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)

This article reviews the experimental and clinical evidence regarding heparin therapy in the prophylaxis of coronary heart disease. The actions of heparin take place at the vascular endothelium where injected heparin concentrates, and within the bloodstream. At the endothelium heparin acts to prevent endothelial injury, prevent thrombin generation, prevent platelet adhesion to endothelium, and to decrease uptake of serum lipoproteins. Within the bloodstream heparin increases lipoprotein lipase activity and reduces the concentration of atherogenic very low-density lipoproteins. The reduction in lipemia enhances oxygen transfer from blood to the tissues, and decreases thrombin or ADP-induced platelet aggregation. Heparin increases the concentration of high-density lipoproteins. It decreases hypercoagulability and inhibits overactivation of serum complement. Heparin reduced atherosclerosis in most studies in cholesterol-fed animals. In human subjects who had a myocardial infarct at least one year before the onset of treatment, long-term intermittent heparin therapy significantly decreased cardiovascular deaths as compared to control groups.
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PMID:Heparin and atherosclerosis. A review of old and recent findings. 698 41

Vascular smooth muscle (VSM) cell proliferation contributes to the pathogenesis of atherosclerosis, restenosis after angioplasty and vein graft disease. The regulation of genes involved in VSM cell proliferation, particularly by naturally occurring inhibitors, is therefore of some importance. We have investigated the role of the c-myc proto-oncogene in growth arrest of exponentially proliferating rat VSM cells, following mitogen withdrawal, treatment with heparin (50 micrograms/ml), interferon-gamma (IFN-gamma) (100 i.u./ml), or the cyclic nucleotide analogues, 8-bromo-adenosine-3'5'-cyclic monophosphate (8-Br-cAMP; 0.1 mM) and 8-bromoguanosine-3'5'-cyclic monophosphate (8-Br-cGMP; 0.1 mM). Growth arrest was accompanied by down-regulation of c-Myc protein and mRNA following treatment with all inhibitors. Serum withdrawal or IFN-gamma treatment suppressed c-myc expression by more than 50% within 2 h, and this occurred throughout the cell cycle. Platelet-derived growth factor, epidermal growth factor and basic fibroblast growth factor all contributed independently to the maintenance of c-myc expression. Heparin, 8-Br-cAMP or 8-Br-cGMP also suppressed c-myc, but this occurred later, after 24-48 h, and was also observed following arrest by metabolic block. We conclude that c-myc expression is linked to VSM cell growth arrest in response to endogenous regulators and metabolic block. Down-regulation of c-myc expression may thus be an essential part of the arrest programme in VSM cells induced by many pharmacological agents.
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PMID:Down-regulation of the c-myc proto-oncogene in inhibition of vascular smooth-muscle cell proliferation: a signal for growth arrest? 752 76

Heparin and heparan sulfate proteoglycans (HSPGs) stabilize FGFs which belong to heparin-binding growth factors (HBGFs) on active conformation. They also strongly potentiate their mitogenic activity on many cell types, and protect them against thermal denaturation and enzymatic degradation. In the present work we have tested two heparin-like substances named mesoglycan and sulodexide obtained from bovine intestinal mucosal extracts. These products are used as heparin, in various of therapeutic fields such as atherosclerosis or antithrombotic therapy. The compositions of mesoglycan and sulodexide are partially known and include chondroitin, dermatan and heparan sulfate. We have shown that mesoglycan and sulodexide potentiated the mitogenic activity of FGF1 and FGF2. The magnitude of this effect was identical with that of heparin used as a control substance but at double concentration. Mesoglycan and sulodexide also exerted stabilizing and protective effects on FGFs for heat denaturation and enzymatic degradation. The suppression of the protective properties after heparinase treatment of mesoglycan and sulodexide indirectly demonstrated the presence of heparan sulfate which was shown to represent about 60% of the commercial products.
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PMID:Mesoglycan and sulodexide act as stabilizers and protectors of fibroblast growth factors (FGFs). 754 22

