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)

1. The effects of A02011-1, a pyrazole derivative, on the proliferation of rat vascular smooth muscle cells (VSMCs) were examined. 2. A02011-1 (1-100 microM) concentration-dependently inhibited [3H]-thymidine incorporation into DNA in rat VSMCs that were synchronized by 48 h serum depletion and then re-stimulated by addition of foetal calf serum (FCS, 10%), platelet-derived growth factor (PDGF, 10 ng ml-1), 5-hydroxytryptamine (10 microM) or ADP (10 microM). The inhibitory effect of A02011-1 was fully reversible. However, FCS-induced [3H]-thymidine incorporation into rat endothelial cells was unaffected by A02011-1. 3. The concentration of A02011-1 necessary for inhibition of the FCS-induced proliferation was similar to that necessary for adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. Adenylyl cyclase activity was increased in A02011-1-treated VSMCs, whereas cyclic AMP-specific phosphodiesterase activity was unchanged. 4. A02011-1 was equipotent with forskolin but was more potent than 8-bromo-cyclic AMP against FCS (10%)-induced proliferation. 5. The antiproliferative action of A02011-1 was mimicked by 8-bromo-cyclic AMP, a membrane-permeable cyclic AMP analogue and was antagonized by 2',5'-dideoxyadenosine, an adenylyl cyclase inhibitor and by Rp-cyclic AMPS, a competitive inhibitor of cyclic AMP-dependent protein kinase (PKA) type I and II. 3-Isobutyl-1-methylxanthine (IBMX) caused significant potentiation of the antiproliferative activity of A02011-1. However, Rp-8-bromo-cyclic GMPS and staurosporine did not affect the antiproliferative activity of A02011-1. 6. A02011-1 still inhibited the FCS-induced DNA synthesis even when added 10-18h after restimulation of the serum-starved VSMCs with 10% FCS. Flow cytometry in synchronized cells revealed an acute blockade of FCS-inducible cell cycle progression at a point in the G,/S phase in A02011-1-treated cells. The inhibition of proliferation by A0201 1-1 was shown to be independent of cell damage,as documented by several criteria of cell viability.7. These results indicate that A0201 1-1 inhibition of VSMC proliferation was mediated by cyclic AMP and was due to a delay in the progression from the G1 into S phase of the cell cycle. A02011-1 did not cause cell toxicity and may thus hold promising potential for the prevention of atherosclerosis or vascular diseases.
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PMID:Antiproliferative effects of A02011-1, an adenylyl cyclase activator, in cultured vascular smooth muscle cells of rat. 762 Jul 13

Adenosine triphosphate (ATP), a co-transmitter in sympathetic nerves and released from platelets, has recently been shown to stimulate growth of vascular smooth muscle cells. It might therefore contribute to the development of vascular hypertrophy seen in hypertension and atherosclerosis. We aimed at characterising the receptor mediating this mitogenic effect in rat aorta smooth muscle cells. The potency of agonists indicates a P2 purinoceptor since ATP > or = ADP >> AMP, adenosine. The P2x-receptor subtype, which is responsible for ATP induced vasoconstriction in rat aorta, does not mediate the mitogenic effect since alpha, beta-methyleneATP had no effect and beta, gamma-methyleneATP had lower potency than ATP. The P2Y-receptor subtype was excluded since the selective agonist 2-methylthioATP had weak effect with lower potency than ATP. When we studied the involvement of other nucleotides similar effects were seen of the purines ATP, GTP and ITP; also the pyrimidine UTP had powerful mitogenic effects (Emax = 52% of ATP) with similar potency. Nucleotides with fewer phosphate groups showed a stepwise fall in mitogenic effect. This indicates involvement of a nucleotide-receptor (P2U). Ap4A were of equal potency and effect as ATP. There was strong correlation between the mitogenic effects of the nucleotides and analogues with both 45Ca(2+)-influx and inositol phosphate (IP) production, indicating that they may participate in mediating the mitogenic response. This is the first study describing the potencies for the mitogenic effects of the selective ATP-analogues and other nucleotides in vascular smooth muscle cells. The receptor characterisation indicates a nucleotide-receptor similar to the receptor which stimulates 45Ca(2+)-influx and inositol phosphate-formation in rat aorta smooth muscle cells. Substances related to ATP such as GTP, ITP, UTP and Ap4A which also can be released extracellularly in vivo stimulate mitogenesis of rat aorta smooth muscle cells through the same receptor.
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PMID:Characterisation of an ATP receptor mediating mitogenesis in vascular smooth muscle cells. 778 5

