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)

A sixty-six-year-old man with known severe atherosclerosis was admitted with painful feet and nonblanching purpuric lesions of his toes. He had undergone cardiac catheterization and coronary artery bypass five and three months, respectively, prior to admission. Initial treatment included: stopping the patient's lisinopril, increasing his nifedipine dose, and adding pentoxifylline 400 mg po tid. Within twenty-four hours pain was markedly decreased. Skin biopsy confirmed a diagnosis of cholesterol embolism. Pentoxifylline was stopped and intravenous heparin therapy was initiated. Within twenty-four hours, pain returned. Nitrol paste applied to the top of each foot had no effect. After forty-eight hours, pentoxifylline was restarted. Once again, pain relief was noted within twenty-four hours, and after forty-eight hours both feet were visibly improved. Heparin and analgesics were discontinued. On the ninth hospital day, the patient was able to walk and was discharged to home. The innocuous nature of the intervention combined with the prompt nature of the therapeutic response support a short trial of pentoxifylline in patients with cholesterol emboli who are not responding to other therapy.
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PMID:Pain relief and clinical improvement temporally related to the use of pentoxifylline in a patient with documented cholesterol emboli--a case report. 828 87

Heparin inhibits smooth muscle cell proliferation in vitro, a property that makes it potentially useful in preventing restenosis after angioplasty. Its utility in this setting is limited by the inability to use high doses (secondary to anticoagulant effects) and the need for subcutaneous administration. We tested the ability of beta-cyclodextrin tetradecasulfate (CDT), a nonanticoagulant synthetic heparin mimic, to inhibit smooth muscle cell proliferation in vitro and tested its efficacy when orally administered for the prevention of angioplasty restenosis in a rabbit atherosclerosis model. Vascular smooth muscle cells were cultured from rabbit aortas by the explant technique. Passaged cells were plated at low density in microtiter plates in the presence or absence of varying concentrations of heparin or CDT in culture medium containing 10% fetal calf serum. Using both 3H-thymidine incorporation and total protein assays, both heparin and CDT caused a similar dose-dependent inhibition of proliferation. We next tested the effect of orally administered CDT in the prevention of restenosis in focal femoral artery arteriosclerotic lesions created in hypercholesterolemic New Zealand White rabbits by air-dessication endothelial injury and subsequent peripheral angioplasty. Animals were followed up for 1 month and were fed normal chow supplemented by tap water with or without CDT. In animals receiving the highest concentration of CDT (2 mg/mL drinking water), the percentage of arterial cross-sectional area with intimal hyperplasia decreased from 50.5 +/- 1.7% (control) to 26.9 +/- 2.2% (p < 0.001), with the intimal/medial ratio being decreased from 1.4 +/- 0.4 to 0.5 +/- 0.2 (p = 0.056).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of smooth muscle cell proliferation and experimental angioplasty restenosis by beta-cyclodextrin tetradecasulfate. 849 13

In the primary prevention of arterial disease, there may be a role for anti-oxidant vitamins and for oestrogen replacement therapy in postmenopausal women. For the secondary prevention of thrombotic complications of atherosclerosis, aspirin has proven efficacious in reducing both mortality and morbidity. Patients with ischaemic heart disease and moderately elevated serum cholesterol benefit from simvastatin administration. Heparin and oral anticoagulants are the mainstay in the primary and secondary prevention of venous thrombosis. More potent antithrombotic compounds, the direct thrombin inhibitors and the glycoprotein IIb-IIIa antagonists, are mainly being evaluated in emergency coronary medicine. Preliminary results are encouraging but haemorrhagic problems need to be solved. The trend toward a decrease in late restenosis following coronary angioplasty using a IIb-IIIa antagonizing Fab fragment may prove to be a major therapeutic breakthrough.
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PMID:Clinical trials of primary and secondary prevention of thrombosis and restenosis. 857 89

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (Sr 60-400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% +/- 28% (P < 0.0005) and cholesterol ester mass by 176% +/- 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% +/- 61%(P < 0.005) and 202% +/- 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% +/- 18%(P < 0.01) and 177% +/- 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% +/- 20%(P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (-97% +/- 13% (P < 0.0005) with anti-apo B 5E11 and -68% +/- 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (-77% +/- 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL+LPL-induced increases in cholesterol ester (+21%, +15% and -22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (-86% +/- 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (-79%) or lipolyzed re-isolated HTg-VLDL (-95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (-95% +/- 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.
Atherosclerosis 1996 Feb
PMID:Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells. 864 51

