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

Human low-density lipoprotein (LDL) was glucosylated by incubation in vitro with glucose (20-80 mM) with or without addition of cyanoborohydride. The incorporation of covalently bound glucose was linear over time, and amino acid analysis showed the presence of glucosyllysine residues. The glucosylated LDL (glc LDL) moved more rapidly than normal LDL on agarose electrophoresis. The rate of degradation of 125I-labeled glucosylated LDL (glc LDL) by cultured human fibroblasts was reduced compared with that of native I-LDL, the difference increasing with extent of glucosylation. Effects were seen with blockage of as few as 6-15% of the LDL lysine residues; high-affinity degradation was completely lost when one-third of the lysine residues were blocked. Conjugation of LDL with glucose-6-phosphate also blocked high-affinity uptake and degradation. Whereas native LDL uptake inhibited the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase and stimulated acyl coenzyme A:cholesterol acyltransferase activity, glc LDL had no effects on these enzymes. The fractional catabolic rate of glc LDL in guinea pigs was reduced. Degradation of glc LDL by mouse peritoneal macrophages was not significantly faster than that of native LDL. Finally, the presence of glc LDL in human plasma was demonstrated. Preliminary data show that 1.3% of lysine residues in normal LDL and 2-5.3% of lysines in diabetic LDL were glucosylated. Since, like other plasma proteins, LDL undergoes glucosylation in diabetes, its turnover and sites of catabolism may differ from normal and this may be relevant to the accelerated atherosclerosis of diabetes.
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PMID:Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity. 681 75

Plasma glucose and insulin responses to an oral dextrose tolerance test and to a mixed-meal test were determined in fully ambulatory residents of a retirement community. The study population consisted of 127 women and 79 men, whose ages ranged from 47 to 90 years. Progressive hyperglycemia and hyperinsulinemia with age could be demonstrated in the women. These changes were observed with either type of tolerance test and could not be attributed to age-related differences in measurements of body mass index or estimates of physical activity. In contrast, no significant changes with age in either glucose or insulin responses were noted in men. The ability to document increases in the plasma glucose or insulin responses were noted in men. The ability to document increases in the plasma glucose and insulin responses to a mixed meal suggests that aging, at least in women, is associated with day-long elevations of both plasma glucose and insulin concentrations. The possible relationship of these metabolic changes to the development of atherosclerosis merits further consideration.
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PMID:Effect of age on plasma glucose and insulin responses to a test mixed meal. 703 14

Mental stress often causes myocardial ischemia in patients with coronary artery disease (CAD). There is increasing evidence that the coronary microcirculation of patients with atherosclerosis may be dysfunctional, with the potential of contributing to myocardial ischemia. This study investigated sympathetically mediated coronary microcirculatory and regional noradrenergic effects of mental stress. We measured left anterior descending coronary artery blood flow and norepinephrine kinetics at rest and during a 10-minute video game in 10 CAD patients with nonsignificant atherosclerosis of this artery and in 5 patients with normal coronary angiograms (NCA). The 2 groups did not differ in their responses of systemic and cardiac norepinephrine spillovers, heart rate, and blood pressure during mental stress. Patients with NCA had microvascular dilation during mental stress (26 +/- 9% [mean +/- SD] decline in coronary vascular resistance from baseline, p < 0.01), whereas patients with CAD did not (9 +/- 20% decline, p = 0.11). Six patients with CAD then received intracoronary phentolamine (1.7 micrograms/kg/min for 5 minutes, followed by 0.17 micrograms/kg/min) and played the video game again. In contrast to nonsignificant changes in coronary resistance during the initial video game (6 +/- 15% decline, p = 0.20), coronary vascular resistance decreased significantly during the repeat video game (25 +/- 19% decline, p = 0.02). Vasomotor responses of epicardial coronary artery segments did not differ between the 2 video game studies. Five other patients (4 with CAD, 1 with NCA) repeated the video game during intracoronary administration of 5% dextrose, with systemic and coronary hemodynamic and noradrenergic responses unchanged from those during the initial video game.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Sympathetically mediated effects of mental stress on the cardiac microcirculation of patients with coronary artery disease. 761 Nov 45