The effect of TFC-612, methyl-6-[(1R,2S,3R)-hydroxy-2-](1E,3S,5R)-3- hydroxy-5-methyl-1-nonenyl]-5-oxocyclopentyl)thio] hexanoate, on intimal thickening of carotid artery 14 days after endothelium denudation with a balloon catheter was examined in rats. This compound significantly suppressed the neointimal area and the ratio of intimal and medial layer by 41.1% and 31.4%, respectively, at 3.2 micrograms/rat/h s.c. infusion. At this dose, this compound did not inhibit platelet aggregation induced by either collagen or ADP. It did not inhibit bromodeoxyuridine incorporation into medial smooth muscle cells at 3 days after injury. In in vitro experiments, TFC-612 did not inhibit the [3H]thymidine uptake into cultured smooth muscle cells, but it showed significant inhibition of smooth muscle cell migration induced by platelet-derived growth factor (PDGF) at more than 10(-9) M. This compound increased cyclic AMP levels dose dependently in cultured smooth muscle cells at more than 10(-8) M. These results suggest that TFC-612 inhibits intimal thickening by inhibition of smooth muscle cell migration from media to intima through cyclic AMP elevation.
Atherosclerosis 1994 Aug
PMID:Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on intimal thickening after endothelial injury with balloon catheter in rats. 798 Jul 15

The mechanism of the unimpaired relaxant effect of ATP in the Watanabe heritable hyperlipidemic rabbit aorta was investigated to elucidate the involvement of P2y purinoceptor at the endothelial level during atherosclerosis. Experiments were carried out on isolated thoracic aorta from such rabbits that were 12 months of age. The potent P2y purinoceptor agonist, 2-methylthio-ATP, did not induce any endothelium- or smooth muscle-dependent relaxation, thus excluding any involvement by the P2y purinoceptor. ADP, but not AMP, produced relaxation of the aorta by acting at both endothelial and smooth muscle levels. Adenosine relaxed the vessel by acting only in smooth muscle. The maintained endothelial relaxant effect of ATP and ADP is therefore not due to activation of P1 or P2y purinoceptors but may involve activation of a remodeled purinergic receptor site that emerges with the progression of atherosclerosis. This site is antagonized by methylene blue. The disorganization of the endothelial monolayer observed in the morphological analysis may be related to functional remodeling of the endothelial purinergic activity in atherosclerosis.
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PMID:Atherosclerosis-related remodeling of aortic relaxation to purines in the Watanabe heritable hyperlipidemic rabbit. 835 83

The fibronectin (FN) gene has become paradigmatic to illustrate genome evolution by exon shuffling, generation of protein diversity by alternative mRNA splicing, and topological coordination between transcription and splicing. Alternative splicing in three sites of the primary transcript gives rise to multiple FN polypeptides. This process is cell type-, development- and age-regulated. The different FN variants seem to play specific roles in FN dimer secretion, blood clotting, adhesion to lymphoid cells, skin wound healing, atherosclerosis, and liver fibrosis. This review focuses on function assignment to the alternatively spliced segments, as well as on the external signals and cis-acting sequences that control the mechanisms of alternative splicing. We also discuss FN transcriptional regulation in response to viral transformation, growth factors, and cyclic AMP in the light of promoter architecture and its interaction with specific transcription factors. The relevance of FN RNA "tracks" as assembly lines of coordinated transcription and RNA processing is also addressed.
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PMID:The fibronectin gene as a model for splicing and transcription studies. 864 58