Defibrotide is a polydeoxyribonucleotide sodium salt extracted from mammalian organs. Its mean molecular weight is 15,000-30,000 daltons. Defibrotide contains aptamers, i.e., single-stranded polynucleotides with a well-defined base sequence and composition (5'-GGTTGG-ATT-GGTTGG-3' and 5'-GGTTGG-ATC-GGTTGG-3') that bind thrombin. For the time being, these aptamers are the only ones that have been identified in defibrotide, but there may also be other aptamers that bind proteins other than thrombin. Defibrotide has no anticoagulant activity, but in some other aspects it probably parallels heparin. Heparin is a sulfated polysaccharide sodium salt with a mean molecular weight ranging from 5,000 to 40,000 daltons extracted from mammalian organs. It contains disaccharide sequences of well-defined structure and frequency. Heparin binds an array of proteins, enzymes, and growth factors and shows inhibitory or stimulatory or protective activity. Defibrotide has a spectrum of interesting pharmacological properties that make this drug very useful for the treatment of arterial and venous thrombotic diseases. In fact, defibrotide has profibrinolytic, antithrombotic-thrombolytic, anti-ischemic, and antiatherosclerotic activity and protective activity in shock. What have all the above activities to do with a single drug? The explanation is that atherosclerosis, myocardial, renal, and liver ischemia, hemorrhagic and septic shock, and shock induced by occlusion of splanchnic artery and thrombosis are different facets of the same entity: the polyhedric inflammatory process.
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PMID:An integrated view of the activities of defibrotide. 880 33

Hypercholesterolemia is associated with abnormalities in arterial vasoactivity which can be reversed with cholesterol-reducing therapies. Heparin-induced extracorporeal LDL precipitation (HELP), an invasive method for treating refractory hypercholesterolemia, causes regression of both xanthomas and atherosclerosis, but its effect on vasoactivity has not been investigated. We tested the effects of HELP on vasoactivity with an ultrasound system for continuous measurement of arterial flow velocity and end-diastolic diameter. We measured brachial artery vasoactivity before, during, and after a 5 min forearm vascular occlusion. Vasoactivity measurements were acquired from 6 subjects with familial hypercholesterolemia (FH) who had been treated chronically with HELP, immediately before and after each of 4 treatments, and from 12 age- and sex-matched normocholesterolemic subjects (2 matched with each HELP subject). Peak arterial dilation after cuff release, relative to the pre-occlusion diameter, was similar for the pre-treatment, post-treatment, and normocholesterolemic groups (0.29 mm pre-treatment, 0.30 mm post-treatment and 0.33 mm normocholesterolemic, P = NS). The slope of arterial diameter during occlusion was also similar for the three groups (-0.10 microm/s pre-treatment, 0.02 microm/s post-treatment, and 0.06 microm/s normocholesterolemic, P = NS). These two parameters are known to be decreased in hypercholesterolemic subjects to an extent which could be readily detected by the power of this study. Interestingly, one homozygous FH subject consistently demonstrated significant improvement in these two parameters immediately after HELP, suggesting an individual difference in arterial physiology. On average, FH patients treated chronically with HELP have similar vasoactivity to age- and sex-matched subjects with low risk for atherosclerosis. This result, in light of the many studies that have associated hypercholesterolemia with abnormal vasoactivity, suggests that chronic HELP therapy improves vasoactivity in patients with severe hypercholesterolemia.
Atherosclerosis 1997 Feb 10
PMID:Peripheral vasoactivity in familial hypercholesterolemic subjects treated with heparin-induced extracorporeal LDL precipitation (HELP). 905 Jul 81

Known atherosclerotic risk factors account today for only 50% of atherogenesis. Evidence is presented that a deficiency of endogenous heparin may account for the other half. Sensitive techniques have shown that there are trace quantities of heparin in plasma of humans. An inverse relationship has been found between plasma heparin levels and triglyceride-bearing Sf 12-400 lipoprotein, and a lower plasma heparin level could be an important determinant of atherogenesis fostering lipid abnormalities. Endogenous heparin also protects endothelium from harmful mediators that can impair normal function. Since atherosclerosis is a chronic inflammatory disease process, with monocyte-mediated release of cytokines and activation of integrins and phospholipase A2-mediated generation of platelet activating factor, heparin inhibits many of these events. Endogenous heparin activity thus opposes the effects of inflammatory activators. Heparin is also kown to inhibit complement activation and to suppress endothelin release from endothelial cells. In addition, endogenous heparin may suppress smooth muscle cell proliferation and decrease microthrombi formation on injured endothelial sites. All of these data seem to suggest that a deficiency of endogenous heparin or heparin-like substances predipose to atherosclerosis. It is conceivable that a genetically determined endogenous heparin deficiency is involved in atherosclerosis.
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PMID:Evidence that endogenous heparin activity deficiency may be an important factor in atherogenesis. 920 Mar 41