Several investigators have reported that feeding a semi-synthetic diet of casein and dextrose to New Zealand White (NZW) rabbits will increase total serum cholesterol concentration, principally through an increase in the beta-lipoprotein fractions, thereby creating a useful model for atherosclerosis research. Although there is evidence to suggest that the dextrose/casein diet alters low-density lipoprotein receptor and bile acid clearance of cholesterol, the underlying mechanism is not completely understood. The effects of the diet on the overall physiology of the rabbit have received little attention. In this study feeding a diet of casein and dextrose of male NZW rabbits for 4 weeks resulted in changes in the serum lipid concentrations. During that time the rabbits fed the dextrose/casein diet gained less weight than did control rabbits. In the test diet rabbits, liver aspartate and alanine transaminase activities were increased from baseline values of 27 +/- 2 U/L and 89 +/- 9 U/L respectively to 112 +/- 21 U/L and 281 +/- 34 U/L respectively, then returned to the high end of the reference range. Necropsy findings included hepatomegaly caused by vacuolar hepatopathy in 19 or 20 experimental rabbits; rabbits fed the control diet had no hepatic lesions. Ultrastructural analysis revealed that enlargement of the liver cells was due to glycogen deposition. Adrenal glands from animals fed the experimental diet had a minimal change in the size of the adrenocortical cells consisting of slight ballooning and rarefaction of the cytoplasm. In a second study the level of dietary fiber was doubled. This resulted in a three-fold increase in lipid concentrations, compared with the fivefold increase in the first study. The liver enzyme activities were increased to the same extent as in the first study. Histologic changes were comparable to those in the first study. The activity of hepatic cholesterol 7alpha-hydroxylase was 3.7 +/- 0.4 pmol/min/mg of protein, compared with the control value of 7.7 +/- 1.1 pmol/min/mg of protein (P < 0.05) in the second study. The improved rate of weight gain and the lesser increase in total serum cholesterol concentration in the second study with increased dietary fiber suggest that two separate activities may be involved. Although the level of dietary fiber may be related to weight gain and total serum cholesterol values, the relation to the decrease in liver transaminase activities in study 1 was probably coincidental. It appears that the dextrose/casein diet causes decreased activity of hepatic cholesterol 7alpha-hydroxylase, which could cause a decrease in the biliary excretion of cholesterol.
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PMID:Hepatic and adrenal changes in rabbits associated with hyperlipidemia caused by a semi-synthetic diet. 874 27

Development of atherosclerosis in diabetes patients is thought to be associated with high D-glucose-induced changes in vascular cell proliferation. This study was designed to investigate the intracellular mechanisms of altered proliferation in porcine aortic endothelial and smooth muscle cells under high D-glucose conditions. Two different technical approaches were used for determination of cell proliferation, a cell counting procedure and bromodeoxyuridine incorporation. D-Glucose diminished endothelial cell proliferation (30.3%) and increased smooth muscle cell proliferation (143%) in a dose-dependent manner. Neither D-mannitol, sucrose nor L-glucose mimicked the effect of D-glucose. Inhibition of D-glucose uptake into vascular cells by cytochalasin B prevented the effect of high D-glucose on cell proliferation. The aldose-reductase inhibitors, sorbinil and zopolrestat, little affected high D-glucose-attenuated endothelial cell proliferation, while the enhanced proliferation of smooth muscle cells was prevented by aldose-reductase inhibitors. Elevation of cellular glutathione levels yielded protection of both cell types from high D-glucose-mediated changes in cell proliferation, suggesting that high D-glucose may act via generation of oxidative species. Finally, aminoguanidine was shown to constitute a very potent inhibitor of D-glucose-induced dysfunction in vascular cell proliferation. These data suggest that high D-glucose-induced changes in cell proliferation of endothelial and smooth muscle cells are related to specific D-glucose uptake rather than hyperosmolality. Aldose-reductase seems to be mainly involved in the effect of high D-glucose only on smooth muscle cell proliferation, while in endothelial cells there is (are) other factor(s) in addition to the sorbitol pathway involved in high D-glucose-induced changes in cell proliferation.
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PMID:Intracellular mechanism of high D-glucose-induced modulation of vascular cell proliferation. 878 35