The inhibitory effect of prostaglandin E1, which has an anti-platelet action and a vasodilating action via intracellular cyclic AMP elevation, was studied on intimal thickening in the rat femoral artery. A segment of the femoral artery was occluded by a platelet and fibrin-rich thrombus due to photochemical reaction between systemically administered Rose Bengal and transluminal green light which causes endothelial injury followed by platelet adhesion and aggregation at the site of photochemical reaction. Three weeks after endothelial injury, intimal thickening occurred at the irradiated site. Prostaglandin E1 (0.3 microgram/kg per min), administered as a continuous infusion 10 min before photochemical reaction significantly (P < 0.05) prolonged the time to occlusion of the femoral artery. In a separate experiment, prostaglandin E1 (0.3 microgram/kg per min) administered as a continuous infusion for 7 days just after endothelial injury significantly (P < 0.05) inhibited intimal thickening compared with a control group. In cultured rat-derived vascular smooth muscle cells, prostaglandin E1 produced concentration-dependent inhibition of migration and proliferation, stimulated by platelet-derived growth factor. These results suggest that prostaglandin E1 may be effective in preventing vascular restenosis after vascular surgery and angioplasty.
Atherosclerosis 1997 Apr
PMID:Inhibitory effect of prostaglandin E1 on intimal thickening following photochemically induced endothelial injury in the rat femoral artery. 912 43

Multiple brief periods of rapid ventricular pacing confer both short- and long-term protection on the ischaemic heart. The duration of the short-term protection does not exceed 2 h, whereas the long-term protective effect appears several hours after the inducing insults, with maximal protection 24-48 h later. Up to now, delayed cardiac protection by preceding ischaemic insults against harmful consequences of stress has been produced in the normal, healthy animal only. The purpose of this study was, therefore, to test whether delayed cardiac protection can be induced in experimental atherosclerosis in rabbits produced by feeding cholesterol-rich diet over 2 months. Repeated brief periods of rapid ventricular pacing were used to induce delayed protection of the heart. Moderation of post-pacing right intracavitary ST segment elevation and that of the left ventricular end-diastolic pressure (both produced by ventricular overpacing: 500 beats/min for 15 min) were found in normal animals as well as in those fed cholesterol-enriched diet. The short-lived protection induced by a single 'preconditioning' pacing was reproducible only in normal animals. As measured by means of radioimmunoassay, the protective effect of either short- or long-term protection appeared in parallel with an attenuation of ischaemia-induced increase in cardiac cyclic AMP content, in both normal and atherosclerotic rabbits. An increase in cardiac cyclic GMP content was characteristic of the short- but not long-term protection. These results suggest that the delayed cardiac protection by preceding multiple brief rapid pacings operates even in experimental atherosclerosis, but the short-term protection induced by a single preconditioning stimulus is lost.
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PMID:Delayed cardiac protection against harmful consequences of stress can be induced in experimental atherosclerosis in rabbits. 923 51

The swine has many similarities to humans, making it an excellent research model in which to study the role of exercise on lipid metabolism. Swine adapt to exercise-training by increasing muscle oxidative enzymes, maximal stroke volume, cardiac output, VO2max, and high density lipoprotein cholesterol levels, while decreasing total cholesterol levels and resting heart rate. The lipoprotein profile of swine and humans is also similar, and low density lipoprotein is the major cholesterol transporting lipoprotein in both species. Several studies in swine report conflicting results on the effect of exercise-training on lipoprotein profile and atherosclerotic lesion appearance. This may result from differences in total exercise time between the studies. With sufficient total exercise, atherosclerosis was reduced and high density lipoprotein cholesterol levels were increased. Exercise may also play a role in reducing obesity, a risk factor for cardiovascular disease, by enhancing lipid mobilization from adipocytes. Recent research suggests that swine adipocyte sensitivity to adenosine, a locally-produced antilipolytic agent, is reduced after exercise treatment. Cellular mechanisms responsible for this metabolic change include a reduction in adenosine A1 receptor number. Current studies are examining the transport of extracellular cyclic AMP from adipocytes and its role as a potential adenosine precursor.
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PMID:The swine as a model for studying exercise-induced changes in lipid metabolism. 937 79

