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)

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

To clarify relationships between the (endothelial vasodilatory and vasoconstrictive function) and leukocyte inflammatory mediators in subjects with asymptomatic atherosclerosis, we measured (intraplatelet cyclic 3',5'-guanosine monophosphate [cGMP] and cyclic 3',5'-adenosine monophosphate [cAMP]), plasma endothelin (ET-1), and plasma neopterin in 197 subjects with asymptomatic atherosclerosis (median age 63 years, range 49-69 years). We measured neutrophil protease 4 (NP4), tumor necrosis factor (TNFmu), soluble tumor necrosis factor receptor-1 (sTNFR-1), and neutrophil gelatinase associated lipocalin (NGAL) in 152 of the 197 subjects. Intraplatelet cGMP correlated inversely with plasma ET-1 (r=-0.22; p=0.01), which confirms earlier in vitro data of the inhibitory effect of ET-1 on NO production and/or the cGMP mediated inhibitory effect of NO on ET-1 production. Plasma neopterin as well as NP4 correlated directly with intraplatelet cGMP (r=0.24; p<0.01 and r=0.33; p<0.001, respectively). Intraplatelet cAMP correlated directly with plasma TNFmu (r=0.17; p<0.05) and sTNFR-1 (r=0.20; p<0.05). The relationship between leukocyte derived inflammatory mediators and intraplatelet cyclic nucleotides suggest an antiaggregating effect of leukocytes upon platelets, which may constitute a negative feedback mechanism that inhibits platelet activation during the atherosclerotic inflammatory process.
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PMID:Endothelial derived vasoactive factors and leukocyte derived inflammatory mediators in subjects with asymptomatic atherosclerosis. 985 70

Cholesterol feeding results in impaired endothelium dependent vasorelaxation. The role of nitric oxide in this process is unclear. The aim of this study was to evaluate the role of nitric oxide in cholesterol-induced vasomotor dysfunction by examining the effect of overexpression of eNOS in the hypercholesterolemic rabbit aorta on vascular reactivity. Vascular rings from the thoracic aorta of hypercholesterolemic rabbits were exposed ex vivo either to an adenoviral vector encoding endothelial nitric oxide synthase (AdeNOS) or Escherichia coli beta Galactosidase (AdbetaGal). Transgene expression was examined by histochemistry for beta galactosidase, immunohistochemistry for eNOS and cyclic GMP measurements and vasomotor studies were performed. Transgene expression was found to localize to the endothelium and adventitia. cGMP levels were significantly greater in AdeNOS compared to AdbetaGal transduced rings. Acetylcholine mediated relaxation was significantly impaired in cholesterol fed rabbits and was markedly improved by overexpression of eNOS. These results suggest that reduced NO bioavailability observed in cholesterol-induced vascular dysfunction can be partially overcome by eNOS gene transfer.
Atherosclerosis 1998 Dec
PMID:Ex vivo gene transfer of endothelial nitric oxide synthase to atherosclerotic rabbit aortic rings improves relaxations to acetylcholine. 986 75