Smooth muscle cell (SMC) proliferation plays a critical role in several pathological states, including atherosclerosis and hypertension. Heparin suppresses SMC proliferation in vivo and in culture, but the mechanism of action is still poorly understood. In an accompanying article in this issue (Letourneur et al. [1995] J. Cell Physiol., 165:676-686), we observed that heparin binding was up-regulated in heparin-sensitive SMC but was rapidly down-regulated in heparin-resistant SMC continuously exposed to heparin. In this communication, we examine the degradation and secretion of internalized heparin in sensitive and resistant SMC, using gel filtration chromatography to analyze heparin degradation products. Pulse-chase experiments using radiolabeled heparin indicate that sensitive and resistant SMC secrete heparin during the first few hours after exposure. Experiments in which cells are continuously exposed to heparin indicate that degradation and secretion occur in both sensitive and resistant SMC for approximately 5-8 hr. After that time, however, binding and internalization in resistant SMC rapidly decrease and degradation and secretion stop. In contrast, heparin binding and uptake continue in sensitive SMC; degradation and secretion also continue. Chloroquine prevents degradation in both sensitive and resistant SMC, suggesting that catabolism occurs in the lysosomal compartment. The results presented in this and the accompanying article (Letourneur et al. [1995] J. Cell. Physiol., 165:676-686) suggest that heparin acts to upregulate its receptors, and that increased binding of heparin is required for the antiproliferative response. Degradation and secretion kinetics parallel the internalization kinetics and appear to be strongly linked to the binding process.
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PMID:Heparin binding, internalization, and metabolism in vascular smooth muscle cells: II. Degradation and secretion in sensitive and resistant cells. 759 49

1. Heparin belongs to a family of polysaccharide species, whose best known property is, undoubtedly, anticoagulant activity. However, heparin has many other pharmacological effects, particularly on the cardiovascular system. 2. The therapeutic use of chronically inhaled heparin has been suggested as prophylaxis in atherosclerosis. 3. Heparin, physiologically stored in mast cells of the respiratory system, has also been recently studied in the prevention of immunological and non-immunological asthmatic attacks. 4. Experimental findings and new hypotheses of heparin action in asthma and atherosclerosis are discussed.
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PMID:Heparin: pharmacological potentials from atherosclerosis to asthma. 763 44

Heparin and heparin-like molecules may function, apart from their effect on hemostasis, as regulators of cell growth and neovascularization. We investigated whether similar effects are exerted by laminarin sulfate, an unrelated polysulfated saccharide isolated from the cell wall of seaweed and composed of chemically O-sulfated beta-(1,3)-linked glucose residues. Laminarin sulfate exhibits about 30% of the anticoagulant activity of heparin and is effective therapeutically in the prevention and treatment of cerebrovascular diseases. We characterized the effect of laminarin sulfate on interaction of the heparin-binding angiogenic factor, basic fibroblast growth factor (bFGF), with a naturally produced subendothelial extra-cellular matrix (ECM) and with cell surface receptor sites. Laminarin sulfate (1-2 micrograms/ml) inhibited the binding of bFGF to ECM and to the surface of vascular smooth muscle cells (SMC) in a manner similar to that observed with heparin. Likewise, laminarin sulfate efficiently displaced both ECM- and cell-bound bFGF at concentrations as low as 1 microgram/ml. Both laminarin sulfate and heparin efficiently induced restoration of bFGF receptor binding in xylosyltransferase-deficient CHO cell mutants defective in initiation of glycosaminoglycan synthesis. Moreover, laminarin sulfate elicited bFGF receptor activation and mitogenic response in heparan sulfate (HS)-deficient, cytokine-dependent lymphoid cells. These results indicate that laminarin sulfate effectively replaced the need for heparin and HS in the induction of bFGF receptor binding and signaling. In other experiments, laminarin sulfate was found to inhibit the proliferation of vascular SMC in a manner similar to that observed with heparin. These effects of laminarin sulfate may have potential clinical applications in diverse situations such as wound healing, angiogenesis, and atherosclerosis.
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PMID:Laminarin sulfate mimics the effects of heparin on smooth muscle cell proliferation and basic fibroblast growth factor-receptor binding and mitogenic activity. 765 58

Heparin is a highly sulfated glycosaminoglycan with many functions such as antilipemic and antithrombotic. In spite of these activities heparin is able to inhibit vascular smooth muscle cells proliferation and migration what seems to be very important event in the pathogenesis of atherosclerosis. The molecular mechanism of the action of heparin on smooth muscle cells has not been completely understood. Heparin inhibits growth factors binding to their receptors, oncogenes expression and has influence on the extracellular matrix protein deposition in the artery wall.
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PMID:[Antiatherogenic action of heparin]. 797 2

