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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) are therapeutically used to lower plasma cholesterol levels. In addition, these drugs can block vascular smooth muscle cell (VSMC) proliferation. The present study addressed the question whether the inhibitory effect of lovastatin on premitotic DNA synthesis correlates with a downregulation of c-fos mRNA levels, a marker of signaling efficiency, in human SMC. Here we show that in human SMC exposed to individual growth factors (platelet-derived growth factor, epidermal growth factor, alpha-thrombin, insulin, insulin-like growth factor I (IGF-I)) and human serum, the maximal [3H]thymidine incorporation and c-fos mRNA expression are closely correlated. Only alpha-thrombin elicited overexpression of c-fos as compared with its effect on [3H]thymidine incorporation. Lovastatin efficiently inhibited [3H]thymidine uptake promoted by all mitogens tested (76-87%); however, it significantly inhibited upregulation of c-fos mRNA levels induced only by insulin (33-67%, P < 0.05) and IGF-I (31 57%, P < 0.05). This inhibition was overcome by mevalonate and geranylgeraniol, and partially by farnesol. c-fos mRNA expression induced by 4-beta-phorbol-12-myristate-13-acetate, an activator of protein kinase C, was insensitive to lovastatin treatment. Thus, in human vascular SMC, lovastatin impairs premitotic DNA synthesis induced by growth factors, but only c-fos expression promoted by insulin and IGF-I. These data indicate that statin-sensitive and -insensitive pathways seem to be involved in the regulation of c-fos in the response of human SMC to proliferative stimuli, and suggest a prominent role of isoprenylated proteins in the activation of VSMC through the IGF-I/insulin dependent pathways.
Atherosclerosis 1997 Dec
PMID:Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells. 943 Mar 71

The preventive effect of vitamin E and Probucol against atherosclerosis in rabbits were compared. Atherosclerosis was induced by a 2% cholesterol-containing vitamin E-poor diet (5-10 ppm). Six groups of five rabbits each were studied. Group I (control) was fed on a vitamin E-poor diet. The other groups had the following supplements: group II, 50 mg/kg vitamin E i.m.; group III, 2% cholesterol; group IV, 2% cholesterol plus 50 mg/kg vitamin E i.m., group V, 2% cholesterol plus 1% Probucol; group VI, 2% cholesterol + 1% Probucol plus 50 mg/kg vitamin E i.m. After 4 weeks, aortas were removed and analyzed by light and scanning electron microscopy for atherosclerotic lesions. Samples of the media were analyzed for protein kinase C activity. The aortas of cholesterol-fed rabbits showed typical atherosclerotic lesions, detected by microscopic examination, their media smooth muscle cells exhibited an increase in protein kinase C activity. Vitamin E fully prevented cholesterol-induced atherosclerotic lesions and the induction of protein kinase C activity. Probucol was not effective in preventing either cholesterol-induced atherosclerotic lesions or the induction of protein kinase C activity. These results show that the protective effect of vitamin E against hypercholesterolemic atherosclerosis is not produced by an other antioxidant such as Probucol, and therefore, may not be linked to the antioxidant properties of this vitamin. The effects observed at the level of smooth muscle cells ex vivo suggest an involvement of signal transduction events in the protective effect of vitamin E against atherosclerosis.
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PMID:Effect of vitamin E and probucol on dietary cholesterol-induced atherosclerosis in rabbits. 943 96