Non-restrictive, porous, external stents inhibit neointima formation in porcine vein grafts. Since the mechanisms underlying these effects are unknown we investigated the impact of this external stent on factors known to inhibit vascular smooth muscle cell proliferation: prostacyclin (PGI2), nitric oxide (NO), cAMP and cGMP formation in different regions of stented and unstented porcine vein grafts. Paired stented and unstented saphenous vein-carotid artery interposition grafting was carried out in Landrace pigs. One month after surgery, the vessels were excised and the formation of PGI2, cAMP and cGMP determined using radioimmunoassay and nitric oxide synthase (NOS) distribution studied using autoradiography and histochemistry. There were no significant differences between PGI2, cAMP and cGMP (nitroprusside-stimulated) formation in the medial/intimal regions of grafts of stented vein graft and ungrafted saphenous vein whereas all were significantly reduced in unstented vein graft. A23187-stimulated cGMP formation (mediated by NO release) and NOS content was significantly greater in the medial/intimal region of stented and unstented vein graft compared to ungrafted saphenous vein, indicating induction of endothelial NOS (eNOS) in both types of graft. This normalisation of the PGI2-cAMP axis and guanylyl cyclase activity in the medial/intimal region may contribute to the beneficial impact of the external stent on vein graft thickening. The increase in eNOS in both stented and unstented vein grafts mitigates against this isoform as playing a role in mediating the inhibitory effect of the stent on neointima formation. In the adventitia of both stented and unstented grafts there was an increase in PGI2, cAMP and cGMP formation compared to ungrafted saphenous vein, the production being greater in the stented compared to the unstented graft. In the adventitia of stented veini grafts, NOS, detected with NAPDH diaphorase staining, was associated with microvessels as well as with inflammatory cells. Taken together, these data are suggestive of a role for PGI2 and NO in promoting microangiogenesis in the adventitia of stented vein grafts which may in turn minimize graft hypoxia, an established contributory factor to neointima formation.
Atherosclerosis 1998 Dec
PMID:Nitric oxide, prostacyclin and cyclic nucleotide formation in externally stented porcine vein grafts. 986 78

Estrogen deficiency, hyperinsulinemia, type II diabetes, atherosclerosis, and a past history of elevated blood pressure may be associated with increased risk of Alzheimer's disease (AD). Common to all of these risk factors is a diminished capacity of vascular endothelium to generate nitric oxide (NO). Vascular NO has the potential to enhance the membrane polarization of cerebral neurons by increasing the open probability of calcium-activated potassium channels; this may protect neurons from the excessive calcium influx, potentiated by beta-amyloid peptides that is thought to mediate neuronal damage in AD. The possibility that NO/cyclic guanosine 3', 5'-phosphate (cGMP) may modulate the synthesis or processing of the amyloid precursor protein, also merits evaluation. Practical measures for promoting vascular NO production may include increased intakes of arginine, potassium, antioxidants, and fish-oil, as well as lifestyle measures that typically lower elevated blood pressure; potential benefits of chromium, glucosamine, and silicon should also be explored. In hypertensives, angiotensin-converting enzyme (ACE) inhibitors and sodium restriction may favorably influence endothelial function. Fish-oil should have the additional benefit of antagonizing the contribution of interleukin-1 to AD pathogenesis. Ancillary anti-excitotoxic measures such as magnesium, taurine, phenytoin, and vasodilators targeting ATP-dependent potassium (KATP) channels, may likewise reduce AD risk. Most of the nutritional measures suggested here would in any case be recommendable for preservation of vascular health.
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PMID:Vascular nitric oxide may lessen Alzheimer's risk. 1005 65

Ascorbic acid has been shown to enhance impaired endothelium-dependent vasodilation in patients with atherosclerosis by a mechanism that is thought to involve protection of nitric oxide (NO) from inactivation by free oxygen radicals. The present study in human endothelial cells from umbilical veins and coronary arteries investigates whether L-ascorbic acid additionally affects cellular NO synthesis. Endothelial cells were incubated for 24 h with 0.1-100 microM ascorbic acid and were subsequently stimulated for 15 min with ionomycin (2 microM) or thrombin (1 unit/ml) in the absence of extracellular ascorbate. Ascorbate pretreatment led to a 3-fold increase of the cellular production of NO measured as the formation of its co-product citrulline and as the accumulation of its effector molecule cGMP. The effect was saturated at 100 microM and followed a similar kinetics as seen for the uptake of ascorbate into the cells. The investigation of the precursor molecule L-gulonolactone and of different ascorbic acid derivatives suggests that the enediol structure of ascorbate is essential for its effect on NO synthesis. Ascorbic acid did not induce the expression of the NO synthase (NOS) protein nor enhance the uptake of the NOS substrate L-arginine into endothelial cells. The ascorbic acid effect was minimal when the citrulline formation was measured in cell lysates from ascorbate-pretreated cells in the presence of known cofactors for NOS activity. However, when the cofactor tetrahydrobiopterin was omitted from the assay, a similar potentiating effect of ascorbate pretreatment as seen in intact cells was demonstrated, suggesting that ascorbic acid may either enhance the availability of tetrahydrobiopterin or increase its affinity for the endothelial NOS. Our data suggest that intracellular ascorbic acid enhances NO synthesis in endothelial cells and that this may explain, in part, the beneficial vascular effects of ascorbic acid.
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PMID:L-Ascorbic acid potentiates nitric oxide synthesis in endothelial cells. 1007 31