Proliferation of bovine aortic smooth muscle cells (SMCs) induced by thrombin, basic fibroblast growth factor, or serum is inhibited by anionic, nonsulfated aromatic compounds that mimic many of the effects of heparin. Among these compounds are aurintricarboxylic acid (ATA) and a newly synthesized polymer of 4-hydroxyphenoxy acetic acid (compound RG-13577). Iodinated- or 14C-labeled compound RG-13577 binds to cultured SMCs in a highly specific and saturable manner. Scatchard analysis of the binding data revealed the presence of an estimated 1 x 10(7) binding sites per cell with an apparent dissociation constant of 3 x 10(-6) mol/L. Binding of radiolabeled RG-13577 was efficiently competed for by related aromatic anionic compounds and by apolipoprotein E, but not by heparin, heparan sulfate, suramin, or various purified growth factors and extracellular matrix proteins. Receptor cross-linking of SMC-bound 125I-RG-13577 revealed a single species of high M(r) (approximately 280 kD) cell surface receptors detected in the absence but not the presence of excess unlabeled compound RG-13577. Binding was susceptible to downregulation and restoration of receptor levels in a manner similar to that of hormone and growth factor receptors. We suggest that the antiproliferative activity of compound RG-13577 and related compounds is initiated by binding to specific growth-inhibiting cell surface receptors. Heparin-mimicking compounds may be applied to inhibit SMC proliferation associated with atherosclerosis and restenosis.
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PMID:Antiproliferative activity to vascular smooth muscle cells and receptor binding of heparin-mimicking polyaromatic anionic compounds. 798 Nov 90

Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides and cholesterol and may be subject to premature atherosclerosis. Missense mutations in the HL gene have been identified in two affected families: substitutions of serine for phenylalanine at amino acid 267 and threonine for methionine at amino acid 383 (S267F and T383M, respectively). To confirm the role of S267F and T383M, respectively). To confirm the role of mutations separately into human HL cDNA by site-directed mutagenesis, and the resulting constructs were independently expressed in COS cells. HL activity and mass were measured and compared with wild-type HL transfectants to determine the effect of these mutations on lipase activity and secretion. Although similar amounts of HL protein were detected intracellularly after transfection with the wild-type and mutant constructs, S267F and T383M HL activity levels were markedly decreased: in S267F, no HL activity was detected, and activity levels in T383M were 38% of wild-type HL. Heparin-induced secretion of the two HL mutants was also severely affected: no detectable activity could be measured in the media of S267F, although some inactive mass (12% of wild-type HL) was secreted; mutant T383M secreted 4% and 20% of wild-type activity and mass, respectively. These results indicate that the single amino acid substitution present in HL S267F is sufficient to render the enzyme completely nonfunctional; in contrast, the T383M mutant retains partial activity but is poorly secreted. Thus, these defects appear capable of accounting for the HL-deficient phenotypes exhibited by individuals carrying the T383M and S267F mutations.
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PMID:Molecular characterization of human hepatic lipase deficiency. In vitro expression of two naturally occurring mutations. 812 42

Patients with atherosclerotic carotid artery stenosis commonly have arterial disease elsewhere, especially coronary artery disease. The aim of the medical treatment is to reduce the incidence of stroke, myocardial infarction and vascular death. Both primary and secondary prevention of these vascular events requires control of vascular risk factors, particularly lowering elevated blood pressure, lowering of elevated blood cholesterol and stopping smoking. Aspirin and ticlopidine are effective in reducing vascular events in patients with atherosclerosis, with a relative reduction of about 25% for the composite outcome event "stroke, myocardial infarction or vascular death". Whether low dose (less than 100 mg/d), medium (300 mg/d) or high dose (1,000 mg/d or more) of aspirin confer the same degree of protection against vascular events is unclear. The gastrointestinal side effects are greater for the high dose than for the medium dose, but the difference between the medium dose and the low dose is very small. Ticlopidine conveys a modest risk of reversible severe neutropenia and is often used as a second-line drug, but this is a controversial issue. Heparin is often used as a short-term preventive treatment in patients with transient ischaemic attacks or minor stroke, especially in those with "crescendo" transient ischaemic attacks, progressing stroke, severe carotid stenosis or intraluminal thrombus.
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PMID:[Medical treatment of atherosclerotic carotid stenoses]. 815 33


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