Renal carcinoma presenting with adrenocortical insufficiency due to a pituitary metastasis.
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Adenocarcinoma, Clear Cell↗
Biomedical subjects
G A Ferns
Publications and source records attributed to G A Ferns.
The possible role of copper ions in atherogenesis: the Blue Janus.
It has been proposed that the oxidative modification of low density lipoprotein (LDL) is a key event in human atherogenesis. Copper ions can catalyse the oxidative modification of LDL in vitro and there is some evidence that they may also participate in the oxidation of LDL within the arterial wall. However, copper ions also form an intrinsic constituent of superoxide dismutase and caeruloplasmin, enzymes that may be involved in preventing oxidative injury. Atherosclerotic lesions frequently contain considerable quantities of extracellular matrix molecules. These may contribute to the expansion of the arterial neointima, causing luminal narrowing. They may also play a beneficial role by stabilising the plaque. Copper is an essential component of lysyl oxidase, an enzyme involved in the biosynthesis of collagen, which is a major constituent of the extracellular matrix. The impact of alterations in body copper status on atherogenesis is therefore difficult to predict. Experimental and epidemiological data are conflicting and therefore do not provide a clear resolution of this issue. We have reviewed the biochemical and cellular effects of copper ions that may play a role in atherogenesis.
Arteriosclerosis↗
Dietary vitamin E supplementation inhibits thrombin-induced platelet aggregation, but not monocyte adhesiveness, in patients with hypercholesterolaemia.
Several recent studies have indicated the possible beneficial effects of antioxidants, specifically vitamin E, in primary and secondary coronary prevention. These studies suggest that a diet enriched in vitamin E is insufficient to have a significant protective effect, whereas supplements, in excess of 200 international units (IU) per day, are efficacious in preventing coronary disease in both men and women. The mechanisms by which vitamin E may exert its protection are uncertain, but, vitamin E is lipophilic and has been shown to inhibit the oxidative modification of low density lipoprotein (LDL), a process thought to be of crucial importance in atherogenesis. We have also previously shown that alpha-tocopherol (the biologically most potent isomer of vitamin E) has important direct effects on vascular endothelial and smooth muscle cells. In the present study we have investigated the effects of oral supplements of vitamin E (400 IU per day) on platelet and mononuclear cell function in patients with hypercholesterolaemia. We found that although vitamin E supplementation had no significant effect on mononuclear cell adhesion ex vivo, it had a significant effect on the thrombin-induced platelet aggregation (P < 0.01; ANOVA): 6 weeks after starting the vitamin E supplements, the mean EC50 for thrombin-induced aggregation increased 132% (P < 0.05; paired t-test) compared to treatment with placebo. The effects of vitamin E on platelet function may, in part, explain its anti-atherogenic properties.
Adult↗
Endogenously elicited antibodies to platelet derived growth factor-BB and platelet cytosolic protein inhibit aortic lesion development in the cholesterol-fed rabbit.
Several studies have indicated that growth factors, such as platelet derived growth factor (PDGF), may be important in atherogenesis. These factors are released from platelets, or expressed by cells of the arterial wall. In order to study their role in atherogenesis more directly, rabbits were immunized with PDGF-BB, platelet cytosolic protein, or human serum albumin (HSA), until high titres of antibody were attained. Atherosclerotic lesions were subsequently induced by feeding the animals with a 2% cholesterol enriched diet. At the end of approximately 3 months, the extent of aortic lesion development was assessed by image analysis of en face preparations of aortae stained with Oil Red-O, and histological segments of aortae taken at the level of the first intercostal artery branch point. The endogenous antibodies were characterized with respect to their cross-reactivity, and ability to neutralize PDGF and platelet cytosol-induced cell proliferation and migration in vitro. The endogenous, anti-PDGF-BB antibody was isoform specific, and neutralized the mitogenic and chemotactic properties of PDGF-BB and rabbit platelet cytosolic protein in vitro. The anti-platelet cytosol antibody partially inhibited the chemotactic and mitogenic properties of rabbit platelet cytosolic protein. Compared to non-immune rabbits (n = 5), animals immunized with HSA (n = 4) had a significantly larger area of aortic lesion involvement (P < 0.01), whereas aortic lesions in rabbits immunized with PDGF-BB (n = 5), or platelet cytosolic protein (n = 7) were significantly smaller than either non-immune animals, or animals immunized with HSA (P < 0.05). The same pattern was observed for other measures of aortic lesion involvement including aortic intima:media ratio at the level of the first intercostal artery. These data suggest that PDGF-BB, and possibly other platelet-associated growth factors, are involved in cholesterol-induced atherosclerosis.
