clearly demonstrated that oxLDL effectively activated p38 MAPK in VSMCs, which was likely mediated via pertussis toxin-sensitive G proteins, and the p38 activation was functionally associated with oxLDL-induced cytotoxicity in VSMCs.
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PMID:Activation of p38 mitogen-activated protein kinase by oxidized LDL in vascular smooth muscle cells: mediation via pertussis toxin-sensitive G proteins and association with oxidized LDL-induced cytotoxicity. 1020 51

Elevated levels of high-density lipoproteins (HDL) appear to delay or prevent the development of atherosclerosis. The intracellular signaling mechanisms activated by HDL in vascular cells are currently under active investigation. In this study the effects of HDL on endothelial intracellular Ca levels (EC Ca(i)) are investigated. We show that HDL, like low density lipoproteins (LDL), increases EC Ca(i) in a dose-dependent fashion by releasing Ca from internal stores. Neither apolipoprotein A-I (apo A-I) nor apolipoprotein A-II (apo A-II) was responsible for the increase in EC Ca(i). HDL appeared to release Ca from the same internal stores as did LDL, since preincubation of EC with LDL prevented subsequent responses to HDL but not to the vasodilator ATP. In addition, preincubation of EC with pertussis toxin, an inhibitor of specific G proteins, as well as U73122, an inhibitor of phospholipase C, prevented a rise in EC Ca(i) in response to HDL. These findings suggest that HDL, like LDL, can modulate EC Ca(i) and that this occurs via a pertussis toxin-sensitive G protein-mediated pathway which involves phospholipase C.
Atherosclerosis 1999 Apr
PMID:High-density lipoprotein increases intracellular calcium levels by releasing calcium from internal stores in human endothelial cells. 1021 58


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