In response to activation of phagocytic cells and during inflammatory disorders, some proteases and very reactive oxygen species are produced. These proteases and oxidants are involved in many diseases like tissue injury or atherosclerosis. We have shown in vitro that verapamil, a calcium channel blocker, had antielastase and antioxidant properties. This drug inhibited the release of elastase by neutrophils in a dose-dependent manner when these cells were stimulated by phorbol-myristate-acetate (PMA), by N-formyl-methionyl-leucylphenylalanine (fMLP) and by the calcium ionophore A23187 (Ca.I). In addition, verapamil inhibited superoxide anion when human neutrophils were stimulated by PMA, fMLP, dioctanoylglycerol (DiC8), Ca.I or by opsonised zymosan (OZ). Verapamil did not act by scavenging elastase or oxidants as demonstrated in cell-free models which showed no direct antielastase or antioxidant effect involved by verapamil. Superoxide anion and elastase inhibition by verapamil has been considered to the mobilization of cytosolic calcium and inhibition of protein kinase C. The results suggest that verapamil might contribute help the development and progression of atheroma where oxidants and elastase are involved.
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PMID:Verapamil inhibits elastase release and superoxide anion production in human neutrophils. 951 2

Lysophosphatidylcholine (lysoPC), which is generated in oxidized LDL (Ox-LDL) and abundantly exists in atherosclerotic arterial walls, has been shown to alter various endothelial functions and induces several endothelial genes expressed in atherosclerotic arterial walls. Nuclear factor-kappa B (NF-kappaB), a pleiotropic transcription factor, plays an important role in regulation of expression of various genes implicated in atherosclerosis. We have previously reported that lysoPC transferred from Ox-LDL to endothelial surface membrane activates endothelial protein kinase C (PKC), leading to modulated endothelial functions. This study was aimed at determining whether lysoPC could modulate activity of transcription factors in cultured human umbilical vein endothelial cells (HUVECs) by using electrophoretic mobility shift assay. LysoPC was found to increase DNA-binding activity of NF-kappaB in HUVECs within 15 minutes, which peaked at 1 to 2 hours and subsequently declined to the baseline level at 6 hours. Lower concentrations (5 to 15 micromol/L) of lysoPC markedly increased NF-kappaB activity, but higher concentration (50 micromol/L) of lysoPC inhibited the activity. Phorbol 12-myristate 13-acetate, a potent activator of PKC, also augmented NF-kappaB activity in HUVECs, mimicking the effects of lysoPC; furthermore, calphostin C and chelerythrine chloride, specific PKC inhibitors, and alpha-tocopherol, a clinically potent PKC inhibitor, suppressed the lysoPC-induced NF-kappaB activation. These results indicate that lysoPC regulates NF-kappaB activity in a biphasic manner dependent on its concentrations and incubation time in human endothelial cells and the endothelial PKC activation may in part be involved in the lysoPC-induced NF-kappaB activation. Thus, the time course and the positive and negative biphasic regulatory actions of lysoPC on NF-kappaB activity in endothelial cells might exhibit a unique effect of lysoPC in arterial walls on the different stages of atherosclerosis.
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PMID:Biphasic regulation of transcription factor nuclear factor-kappaB activity in human endothelial cells by lysophosphatidylcholine through protein kinase C-mediated pathway. 955 62

The primary etiologic factor in diabetic glomerulosclerosis appears to be an overproduction of transforming growth factor-beta by mesangial cells, which in turn reflects a hyperglycemically mediated overactivation of protein kinase C (PKC) throughout the glomerulus. Membrane-active antioxidants, fish oil, and angiotensin-converting enzyme inhibitors can act to down-regulate glomerular PKC activity, via a variety of mechanisms that may include activation of diacylglycerol kinase and suppression of phosphatidate phosphohydrolase, support of endothelial nitric oxide and heparan sulfate production, inhibition of thromboxane and angiotensin synthesis/activity, and correction of glomerular hypertension. The beneficial impact of these measures on vascular endothelial function may be of more general utility in the prevention of diabetic complications such as retinopathy, neuropathy, and atherosclerosis. Adjunctive use of gamma-linolenic acid is indicated for prevention of neuropathy, and it is conceivable that bioactive chromium will have protective activity not solely attributable to improved glycemic control. Re-establishing euglycemia must clearly remain the core strategy for preventing diabetic complications, but when glycemic control remains suboptimal, practical, safe measures are at hand for decreasing risk.
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PMID:A central role for protein kinase C overactivity in diabetic glomerulosclerosis: implications for prevention with antioxidants, fish oil, and ACE inhibitors. 957 71