Following a screening program for orally active antithrombotic drugs, it was found that a series of thioxyloside compounds presented with good venous antithrombotic properties. Of more than 500 compounds, LF 09-0055, LF 04-0212, and LF 05-0030 were the most active at inhibiting venous thrombus formation in the rat and rabbit Wessler model after intravenous and oral dosing. LF 05-0030 showed the greatest activity with an ED80 value of 6 mg/kg on oral administration in rats. This activity was maintained in several different models of venous thrombosis and shown to be devoid of anticoagulant effects or hemorrhage. Kinetic studies have demonstrated that maximal levels of activity, following either intravenous or oral dosing, occurred between 2 and 4 hours after administration. This may reflect the type of mechanism involved, since it has been well documented in the literature that xylosides are capable of initiating glycosaminoglycan (GAG) synthesis. Moreover, in vitro galactosyltransferase 1 (the second enzyme involved in GAG polymerization) enzymic assays showed that these thioxyloside derivatives were good acceptors for galactose transfer and therefore at initiating GAG formation. Further in vivo experimentation demonstrated that after treatment by these molecules an important elevation in circulating GAG occurred, with LF 05-0030 presenting the greatest activity, being five times higher than control levels. In addition it was found that dermatan sulfate levels, expressed as antithrombin activity by heparin cofactor II, were significantly increased over control values. As such, this dermatan sulfate moiety is believed to support the antithrombotic activity observed. Studies are underway to investigate the activity of these interesting molecules in atherosclerosis and other vessel wall diseases.
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PMID:Pharmacologic and biochemical profiles of new venous antithrombotic beta-D-xyloside derivatives: potential antiathero/thrombotic drugs. 883 9

The adherence of circulating monocytes to the endothelium, their migration into the subendothelium, and the subsequent formation of foam cells are initial events in the pathogenesis of atherosclerosis. However, the effect of hyperglycemia on the transendothelial migration of monocytes is not known. Exposure of human umbilical vein endothelial cells (HUVEC) cultured in a Transwell chamber to 25 mM D-glucose (a concentration representing a hyperglycemic state) for 2 h resulted in a twofold increase in the migration of vitamin D3-differentiated monocyte-like HL-60 cells. The migration was inhibited by addition of either an antibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1) or a protein kinase C inhibitor, GF-109203X. In HUVEC, high concentrations of D-glucose (25 mM), but not of other sugars such as L-glucose, 2-deoxyglucose, D-galactose, or D-mannitol, caused a sevenfold increase in the phosphorylation of PECAM-1 as a result of activation of protein kinase C. The 25 mM D-glucose-induced PECAM-1 phosphorylation and transmigration of monocyte-like HL-60 cells were further increased by treatment of HUVEC with the phosphatase inhibitor calyculin A. These results suggest that direct phosphorylation of PECAM-1 in response to elevated glucose promotes transendothelial migration of monocytes, contributing to accelerated atherogenesis in diabetics.
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PMID:Glucose-induced transmigration of monocytes is linked to phosphorylation of PECAM-1 in cultured endothelial cells. 889 59

Endothelial cells are known to secrete various antiproliferative and vasodilating factors. Although injury of endothelial cells has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes, the mechanisms of endothelial injury in diabetes are not yet clarified. Therefore, it is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. To investigate the effects of high glucose on vascular cells, we examined 1) the effects of high glucose on endothelial cell and vascular smooth muscle cell (VSMC) growth and 2) the effects of high glucose on local HGF production in endothelial cell and VSMC. Treatment of human aortic endothelial cell with a high concentration of D-glucose, but not mannitol and L-glucose, resulted in a significant decrease in cell number. Interestingly, addition of recombinant HGF attenuated high D-glucose-induced endothelial cell death. Therefore, we measured local HGF secretion of endothelial cell. Importantly, local HGF production was significantly decreased by high D-glucose treatment. In contrast, high D-glucose treatment resulted in a significant increase in the number of human aortic VSMCs, whereas local HGF production was significantly decreased in accordance with increase in D-glucose concentration. No significant changes in numbers were observed in VSMC treated with high mannitol and L-glucose. We also studied the mechanisms of local HGF suppression by high D-glucose. High D-glucose treatment stimulated transforming growth factor-beta (TGF-beta) concentration in endothelial cell and VSMC. Decreased local vascular HGF production was abolished by addition of anti-TGF-beta antibody. As TGF-beta inhibited local HGF production in endothelial cell and VSMC, increased TGF-beta induced by high D-glucose may suppress local HGF production. This study demonstrated that high D-glucose induced endothelial cell death, stimulated VSMC growth, and decreased local HGF production through the stimulation of TGF-beta production both in endothelial cell and VSMC. Overall, decrease in a local endothelial stimulant, HGF, by high D-glucose may be a trigger of endothelial injury in diabetes, potentially resulting in the progression of atherosclerosis.
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PMID:Potential role of an endothelium-specific growth factor, hepatocyte growth factor, on endothelial damage in diabetes. 897 Oct 94