Shear forces induce platelet aggregation and stimulate the endothelial production of anti-aggregatory factors. Among them, endothelin-3 (ET-3) has been reported to reduce aggregation and to increase platelet cyclic GMP (cGMP) content. Since hypercholesterolemia modifies both platelet aggregability and endothelial function, we compared in 14 hypercholesterolemic and 15 normocholesterolemic subjects the influences of shear forces (240 and 650 s(-1)) on platelet aggregation and cGMP content, and their modulation by ET-3. Spontaneous maximal aggregation occurred earlier and at a greater extent in hypercholesterolemic than in normocholesterolemic subjects (63+/-2 vs 46+/-6% P < 0.01). Pre-treatment with ET-3 abolished the shear-induced facilitation of maximal aggregation in platelets of normocholesterolemic (from 70+/-2 to 52+2% at 240 s(-1) and from 73+/-1 to 59+/-2S at 650s(-1); P < 0.05) and hypercholesterolemic (from 78+/-3 to 64+/-2 at 240 s(-1) and from 78+/-2 to 66+/-3 at 650 s(-1); P < 0.05) subjects. cGMP content did not significantly differ between normocholesterolemic and hypercholesterolemic subjects (6.1+/-0.5 vs 6.9+/-0.7 pmol/10(9) platelets). It was reduced in platelets submitted to shear forces (P < 0.05). This shear-dependent reduction was suppressed by ET-3 pre-treatment. These results demonstrate that shear forces enhance platelet aggregation and diminish their cGMP content. ET-3 reduces the pro-aggregating effects of shear, suggesting a rise in cGMP content as a dynamic associated mechanism.
Atherosclerosis 1999 Mar
PMID:Influence of hypercholesterolemia and endothelin-3 pre-treatment on the effects of shear forces on platelet aggregation and cyclic GMP content. 1020 83

There is growing evidence that pentoxifylline (PTX) may have potential value as an antiproliferative and antifibrogenic agent. To assess whether this drug may be of use in the prevention of atherosclerosis or restenosis after angioplasty, we investigated the ability of PTX to inhibit proliferation and collagen synthesis in rat vascular smooth muscle cells (VSMCs) under both basal and platelet-derived growth factor (PDGF)- or transforming growth factor-beta (TGF-beta)- stimulated conditions. Intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels were measured in confluent cells using enzyme immunoassay kits. Cell proliferation was measured by methyltetrazolium assay. Cell cycle distribution was determined by flow cytometry. Total collagen synthesis was measured by 3H-proline incorporation assay. Expression of collagen alpha 1(I) and collagen alpha 1(III) mRNAs was detected by northern blotting. Addition of PTX to VSMC cultures suppressed both basal and PDGF-AB (25 ng/ml)-driven cell proliferation, in conjunction with a cell cycle blockade at the G1/S phase at 24 h. This effect was predominantly cAMP-dependent, as PTX increased cAMP in a dose-dependent manner (0.03 to 0.33 mg/ml) but not cGMP level, and the addition of dibutyryl-cAMP (0.2 to 2 m m) closely mimicked the effect of PTX. Furthermore, co-incubation with a selective inhibitor of cAMP-dependent protein kinase (PKA), H-89 (2.0 microm), or an N -myristoylated PKA pseudosubstrate nonapeptide, m-phi PKA (10 microm), prevented the antimitogenic effect of PTX. PTX also suppressed both basal and TGF- beta 1-augmented collagen alpha 1(I) and collagen alpha 1(III) mRNA levels beginning at 24 h, and attenuated both basal and TGF-beta 1 (5 ng/ml)-stimulated total collagen synthesis at 48 h. Co-incubation with H-89 or m-phi PKA reversed PTX-attenuated collagen alpha 1(I) and collagen alpha 1(III) mRNA levels at 24 h. These data suggest that the antimotigenic and anticollagen effects of PTX were mediated predominantly through a cAMP-PKA effector pathway. The dual effect of PTX on VSMC proliferation and collagen synthesis may form the rationale for animal or clinical trials for the treatment of vascular occlusion due to atherosclerosis and restenosis following angioplasty.
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PMID:Pentoxifylline inhibits PDGF-induced proliferation of and TGF-beta-stimulated collagen synthesis by vascular smooth muscle cells. 1032 5