Mechanical forces are important modulators of cellular function in many tissues and are particularly important in the cardiovascular system. The endothelium, by virtue of its unique location in the vessel wall, responds rapidly and sensitively to the mechanical conditions created by blood flow and the cardiac cycle. In this study, we examine data which suggest that steady laminar shear stress stimulates cellular responses that are essential for endothelial cell function and are atheroprotective. We explore the ability of shear stress to modulate atherogenesis via its effects on endothelial-mediated alterations in coagulation, leukocyte and monocyte migration, smooth muscle growth, lipoprotein uptake and metabolism, and endothelial cell survival. We also propose a model of signal transduction for the endothelial cell response to shear stress including possible mechanotransducers (integrins, caveolae, ion channels, and G proteins), intermediate signaling molecules (c-Src, ras, Raf, protein kinase C) and the mitogen activated protein kinases (ERK1/2, JNK, p38, BMK-1), and effector molecules (nitric oxide). The endothelial cell response to shear stress may also provide a mechanism by which risk factors such as hypertension, diabetes, hypercholesterolemia, and sedentary lifestyle act to promote atherosclerosis.
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PMID:Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. 959 24

Lysophosphatidylcholine (lysoPC), a component of oxidatively modified lipoproteins, is present in atherosclerotic lesions, and its proatherogenic properties have been demonstrated. To gain an insight into lysoPC-mediated endothelial gene expression, we applied nonradioactive differential display analysis of mRNA from lysoPC-treated and untreated human umbilical vein endothelial cells. We identified 12 up-regulated distinct genes including 5 cell growth-related genes (two phosphatases CL100 and B23/hVH-3, gravin, activating transcription factor-4, and heparin-binding epidermal growth factor-like growth factor), 3 thrombosis-related genes (plasminogen activator inhibitor-1, tissue plasminogen activator, and thrombomodulin), and 4 others (stanniocalcin, NAD-dependent methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase, BENE, and reducing agents and tunicamycin-responsive protein). We isolated a full-length cDNA of human gravin. The cDNA sequence of gravin was homologous with rat mitogenic regulatory gene or rat protein kinase C binding protein and substrate, suggesting that gravin would regulate cell growth. Thus, lysoPC apparently accelerates atherosclerosis by regulating the expression of a wide variety of genes. Our data suggest the involvement in atherogenesis of the genes hitherto regarded as atherosclerosis-unrelated.
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PMID:Changes of gene expression by lysophosphatidylcholine in vascular endothelial cells: 12 up-regulated distinct genes including 5 cell growth-related, 3 thrombosis-related, and 4 others. 960 1

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that has been demonstrated to regulate fat cell development and glucose homeostasis. PPARgamma is also expressed in a subset of macrophages and negatively regulates the expression of several proinflammatory genes in response to natural and synthetic ligands. We here demonstrate that PPARgamma is expressed in macrophage foam cells of human atherosclerotic lesions, in a pattern that is highly correlated with that of oxidation-specific epitopes. Oxidized low density lipoprotein (oxLDL) and macrophage colony-stimulating factor, which are known to be present in atherosclerotic lesions, stimulated PPARgamma expression in primary macrophages and monocytic cell lines. PPARgamma mRNA expression was also induced in primary macrophages and THP-1 monocytic leukemia cells by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA). Inhibition of protein kinase C blocked the induction of PPARgamma expression by TPA, but not by oxLDL, suggesting that more than one signaling pathway regulates PPARgamma expression in macrophages. TPA induced the expression of PPARgamma in RAW 264.7 macrophages by increasing transcription from the PPARgamma1 and PPARgamma3 promoters. In concert, these observations provide insights into the regulation of PPARgamma expression in activated macrophages and raise the possibility that PPARgamma ligands may influence the progression of atherosclerosis.
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PMID:Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. 963 98


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