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)

In seeking an explanation of the inverse relationship between serum high density lipoprotein (HDL) concentration and coronary heart disease (CHD) incidence, most investigations have been directed at its role in reverse cholesterol transport. However, recently it has become clear that HDL has the potential to limit oxidative modification of low density lipoprotein (LDL) whether induced by transition metals or by cells in tissue culture. In view of the current theory that oxidative modification of LDL is an important element in atherogenesis, this suggests another potential mechanism by which HDL might impede the development of CHD. HDL is the major carrier of cholesteryl ester hydroperoxides, but more than this it appears to have the prolonged capacity to decrease the total amount of lipid peroxides generated on LDL during oxidation while the quantity accumulating on HDL itself reaches an early plateau. These effects are not explained by chain-breaking antioxidants present in HDL and are likely to involve an enzymic mechanism. Several enzymes are present on HDL: paraoxonase, lecithin:cholesterol acyl transferase, platelet activating factor acetylhydrolase, phospholipase D and protease. Apolipoproteins, such as apolipoprotein AI, could also have enzymic activity. Evidence that some of these might act to metabolise lipid peroxidation products, such as oxidised phospholipids and lyso-phosphatidylcholine, is discussed in this review.
Atherosclerosis 1995 Jun
PMID:HDL, its enzymes and its potential to influence lipid peroxidation. 766 83

Low density lipoproteins (LDL) are risk factors in atherosclerosis and oxidative modification of LDL to oxidized LDL (OX-LDL) increases its atherogenicity. Development of atherosclerosis likely involves OX-LDL-mediated smooth muscle cell (SMC) proliferation. However, the mechanism(s) of SMC proliferation by OX-LDL is unknown. We hypothesized that OX-LDL may mediate SMC proliferation by activation of phospholipase D (PLD) through the generation of the second-messenger, phosphatidic acid (PA). To test this hypothesis, activation of PLD by OX-LDL was investigated in [3H]myristic acid- or [32P]orthophosphate-labeled rabbit femoral artery smooth muscle cells (RFASMC) in the presence of 0.5% ethanol or 0.05% butanol. Phospholipase D activation, as measured by labeled phosphatidylethanol (PEt) or phosphatidylbutanol (PBt) formation, was enhanced (3- to 5-fold) by OX-LDL. This activation of PLD was specific for OX-LDL, as native LDL or acetylated LDL had no effect. Further, OX-LDL-mediated [32P]PEt formation was dose- and time-dependent. To determine the mechanism(s) of OX-LDL-induced PLD activation, the role of protein kinase C (PKC) and Ca2+ was investigated. Pretreatment of [32P]orthophosphate-labeled RFASMC with known inhibitors of PKC such as staurosporine, calphostin-C, or H-7, had no effect on OX-LDL-induced PLD activation. Also, down-regulation of PKC by 12-O-tetradecanoylphorbol 13-acetate (TPA) (100 nM, 18 h) did not alter the OX-LDL-mediated [32P]PEt formation. However, pretreatment of RFASMC with genistein, a putative inhibitor of tyrosine kinases, attenuated the OX-LDL-mediated [32P]PEt formation. In addition, exposure of RFASMC to sodium orthovanadate, an inhibitor of phosphatases, enhanced the OX-LDL-mediated PLD activation. The effects of genistein and vanadate on PLD activation were specific for OX-LDL as these agents did not alter the TPA-induced [32P]PEt formation. Treatment of quiescent RFASMC with OX-LDL increased [3H]thymidine incorporation into DNA. This enhanced incorporation of [3H]thymidine into DNA was also mimicked by exogenously added phosphatidic acid (PA) or lysophosphatidic acid (LPA). These findings suggest that OX-LDL is a potent activator of the PLD pathway in SMC. The activation of PLD by OX-LDL generates second-messengers like PA and/or LPA which modulate mitogenesis. Thus, these results indicate that OX-LDL, in atherosclerotic lesions, may enhance SMC proliferation through the modulation of signal transduction pathways including activation of PLD.
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PMID:Oxidized low density lipoprotein-mediated activation of phospholipase D in smooth muscle cells: a possible role in cell proliferation and atherogenesis. 855 88