Animals↗
Recombinant insulin-like growth factor-1 modulates aggregation in human platelets via extracellular calcium.
Insulin like growth factor-1 (IGF-1) potentiated aggregation of human platelets induced by thrombin-, collagen- and ADP in a dose-dependent manner over the range 30-300 nM. IGF-1 (100 nM) reduced EC50 values for thrombin, collagen and ADP-induced aggregation by 19.6%, 53.6% and 22.8% respectively. Potentiation by IGF-1 was dependent on the presence of extracellular Ca2+ and was inhibited by verapamil or nifedipine. Further, IGF-1 enhanced the elevation in free intraplatelet Ca2+ induced by the platelet agonists collagen and thrombin.
Adenosine Diphosphate↗
Insulin-like growth factor-I modulates monocyte adhesion to EAhy 926 endothelial cells.
IGF-I is a ubiquitous growth factor, found in platelets and elaborated by many other cell types. It is thought to be involved in several pathophysiological processes including embryonic development, angiogenesis and wound healing. We report that the adherence of human peripheral blood monocytes to an endothelial cell line (EAhy 926) is inhibited in a dose and time-dependent manner by pre-incubating the endothelial cells with IGF-I (P < 0.001). Monocyte adhesion was inhibited 17.9 +/- 1.9% by IGF-I at a dose of 1000 ng/ml (P < 0.01). In contrast, IGF-I had no significant effect on monocyte adherence to plastic. The inhibitory effects of IGF-I were reversed by co-incubating the endothelial cells with the nitric oxide synthase inhibitor, L-NAME. These data suggest that the effects of IGF-I are mediated by the release of nitric oxide from the endothelial cells.
Adult↗
Hyaluronan (HYAL-BV 5200) inhibits neo-intimal macrophage influx after balloon-catheter induced injury in the cholesterol-fed rabbit.
Hyaluronan is a glycosaminoglycan, elaborated by several cell types, and is a major constituent of the extracellular matrix. Recent studies suggest that hyaluronan influences cell migration and proliferation. At high concentrations, it has been shown to inhibit macrophage migration in vitro. We have investigated the effects of hyaluronan administration on neo-intimal lesion development following balloon catheter injury of the common carotid artery in the cholesterol-fed New Zealand White rabbit. Hyaluronan, administered as sodium hyaluronate at the time of surgery and daily until sacrifice, 2 weeks later, reduced the absolute neo-intimal response to injury by 42% (117 +/- 16 microns to 68 +/- 11 microns; P < 0.05), and the intima-media ratio by 35% (0.91 +/- 0.10 to 0.59 +/- 0.11; P < 0.05). This was associated with a 62% reduction in intimal macrophage content (8.63 +/- 1.85% to 3.25 +/- 1.05%; P < 0.02). At the time of killing, serum cholesterol levels and weight gain were comparable between the groups of animals receiving a cholesterol diet (P > 0.05). In both groups mean serum cholesterol levels at the time of the balloon injury and killing were significantly greater than at entry (P < 0.001), and significantly higher than in a group receiving control chow (P < 0.001). These data suggest that the effect of hyaluronic acid on neo-intimal size may be mediated, in part, by an inhibition of monocyte/macrophage influx, and support the view that hyaluronan impairs monocyte migration.
Angioplasty, Balloon↗
Recent insights into the mechanisms of iatrogenic arteriosclerosis.
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Angioplasty, Balloon, Coronary↗
Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat.
We have investigated the effect of the naturally occurring, lipid-soluble antioxidant, vitamin E, on the intimal response to balloon injury in the cholesterol-fed rat. We found that in animals receiving a 0.5% vitamin E plus 1% cholesterol diet, neo-intimal thickening was reduced by 30% (P < 0.025) compared to animals receiving either cholesterol alone, or a control chow diet. In all three dietary groups, the intimal lesion consisted predominantly of smooth muscle cells, and few monocytes/macrophages (< 0.5%) could be identified by staining with the monoclonal antibody ED-1. In vitro, vitamin E inhibited platelet-derived growth factor- (PDGF) (20 ng/ml) and serum (2%)-induced mitogenesis of both adult rat thoracic aortic smooth muscle cells and an embryonic rat aortic smooth muscle cell line (A7r5), dose-dependently. These data suggest that reactive oxygen species may be involved in the intimal response to balloon catheter injury, and that antioxidants, such as vitamin E, may offer some protection against restenosis. Although the way by which it does so is unclear, one possible mechanism is by a direct inhibitory effect on the accumulation of smooth muscle cells within the developing neo-intima.