Proliferation of vascular smooth muscle cells (SMCs) is implicated in pathological events, including atherosclerosis and intimal hyperplasia following angioplasty. The glycosaminoglycan heparin is a growth inhibitor of SMCs in vitro and in vivo. The underlying mechanism, however, is still poorly understood. In the present study, we report that heparin inhibited the activation of the mitogen-activated protein kinase (MAPK) in baboon SMCs by serum but not by platelet-derived growth factor (PDGF). When fibroblast growth factor was used, heparin had a stimulatory effect on MAPK. The only MAPK-activating kinase found in SMCs was MAPK kinase (MAPKK)-1, although MAPKK-2 was present in comparable amounts. Activation of MAPKK-1 and DNA synthesis were affected by heparin in a similar fashion. Heparin does not appear to exert its effects through members of the protein kinase C family, which are downregulated by phorbol esters, because it was still capable of inhibiting MAPK/MAPKK-1 stimulation by FCS in phorbol ester-pretreated cells. The present findings support the conclusions that the effects of heparin depend on the nature of the mitogen and that heparin inhibits SMC proliferation by preventing activation of MAPKK-1.
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PMID:Diverse effects of heparin on mitogen-activated protein kinase-dependent signal transduction in vascular smooth muscle cells. 920 Oct 23

Smooth muscle cell proliferation is a key event in the development of atherosclerosis. Inhibition of this proliferation may lead to better prevention and treatment of the disease. While a number of agents have been found to inhibit SMC proliferation, their mechanisms of action are not fully understood. We wanted to determine the effects of three physiologically relevant anti-mitogenic agents on two classes of proteins which have major roles in cellular proliferation, namely cyclins and cyclin-dependent kinases (cdks). Following stimulation with fetal calf serum (FCS), quiescent human umbilical artery smooth muscle cells (HUASMC) synthesised cyclin D1 mRNA and protein and cdk2 mRNA in the G1 phase, whereas cdc2 protein was expressed after the onset of the S phase. Heparin, a strong inhibitor of HUASMC proliferation, strongly down-modulated the levels of cyclin D1 mRNA and protein, cdk2 mRNA and cdc2 protein. Interleukin-4 (IL-4) or 8-bromo-adenosine 3',5'-cyclic monophosphate (cAMP) also lowered the levels of these cell cycle regulatory proteins, although their effects were relatively weak, reflecting their only partial inhibition of HUASMC DNA synthesis. There was specificity in the cell cycle targets of the agents since none appeared to affect the levels of cdk4 protein.
Atherosclerosis 1997 Aug
PMID:G1 phase arrest of human smooth muscle cells by heparin, IL-4 and cAMP is linked to repression of cyclin D1 and cdk2. 925 8

Lipoprotein lipase (LPL)-mediated lipolysis of very low density lipoprotein (VLDL) has been demonstrated to increase U937 monocyte adhesion to endothelial cells. In the present study, we evaluated the ability of LPL to enhance human monocyte adhesion to bovine aortic endothelial cells (BAEC) in the absence of exogenous lipoproteins. Exposure of BAEC to 1 microgram/ml LPL at 37 degrees C resulted in a significant increase in monocyte adhesion over control values. Addition of VLDL in the culture media further enhanced the LPL effect. A significant increase in monocyte adhesion was also observed when BAEC were incubated with LPL at 4 degrees C. Heparin or heparinase treatment of BAEC totally abolished the LPL stimulatory effect on monocyte adhesion. In addition, incubation of monocytes with heparinase suppressed the ability of LPL to stimulate monocyte adhesion to endothelial cells. These treatments also markedly decreased LPL binding to the monocyte and endothelial cell surfaces. In contrast to native LPL, heat inactivated or phenylmethylsulfonyl fluoride (PMSF)-treated LPL did not increase monocyte adhesion to BAEC. Finally, incubation of LPL in the presence of the 5D2 antibody resulted in a total suppression of the LPL-induced monocyte adhesion to BAEC. Taken together, these data demonstrate that LPL activity plays an important role in LPL-induced monocyte adhesion and that LPL binding to heparan sulfate proteoglycans expressed on both monocytes and endothelial cells surfaces is required for the enhanced monocyte adhesion. These results suggest a new mechanism by which LPL may promote the development of atherosclerosis, that of facilitating monocyte adhesion to the endothelium.
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PMID:Lipoprotein lipase enhances human monocyte adhesion to aortic endothelial cells. 932 82


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