Glucose transport activity in cultured rat vascular smooth muscle cells (VSMCs) was examined under various concentrations of D-glucose, insulin, and insulin-like growth factor-I (IGF-I). Confluent cultures of VSMCs were incubated with serum-free medium containing 0-25 mmol/l of D-glucose for 24-49 h. The basal rate of 2-deoxyglucose uptake was reduced in association with increasing concentrations of D-glucose. Uptake of 2-deoxyglucose into the cells was linear between 0 and 15 min of incubation regardless of the glucose concentration. The uptake was inhibited by the addition of 10 mumol/l cytochalasin B or 100 mmol/l D-glucose indicating that the effects were mediated by specific integral glucose carriers. The effect of D-glucose was time-dependent and reversible. Insulin increased the uptake of 2-deoxyglucose in a dose-dependent manner, and its effect was dependent on the preincubation dose of D-glucose. Insulin-stimulated uptake was lower in the cells pre-exposed to 25 mmol/l D-glucose than in the cells pre-exposed to concentrations of D-glucose below 5.5 mmol/l. After a long-term incubation with insulin, the insulin-stimulated glucose transport was inhibited. Recovery of glucose transport activity was assessed by incubating cells with D-glucose for 24-48 h to induce desensitization. After a 24 h glucose conditioning, the uptake of 2-deoxyglucose was lower in the cells preincubated with 25 mmol/l glucose than in the cells preincubated with 5.5 mmol/l glucose. The effect of the glucose conditioning was reversible and dependent on the preincubation dose of D-glucose. IGF-I was a more potent stimulator of glucose transport than insulin. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase), inhibited the uptake of glucose stimulated by insulin or IGF-I in a dose-dependent manner. Our results suggest that D-glucose regulates its own uptake independently of insulin and modulates the ability of insulin to induce insulin resistance in the cultured rat VSMCs. Glucose attenuated the effect of insulin, and led to a progressive decrease in the activity of the glucose transport effector system. Activation of wortmannin-sensitive PI3-kinase may be involved in the signaling pathways of the insulin- and IGF-I-stimulated glucose uptake in VSMCs. This mechanism of insulin resistance may be relevant to the formation of cellular defects in the vascular wall in patients with diabetes mellitus.
Atherosclerosis 1996 Nov 15
PMID:Effect of glucose, insulin, and insulin-like growth factor-I on glucose transport activity in cultured rat vascular smooth muscle cells. 900 4

The present study was performed to elucidate the mechanism underlying the anti-atherogenic action of estrogen. We investigated the effect of estrogen on intimal thickening of the rat femoral artery induced by cuff placement and further examined the effect of estrogen on migration and proliferation of vascular smooth muscle cells (VSMCs) in culture. Intimal thickening was significantly greater in males than in control females. Intimal thickening in females was increased to the level in males by ovariectomy. Estrogen replacement to ovariectomized rats reversed this effect. Proliferating cell nuclear antigen immunohistochemistry showed that in vivo proliferation of VSMCs contributed to the difference in intimal thickening. There was no difference in blood pressure and serum lipids, suggesting that estrogen directly acted on artery and inhibited intimal thickening. 17 beta-Estradiol (E2, 1-100 nmol/l) inhibited migration of cultured rat VSMCs, assayed using a microchemotaxis chamber, in a concentration-dependent manner. E2 (0.01-100 nmol/l), but not progesterone or testosterone, also inhibited [3H]thymidine incorporation in rat VSMCs in a concentration-dependent manner. Indomethacin, NG-monomethyl-L-arginine and methylene blue did not influence the inhibitory action of E2 on [3H]thymidine incorporation, suggesting that prostanoids and nitric oxide are not involved in the action of E2. E2 did not provoke VSMC injury, as measured by the release of incorporated [3H]2-deoxy-D-glucose. These results suggest that the inhibition of migration and proliferation of VSMCs contributes to the inhibitory effect of estrogen on intimal thickening.
Atherosclerosis 1997 Apr
PMID:Estrogen inhibits cuff-induced intimal thickening of rat femoral artery: effects on migration and proliferation of vascular smooth muscle cells. 912 42


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