Analysis of Variance↗
Insulin-like growth factor binding protein-1 inhibits arterial smooth muscle cell proliferation in vitro but does not reduce the neointimal response to balloon catheter injury.
The biological effects of the insulin-like growth factors (IGFs) are modulated by circulating binding proteins (BPs), including IGFBP-1. We have investigated the effects of recombinant IGFBP-1 on smooth muscle cell (SMC) proliferation in vitro using cultured rat aortic SMCs and in vivo using the ballooned rat carotid artery model. IGFBP-1 inhibited IGF-1 induced and spontaneous SMC proliferation dose-dependently. In vivo, the effective half-life of IGFBP-1 was approximately 5 h when administered by intraperitoneal injection. High peri-operative plasma levels of IGFBP-1 (mean 1780 ng/ml) were attained by giving and intravenous dose immediately prior to balloon injury in 9 rats. Animals injected with human serum albumin or saline were used as controls. In vivo cell proliferation was assessed by BrdU pulse labeling each animal prior to the termination of the experiment, 6 days after balloon injury. Absolute intimal thickness, intima-media ratio and cell proliferation indices were measured for each animal. Although IGFBP-1 inhibited SMC proliferation in vitro, high plasma concentrations of IGFBP-1 did not reduce neointimal size or cell proliferation. IGFBP-1 administration was, however, associated with a significantly greater loss of body weight (P < 0.05), indicating that the peptide had a profound metabolic effect. Our data suggest that IGF-1 does not have a major role in inducing SMC proliferation in the early phases following angioplasty.
Animals↗
Differences in onset of impaired endothelial responses and in effects of vitamin E in the hypercholesterolemic rabbit carotid and renal arteries.
Hypercholesterolemia (HC) is known to be associated with impaired endothelium-mediated responses in the vasculature. Evidence suggests that increased levels of reactive oxygen species (ROS) in the vessel wall may contribute to the impairment by decreasing the biological activity of endothelium-derived relaxing factor (EDRF). We compared the relative onset of HC-induced impairment of endothelial responses in the carotid and renal arteries and investigated the potentially beneficial effect of the antioxidant vitamin E. Rabbits were fed a 1% cholesterol-enriched diet for 4 and 8 weeks, and vascular responses were compared using isolated ring segments of the carotid and renal arteries. In the carotid artery, relaxant responses to acetylcholine (ACh) were significantly and progressively impaired after 4 and 8 weeks; in the renal artery, however, responses were only slightly impaired after 8 weeks. There were no changes in responsiveness to A23187 or sodium nitroprusside (SNP) in either artery. We tested the effect of 0.2% vitamin E by adding it to the diet for 4 weeks, after an initial 4-week of feeding of 1% cholesterol alone. Vitamin E reversed impaired responses to ACh in the carotid but not the renal artery and also enhanced relaxant responses to A23187. We conclude that the carotid artery is more susceptible than the renal artery to HC-induced endothelial impairment and that ROS may play a role in this impairment in the carotid artery but not in the renal artery.
Animals↗
Tissue distribution of alpha-tocopherol following dietary supplementation in the rat: effects of concomitant cholesterol feeding.
Vitamin E is a potent, naturally occurring, lipid-soluble antioxidant, which is reported to be protective against several disease processes, including coronary atherosclerosis. We have measured the alpha-tocopherol content of the aorta, liver, skeletal muscle, and kidney of rats fed one of the following diets for 10 weeks: a normal control chow diet (i); or the same diet containing 1% cholesterol (ii); 0.5% vitamin E (iii); or 1% cholesterol plus 0.5% vitamin E (iv). The alpha-tocopherol content of serum and tissue extracts was measured by HPLC using gamma-tocopherol as an internal standard. Tissue and serum cholesterol content was measured using a cholesterol oxidase enzyme reagent kit. In all animals receiving the 1% cholesterol diet, serum cholesterol levels increased significantly (P < 0.005). By the 10th week, mean serum alpha-tocopherol levels rose significantly in both groups of animals receiving dietary vitamin E supplements (P < 0.0001) compared with their respective control group. This was accompanied by a significant increase in the absolute alpha-tocopherol content of liver (8- to 9-fold) and aorta (3- to 4-fold). The alpha-tocopherol content of renal and skeletal muscle tissue was raised 1- to 2-fold in both groups of rats on vitamin E supplements, however the increased attained significance only for the renal tissue. The aortic tissue alpha-tocopherol/cholesterol ratio was 4-fold higher in the rats receiving concomitant 1% cholesterol plus 0.5% vitamin E compared with animals receiving 1% cholesterol alone (P < 0.02), and was 5-fold higher in the rats receiving 0.5% vitamin E compared with those receiving control chow (P < 0.01). These data suggest that dietary vitamin E supplementation results in a differential uptake of alpha-tocopherol, which may be dependent, in part, on selective lipoprotein particle accumulation.
