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Biomedical subjects

G A Ferns

Publications and source records attributed to G A Ferns.

At least 55 records · Page 3Linked to original sources
PubMed1993

Probucol inhibits mononuclear cell adhesion to vascular endothelium in the cholesterol-fed rabbit.

Mononuclear cells, isolated from the blood of hyperlipidaemic patients, are hyper-reactive and possess an increased propensity to adhere to vascular endothelial cells. Hyperlipidaemia is also associated with a dysfunctional endothelium, to which mononuclear cells stick with greater avidity. In order to assess the importance of lipid peroxidation and free-radical generation in these processes, we have investigated the effects of probucol on mononuclear cell adhesion to vascular endothelial cells in vivo and in vitro in the cholesterol-fed rabbit. New Zealand White rabbits were fed either: (i) control chow (n = 15), (ii) 2% cholesterol (n = 11), or (iii) 2% cholesterol with 1% probucol (n = 11). Mononuclear cell adherence to endothelium in the common carotid artery was assessed 5 weeks after the start of the experimental diet using the Hoechst 33342 staining technique. The 2% cholesterol diet caused a more than 6-fold increase in mean mononuclear cell adherence (P < 0.001). Concurrent probucol therapy abrogated the effects of cholesterol feeding, and in animals in this group, in vivo mononuclear cell adherence did not differ significantly from control animals. In vivo mononuclear cell adherence was directly related to serum cholesterol levels (r = 0.68, P < 0.0001) and inversely related to serum probucol concentrations (r = -0.63, P < 0.002). Concurrent probucol therapy also reduced the in vitro binding of mononuclear cells, isolated from hypercholesterolaemic animals, to endothelial cell monolayers (P < 0.01). These data suggest that the increased binding of mononuclear cells to vascular endothelium of cholesterol-fed rabbits may be a free radical mediated process that is inhibited by antioxidants.

Animals↗
PubMed1993

Vitamin E: the evidence for an anti-atherogenic role.

Vitamin E is the major lipid-soluble antioxidant present in blood. It acts synergistically with other circulating and cellular antioxidants, to protect cells from damage and lysis induced by oxidative stress. Most of the vitamin E in blood plasma is present in the low density lipoprotein (LDL) fraction, hence it is optimally placed to prevent free-radical mediated modification of this lipoprotein. There is compelling evidence indicating that LDL oxidation, which occurs during atherogenesis and which is probably involved in lesion initiation and progression, is inhibited by vitamin E, and it has been proposed that vitamin E may be anti-atherogenic by virtue of its antioxidant properties alone. However recent studies suggest it may also act by other mechanisms.

Animals↗
PubMed1992

Probucol inhibits neointimal thickening and macrophage accumulation after balloon injury in the cholesterol-fed rabbit.

Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.

Animals↗
PubMed1992

Arterial response to mechanical injury: balloon catheter de-endothelialization.

Coronary angioplasty has been used clinically for over a decade. Its initial promise as an alternative to coronary bypass surgery has only partially been fulfilled because of the high rate of post-operative restenosis. A number of animal models have been devised to study this phenomenon and although none is entirely satisfactory, they have, together with recent advances in molecular biology provided an insight into the cellular mechanisms that may contribute to this complication. This knowledge may ultimately lead to a means of therapeutic intervention. This review summarises our present understanding of the pathology of post-angioplasty re-stenosis as revealed by studies using the balloon catheter de-endothelialization model, and discusses some of the intervention strategies that have been attempted.

Angioplasty, Balloon↗
PubMed1991

Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF.

Approximately 30 to 40 percent of atherosclerotic coronary arteries treated by angioplasty or by bypass surgery occlude as a result of restenosis. This restenosis is due principally to the accumulation of neointimal smooth muscle cells, which is also a prominent feature of the advanced lesions of atherosclerosis. The factors responsible for the accumulation of intimal smooth muscle cells have not been identified. Platelet-derived growth factor (PDGF) is a potent smooth muscle chemoattractant and mitogen. It is present in platelets and can be formed by endothelium, smooth muscle, and monocyte-derived macrophages. The development of an intimal lesion in the carotid artery of athymic nude rats induced by intraarterial balloon catheter deendothelialization was inhibited by a polyclonal antibody to PDGF. These data demonstrate that endogenous PDGF is involved in the accumulation of neointimal smooth muscle cells associated with balloon injury and may be involved in restenosis after angioplasty, and perhaps in atherogenesis as well.

Angioplasty, Balloon↗
PubMed1991

The insulin-like growth factors: their putative role in atherogenesis.

Smooth muscle cell proliferation and leukocyte infiltration are characteristic features of all lesions of atherosclerosis. Although platelet derived growth factor (PDGF) is one of the major smooth muscle mitogens, other important mitogenic factors are found in plasma and in platelets. The insulin-like growth factors (IGF-I and IGF-II) are present in plasma complexed to one of a number of IGF-binding proteins (IGF-BP). They are also found at high concentrations within the alpha-granules of platelets. The IGFs are secreted by a number of cell types in-vitro and in-vivo, including smooth muscle cells and macrophages. The cellular effects of the IGFs are mediated by membrane bound high affinity receptors. IGF receptors are of two distinct types and are expressed by a wide variety of cells. The IGFs are potent smooth muscle cell mitogens and it is therefore possible that these polypeptides contribute to the formation of the atherosclerotic lesion by paracrine, autocrine or endocrine mechanisms.