In the present study, we examined the effect of angiotensin II (Ang II) on phosphatidylcholine-hydrolyzing phospholipase D activity in subcultured rat aortic smooth muscle cells (SMC). Ang II dose-dependently stimulated the formation of choline and inositol phosphates. The effect of Ang II on the formation of inositol phosphates (EC50 was 0.249 +/- 0.091 nM) was more potent than that on the formation of choline (EC50 was 2.39 +/- 1.29 nM). A combination of Ang II and 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, additively stimulated the formation of choline. Staurosporine, an inhibitor of protein kinases, inhibited the TPA-induced formation of choline, but had little effect on the Ang II-induced choline formation. Ang II stimulated Ca2+ influx from extracellular space time- and dose-dependently. The depletion of extracellular Ca2+ by (ethylenebis(oxyethylenenitrilo)) tetraacetic acid (EGTA) significantly reduced the Ang II-induced formation of choline. Genistein and tyrphostin, protein tyrosine kinase inhibitors, significantly suppressed the Ang II-induced Ca2+ influx. Genistein and tyrphostin also suppressed the Ang II-induced formation of choline. These results suggest that Ang II stimulates phosphatidylcholine-hydrolyzing phospholipase D due to Ca2+ influx from the extracellular space in rat aortic SMC, and that protein tyrosine kinase is involved in the Ang II-induced Ca2+ influx, resulting in the promotion of phosphatidylcholine hydrolysis.
Atherosclerosis 1996 Mar
PMID:Tyrosine kinase is involved in angiotensin II-stimulated phospholipase D activation in aortic smooth muscle cells: function of Ca2+ influx. 867 16

Polymorphonuclear leukocytes (PMN) generate highly reactive oxygen derived free radicals that may cause lipoprotein lipid oxidation and so contribute to the pathogenesis of atherosclerosis. On the other hand it has been shown that lipoproteins can alter cell functions in vitro. We therefore studied the effects of atherogenic lipoproteins, VLDL and LDL, on the production of superoxide anion by human PMN in the presence or absence of formyl-methionyl-leucyl-phenylalanine (fMLP). VLDL and LDL stimulate PMN superoxide production and potentialize PMN stimulation by fMLP. The lipid moiety of the lipoproteins might be mainly involved in these effects. The binding of radio-labelled fMLP to its specific membrane receptor was significantly enhanced in the presence of VLDL and only slightly in the presence of LDL. The study of the signal transduction suggests that modulation of phospholipase D and A2 activities could be involved in the modification by LDL of PMN response to fMLP.
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PMID:Effects of plasma lipoproteins on the production of superoxide anion by human polymorphonuclear leukocytes in vitro. 925 97

Recent findings suggest that high glucose levels may promote atherosclerosis in coronary vascular smooth muscle cells (VSMCs). To explore the intracellular mechanisms of action by which troglitazone affects this process, we examined the effect of troglitazone on the migration and growth characteristics of cultured rabbit coronary VSMCs. Treatment with chronic high glucose medium (22.2 mmol/L) for 5 days increased VSMC migration by 92%, [3H]thymidine incorporation by 135%, and cell number by 32% compared with VSMCs treated with normal glucose (5.5 mmol/L glucose + 16.6 mmol/L mannose) medium. Trolitazone at 100 nmol/L and 1 mumol/L significantly suppressed high glucose-induced VSMC migration by 34% and 42%, respectively, the proliferative effect (as measured by cell number) by 17% and 27%, and [3H]thymidine incorporation by 45% and 60% (n = 6, P < .05). The high glucose-induced impairment of insulin-mediated [3H]deoxyglucose uptake was blocked by a protein kinase C (PKC) inhibitor (calphostin C, 1 mumol/L) and was also improved by troglitazone without any change in insulin receptor number and affinity. The high glucose-induced insulin-mediated increase in cell number and in [3H]thymidine incorporation was suppressed by troglitazone. Troglitazone (1 mumol/L) also suppressed high glucose-induced phospholipase D activation, elevation of the cytosolic NADH/NAD+ ratio (as measured by the cytosolic ratio of lactate/pyruvate), and membrane-bound PKC activation. Flow cytometric DNA histogram analysis of cell cycle stage showed that high glucose-induced increase in the percentage of cells in the S phase was suppressed by 1 mumol/L troglitazone. These findings suggest that PKC may be a link between impairment of insulin-mediated glucose uptake and the increase in migration and proliferation induced by high glucose levels and that troglitazone may be clinically useful for the treatment of high glucose-induced coronary atherosclerosis.
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PMID:Mechanisms of action of troglitazone in the prevention of high glucose-induced migration and proliferation of cultured coronary smooth muscle cells. 940 Mar 75