Animal Feed↗
Oxidative modification of low-density lipoprotein by human polymorphonuclear leucocytes to a form recognised by the lipoprotein scavenger pathway.
The oxidative modification of low-density lipoprotein (LDL) results in the formation of cytotoxic and chemotactic lipids which are thought to be of importance in the development of atherosclerotic lesions. In the present study we show that polymorphonuclear leucocytes (PMNs) can modify LDL to a form which is rapidly incorporated by macrophages via a scavenger receptor pathway. Incubation of 125I-labelled LDL with PMNs in Ham's F-10 medium resulted in oxidation as shown by the appearance of thiobarbituric acid-reactive substances, increased electrophoretic mobility of the LDL and increased degradation of the LDL by mouse peritoneal macrophages. The presence of the anti-oxidant butylated hydroxytoluene or the metal ion chelator, EDTA inhibited the PMN-mediated modification. The degradation of 125I-labelled PMN modified LDL by macrophages was competitively inhibited by unlabelled copper-oxidised LDL but not by native LDL, indicating that the degradation was mediated by the scavenger receptor. The oxidative modification of LDL by PMNs could be of pathophysiological importance in inflammation and in the accelerated atherosclerosis seen following cardiac reperfusion injury.
Animals↗
Measurement of plasma probucol levels by high-performance liquid chromatography.
An improved assay for measuring plasma levels of probucol using reversed-phase high-performance liquid chromatography has been developed and used to measure probucol in cholesterol-fed rabbits. The sample was extracted with iso-octane, reconstituted in acetonitrile and was analysed using a Hypersil ODS column with a mobile phase consisting of acetonitrile-water (96:4, v/v). Detection was carried out using ultraviolet absorption at 241 nm. The lower detection limit for plasma probucol was 0.5 micrograms/ml. Inter-assay and intra-assay coefficients of variation were 1.8-4.8% and 1.6-3.3%, respectively. The method was applied to measurements of probucol in plasma from rabbits receiving a diet containing 1% probucol and 2% cholesterol for five weeks. Probucol levels at five weeks were significantly higher in the animals receiving concomitant cholesterol, and were close to the steady-state values predicted from the one week measurements. Also, the plasma probucol levels were positively correlated with total plasma cholesterol (r = 0.87, p < 0.001). The results indicate that bioavailability of probucol is dependent on the lipid content of the diet.
Animals↗
Vitamin E reverses cholesterol-induced endothelial dysfunction in the rabbit coronary circulation.
Hypercholesterolaemia and atherosclerosis are associated with impaired endothelium-dependent vasodilation. In this study we have examined the effects of vitamin E on cholesterol-induced endothelial dysfunction in the rabbit coronary circulation. Rabbits were maintained for 4 or 8 weeks on one of three experimental diets: (a) control chow, (b) 1% cholesterol or (c) 1% cholesterol for the first half of the treatment period followed by 1% cholesterol + 0.2% vitamin E during the last half of the treatment. After sacrifice, vasodilator responses to acetylcholine and sodium nitroprusside in the isolated perfused heart were studied. Responses to sodium nitroprusside were similar between the groups whereas responses to acetylcholine were significantly impaired in cholesterol-fed rabbits after both 4 and 8 weeks when compared to controls. In the cholesterol + vitamin E group, responses to acetylcholine were similar to controls and significantly greater than in the group receiving cholesterol alone. These results show that both 4 and 8 weeks of cholesterol-feeding induces an endothelial dysfunction in the coronary circulation of the rabbit, and that vitamin E protects against this dysfunction. By comparing responses to acetylcholine in the 4 week cholesterol group with the 8 week cholesterol + vitamin E group it was shown that vitamin E may not only prevent further deterioration of the endothelial function in the rabbit heart, but may also reverse the adverse effects of hypercholesterolaemia.
Acetylcholine↗
Dietary vitamin E increases the resistance to lipoprotein oxidation and attenuates endothelial dysfunction in the cholesterol-fed rabbit.