Vascular smooth muscle cell (VSMC) migration and proliferation are believed to play key roles in atherosclerosis. To elucidate the role of vascular dopamine D1-like receptors in atherosclerosis, the effects of dopamine, specific D1-like agonists SKF 38,393, and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration, proliferation, and hypertrophy were studied. We observed that cells stimulated by 5 ng/ml PDGF BB showed increased migration, proliferation and hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 at 1-10 mumol/l, and this prevention was reversed by Sch 23,390 (1-10 mumol/l), a specific D1-like antagonist. These actions are mimicked by 1-10 mumol/l forskolin, a direct activator of adenylate cyclase and 8-bromocyclic AMP at 0.1-1 mmol/l. The actions are blocked by a specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide (H 89), but are not blocked by its negative control, N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/ml)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through PKA activation and suppression of activated PLD, PKC and MAPK activity.
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PMID:Vascular dopamine-I receptors and atherosclerosis. 963 15

The action of lipoprotein lipase on chylomicrons (CM) and very low density lipoproteins (VLDL) produces remnant lipoproteins (RLP) which are rich in triglycerides, cholesterol and apolipoprotein E (apo E). Apo E serves as a ligand for uptake of RLP by macrophages, platelets, endothelial cells and other cells expressing the LDL-receptor or the remnant receptor, thus having a major role in the clearance of plasma cholesterol and triglycerides, but at the same time, uptake of apo E-bearing RLP can profoundly alter the physiology of these cells and promote atherosclerosis. Like RLP, blood platelets also have roles in atherosclerosis and thrombosis, hence it is likely that RLP influence platelet activity as well. RLP derived from normal human plasma VLDL and CM were prepared using two monoclonal antibodies, anti-apo B-100 (JI-H) and anti-apo A-I (H-12) coupled to Sepharose 4B gel to form an immunoaffinity column. Lipoproteins containing apo B-100 including VLDL and LDL adsorb to (JI-H)-gel, while CM and HDL with apo A-I adsorb to (H-12)-gel. The particles in the unbound fraction (RLP) are rich in apo B-48, apo E and apo B-100 containing particles with multiple molecules of apo E. The RLP fraction with a total triglyceride of 14+/-3.2 mg/ml; cholesterol, 0.39+/-0.1 mg/ml and protein, 0.78+/-0.24 mg/ml (n=19) was added to aliquots of blood of man, rabbits, guinea pigs, mice, and rats at protein equivalents of 0.98 to 78 microg/ml blood and agitated gently at 37 degrees C for 40 sec. Platelet aggregation was measured as a fall in single platelet count. RLP induced aggregation of platelets in man (p<0.005) rabbit (p<0.0005), guinea pig (p<0.002) and mouse (p<0.0001), but no RLP induced platelet aggregation was observed in the rat blood. Scanning electron microscopy revealed that in the presence of RLP, platelets had adhered to and formed aggregates on red cells. The platelet response to RLP was inhibited by apyrase known to scavenge ADP, by 5 microM 2-chloroadenosine, a platelet ADP receptor antagonist and by 3.4 microM cilostazol, a phosphodiesterase type III inhibitor known to raise cyclic AMP level in platelets. It is thought that RLP cause leakage of ADP from red cells which then mediates platelet aggregation.
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PMID:Adenosine 5'-diphosphate as a factor in platelet aggregation induced by human plasma remnant lipoproteins. 974 29


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