Atherosclerosis is a major contributor to cardiovascular disease, and genetic disorders of lipoprotein metabolism are recognized risk factors in atherogenesis. The gaseous monoxides nitric oxide (NO) and carbon monoxide (CO), generated within the blood vessel wall, have been identified as important cellular messengers involved in the regulation of vascular smooth muscle tone. Microsomal heme oxygenases degrade heme to biliverdin and CO, and the cytosolic enzyme biliverdin reductase then catalyzes reduction of biliverdin to bilirubin, both powerful chain-breaking antioxidants. Two principal isozymes of heme oxygenase have been identified, a constitutive isoform HO-2 (M(r) approximately 34,000) and an inducible isoform HO-1 (M(r) approximately 32,000), which is expressed at a low basal level in vascular endothelial and smooth muscle cells and is induced by heavy metals, oxidative stress, inflammatory mediators and oxidized low density lipoproteins. Although NO and CO modulate intracellular cGMP levels, platelet aggregation and smooth muscle relaxation, CO has a much lower affinity for soluble guanylyl cyclase than NO. Decreased production or sensitivity to NO in atherosclerosis may be compensated for by an induction of HO-1, with bilirubin acting as a cellular antioxidant and CO as a vasodilator. This review examines the evidence that oxidized low density lipoproteins (LDL), hypoxia and pro-inflammatory cytokines induce HO-1 expression and activity in vascular endothelial and smooth muscle cells, and evaluates the anti-atherogenic potential of the heme oxygenase signalling pathway.
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PMID:Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? 1034 38

Angiotensin (A) II is a potent constrictor as well as growth stimulant of vascular smooth muscle cell caused by activation of AT1 receptor signal transduction systems. There are two major signal systems of AT1 receptor: one leads to an increase in cytosolic free calcium levels causing smooth muscle contraction which may result in high blood pressure, and the other leads to smooth muscle proliferation and inflammation which may result in atherosclerosis. AT1 receptor activation induces phosphinositide hydrolysis by phospholipase C and creates an inositol phosphate, which release calcium from cytosolic calcium pools. Cytosolic calcium can also be elevated by activation of calcium channel via a link between AT1 receptor and a G protein. Protein phosphorylation triggered by AT1 receptor is important for cell growth, in which tyrosine kinase, serine/threonine kinase and protein kinase C are involved. Free radicals are generated by NADH/NADPH oxidase in response to AT1 receptor activation, causing expression of genes leading to atherosclerosis. On the other hand, activation of AT2 receptor is shown to play a role of lowering blood pressure. Some phosphatases and NO/cyclic GMP would be involved in the mechanism. In renal vasculature, endothelium dependent epoxygenase products are synthesized by AT2 receptor stimulation causing vasorelaxation. In summary, AT1 receptor signals are vasopressive and evoke atherosclerosis, whereas AT2 receptor signals may possibly be vasodilatory.
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PMID:[Signal transduction systems of angiotensin II receptors]. 1036 37


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