This study was conducted to determine if vitamin E could reverse or attenuate endothelial dysfunction following an atherogenic diet. Rabbits were initially fed 1% cholesterol for 4 weeks to induce endothelial dysfunction. During the next 4 weeks the rabbits were fed either 1% cholesterol +0.2% vitamin E or 1% cholesterol alone, and were then killed. Endothelium-dependent responses to acetylcholine, calcium ionophore A23187 and sodium nitroprusside (SNP) were studied in the preconstricted perfused rabbit ear. Dietary vitamin E partially reversed the impaired endothelium-dependent responses to acetylcholine associated with cholesterol feeding. The maximum decrease in perfusion pressure in response to acetylcholine was 77.8% +/- 3.6% in control animals, 35.3% +/- 2.6% in cholesterol-fed animals, and 49.1% +/- 4.7% in cholesterol+vitamin E treated animals. The response to A23187 or sodium nitroprusside did not differ between the groups. The susceptibility of rabbit beta-VLDL to oxidation was markedly decreased in the vitamin E treated animals as assessed by the formation of conjugated dienes. The formation of lipid peroxidation products were also significantly inhibited by vitamin E. These data suggest that dietary vitamin E is beneficial in reducing the oxidative injury that may lead to the impairment of nitric oxide (NO)-mediated responses in early hypercholesterolaemia.
Acetylcholine↗
Vitamin E restores endothelium dependent vasodilatation in cholesterol fed rabbits: in vivo measurements by photoplethysmography.
OBJECTIVE: Pulse curve plethysmography was used to examine the effect of vitamin E on endothelium dependent and independent vasodilatation in unanaesthetised cholesterol fed rabbits in vivo. The height of the dicrotic notch was used as an index of general arterial vasodilatation. METHODS: Twenty eight rabbits were divided into three study groups; a control group (group 1, n = 8), a group fed 1% cholesterol (group 2, n = 10), and a group fed 1% cholesterol with the addition of 0.2% vitamin E after four weeks (group 3, n = 10). After six weeks on diet the vasodilator responses to acetylcholine and glyceryl trinitrate were measured by photoplethysmography of the rabbit ear. Recordings were made during light sedation at baseline and during infusion of acetylcholine (1.5, 3.0, 6.0, and 12 micrograms.min-1) and glyceryl trinitrate (3.75, 7.5, and 15.0 micrograms.min-1). In a second set of experiments with control fed rabbits (n = 5), acetylcholine infusions were given before and after infusion of L-nitro-arginine (15 mg). RESULTS: The relative height of the dicrotic notch (which predominantly indicates arterial tone in the larger vessels) was reduced by acetylcholine in a dose dependent manner, but in cholesterol fed rabbits (group 2) this response was significantly decreased. Rabbits receiving concomitant dietary vitamin E responded in a similar manner to controls. The difference was most prominent using acetylcholine at a dose of 3.0 micrograms.min-1, where the mean change from baseline was 11(SEM 4)% in group 2, compared to 31(6)% in group 1 (p = 0.01), and to 26(5)% in group 3 (p = 0.02). Similar differences between the groups were observed for the increase in heart rate during acetylcholine infusions. In contrast, the responses to glyceryl trinitrate were similar in all groups. After infusions of L-nitro-arginine, the responses to acetylcholine were blunted. CONCLUSIONS: Supplementation with vitamin E restored the otherwise reduced vascular response to acetylcholine in cholesterol fed rabbits. Analysis of photoplethysmographic pulse curves is a simple non-invasive method of evaluating arterial vasodilator effects. However, the nature of the measured dilator response needs to be characterised further.
Acetylcholine↗
Vitamin E protects against impairment of endothelium-mediated relaxations in cholesterol-fed rabbits.
The vascular effects of dietary vitamin E were investigated in isolated carotid artery preparations from cholesterol-fed New Zealand White rabbits. Rabbits were fed either a control, 1% cholesterol, or 1% cholesterol plus 0.2% vitamin E diet for 4 weeks. In raised-tone preparations, relaxant responses to acetylcholine were enhanced in rabbits fed cholesterol plus vitamin E, reversing the reduction in responses measured in preparations from cholesterol-fed rabbits. Relaxant responses to the calcium ionophore A23187 were significantly enhanced in cholesterol plus vitamin E-fed rabbits compared with those fed cholesterol alone, with no difference between control and cholesterol-fed rabbits. Relaxant responses to sodium nitroprusside were not different between the three dietary groups. Constrictor responses to noradrenaline and serotonin in isolated carotid artery preparations at basal tone were unaltered after cholesterol and cholesterol plus vitamin E diets. The copper-induced oxidation of beta-very-low-density lipoproteins (beta VLDL) isolated from plasma of rabbits fed a cholesterol plus vitamin E diet was almost completely inhibited compared with the oxidation of beta VLDL from rabbits fed cholesterol alone. These results show that vitamin E prevents endothelial dysfunction associated with cholesterol feeding and suggests that vitamin E may be beneficial in preventing functional impairment associated with atherosclerosis.
Animals↗