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 and specific D1-like agonists SKF 38,393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC migration and proliferation were studied. We observed that cells stimulated by PDGF-BB (5 ng/mL), showed increased migration and proliferation. These effects were prevented by coincubation with dopamine, SKF 38,393, or YM 435 (1 to 10 mumol/L), and this prevention was reversed by Sch 23,390 (1 to 10 mumol/l), a specific D1-like antagonist. These actions are mimicked by forskolin (1 to 10 mumol/L), a direct activator of adenylate cyclase and 8-bromo-cAMP at 0.1 to 1 mmol/L and are blocked by a specific protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H 89), but not blocked by its negative control, N-[2-(N-formyl)-p-chlorociannamylamino)ethyl]-5-isoquinoline sulfonamide (H 85). PDGF-BB (5 ng/mL)-mediated activation of phospholipase D, protein kinase C, and mitogen activated protein kinase activity were significantly suppressed by coincubation with dopamine. These results suggest that vascular D1-like receptor agonists inhibit migration and proliferation of VSMC, possibly through protein kinase A activation and suppression of activated phospholipase D, protein kinase C, and mitogen-activated protein kinase activity.
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PMID:Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D1-like receptors. 940 7

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

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

1. 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 (D1 and D5) receptors in atherosclerosis, the effects of dopamine and the specific D1-like receptor agonists SKF 38393 and YM 435 on platelet-derived growth factor (PDGF)-BB-mediated VSMC migration, proliferation and hypertrophy were investigated. 2. We observed that cell stimulated by 5 ng/mL PDGF-BB showed increased migration, proliferation and hypertrophy. These effects were prevented by co-incubation with dopamine, SKF 38393 or YM 435 at 1-10 mumol/L and this prevention was reversed by Sch 23390 (1-10 mumol/L), a specific D1-like receptor antagonist. These actions of D1-like receptor agonists were mimicked by 1-10 mumol/L forskolin, a direct activator of adenylate cyclase, and 0.1-1 mmol/L 8-bromo-cAMP. The actions were blocked by the specific protein kinase A (PKA) inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinoline-sulphonamide (H 89), but were not blocked by its negative control N-[2-(N-formyl-p-chlorocinnamylamino) ethyl]-5-isoquinoline sulphonamide (H 85). Platelet-derived growth factor-BB (5 ng/mL)-mediated activation of phospholipase D (PLD), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) activity was significantly suppressed by co-incubation with dopamine. 3. These results suggest that vascular D1-like receptor agonists inhibit migration, proliferation and hypertrophy of VSMC, possibly through the activation of PKA and the suppression of activated PLD, PKC and MAPK activity.
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PMID:Anti-atherosclerotic action of vascular D1 receptors. 1038 52

Oxidation of LDL is an important factor in the development of atherosclerosis. However, the mechanisms by which oxidized LDL exerts its atherogenic actions are poorly understood. In the present work, we show that oxidized LDL stimulates phospholipase D (PLD) activity in mouse peritoneal macrophages and that this effect increases with the degree of LDL oxidation. Oxidative modification of LDL results in the production of lipid peroxides and the conversion of phosphatidylcholine to lysophosphatidylcholine. Although we found that lysophosphatidylcholine alone activates PLD, the stimulation of this enzyme activity by oxidized LDL is independent of lysophosphatidylcholine formation. Also, 7-ketocholesterol, the major oxysterol in oxidized LDL, failed to stimulate PLD activity. To determine the mechanism(s) whereby oxidized LDL activates PLD, the possible involvements of protein kinase C and tyrosine phosphorylation were investigated. Pretreatment of macrophages with the protein kinase C inhibitor Ro-32-0432 or downregulation of protein kinase C activity by prolonged incubation with 100 nmol/L 4beta-phorbol 12-myristate 13-acetate did not alter the stimulatory effect of oxidized LDL on PLD activation. However, oxidized LDL stimulated tyrosine phosphorylation of several macrophage proteins, and preincubation of the macrophages with genistein, a tyrosine kinase inhibitor, blocked the activation of PLD by oxidized LDL. In addition, pretreatment with orthovanadate, which inhibits tyrosine phosphatases, enhanced basal and oxidized LDL-stimulated PLD activity. Pretreatment of macrophages with pertussis toxin decreased the stimulatory effect of oxidized LDL, indicating that GTP-binding proteins may also be involved in the activation of PLD by oxidized LDL. We also found that the platelet-activating factor receptor antagonists WEB 2086 and L-659,989 inhibit the oxidized LDL stimulation of PLD, suggesting a role for platelet-activating factor receptor in this process. The stimulation of the PLD pathway by oxidized LDL may be of importance in atherogenesis, because PLD activation leads to generation of important second messengers such as phosphatidate, lysophosphatidate, and diacylglycerol, which are known to regulate many cellular functions.
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PMID:Stimulation of phospholipase D activity by oxidized LDL in mouse peritoneal macrophages. 1063 10


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