Animals↗
PubMed1991

Balloon catheter de-endothelialization of the nude rat carotid. Response to injury in the absence of functional T lymphocytes.

The development of an intimal proliferative lesion after balloon catheter de-endothelialization was studied in congenitally athymic nude rats lacking T lymphocytes. Significant intimal thickening was observed in both the homozygous (nu/nu) and euthymic heterozygous (nu/+) animals 6 days after injury, which increased further after 10 days. There was no significant difference in mean intimal:medial cross-sectional area between the nu/nu and nu/+ animals at either time. Approximately 1% of the cells in the neointima of both groups of animals were leukocytes (OX-1 positive); 0.7% were macrophages (ED-1 positive). In neither nu/nu nor nu/+ animals did T lymphocytes (OX-19-positive cells) constitute more than 0.1% of the neointimal cell population. These data suggest that T lymphocytes do not play a significant role in the accumulation of neointimal cells. The presence of macrophages within the lesions raises the possibility that they may be involved in the recruitment and proliferation of smooth muscle cells. In vitro characterization of nu/nu carotid medial smooth muscle cells demonstrated approximately 500,000 binding sites for platelet-derived growth factor (PDGF)-BB and few PDGF-AA binding sites (less than 10,000). The mitogenic and chemotactic responses of these cells to the three dimeric forms of PDGF correlated with this receptor subunit distribution. Platelet-derived growth factor accounted for approximately 50% of the mitogenic activity of a rat platelet releasate. Platelet-derived growth factor-BB and PDGF-AB were both potent chemotactic agents for the nude rat carotid smooth muscle cells with a peak response at approximately 10 ng/ml. In contrast, PDGF-AA, transforming growth factor beta, and basic fibroblast growth factor were only weak chemoattractants for these cells.

Animals↗
PubMed1990

Relative platelet-derived growth factor receptor subunit expression determines cell migration to different dimeric forms of PDGF.

Platelet-derived growth factor (PDGF) receptor transfectants of a fibroblastoid cell line (BHK) have been used to investigate the ability of the three dimeric forms of PDGF to elicit a chemotactic response. Cells transfected with the beta receptor subunit were only responsive to PDGF-BB, whereas cells expressing the alpha-receptor subunit were equally responsive to all three dimeric forms, PDGF-AA, PDGF-AB, and PDGF-BB. A positive chemotactic response correlated with rearrangement of actin organization. In a study of human arterial smooth muscle cells that express both PDGF receptor subunits endogenously, we again found that recombinant PDGF-AA could elicit a chemotactic response. However, the two smooth muscle cell isolates we examined differed in their chemotactic response to PDGF-AA. This difference correlated closely with their ability to respond mitogenically to this PDGF dimeric form, and the magnitude of both chemotactic and mitogenic responses was related to the proportion of the two receptor subunit species at the cell surface.

Animals↗
PubMed1988

DNA haplotypes of the human apoprotein B gene in coronary atherosclerosis.

Haplotypes of the apoprotein B gene, localised to chromosome 2, were identified using restriction fragment length polymorphisms (RFLPs) for the enzymes XbaI and EcoRI. Four haplotypes were identified at this locus, X1R1 (H1), X1R2 (H2), X2R1 (H3) and X2R2 (H4); where the X1 and X2 alleles were characterised by gene-related fragments of 5.0 and 8.6 kb respectively and the R1 and R2 alleles by fragments of 13.0 and 11.0 kb respectively. Although the polymorphic sites are less than 10 kb apart, they were found to be in linkage equilibrium. The value of the disequilibrium parameter (D) was 0.0042, approximately 7.5% of the theoretical maximum (Dmax = 0.054). No disease association could be demonstrated between either apoB RFLP, or haplotype, and coronary athersclerosis in our population from south-east England. This was in accordance with a study of apoB RFLPs for a population from the West Coast of the United States, but in contrast to a study of an East-Coast population. There are no previous data for the association between apoB haplotypes and coronary atherosclerosis.

Alleles↗
PubMed1988

A DNA polymorphism of an apoprotein gene associates with the hypertriglyceridaemia of primary gout.

Genomic hybridization analysis has been used to investigate allelic frequencies of the genes coding for the four major apoproteins of high density lipoprotein (HDL); apoproteins AI, AII, CII and CIII, in a group of Caucasian subjects with primary gout. An uncommon allelic variant of the apoprotein CIII gene (the S2 allele) was significantly more common among the patients with gout (9/48, 19%) than among normouricaemic controls who were either randomly selected (1/41, 2%, P = 0.03) or normotriglyceidaemic (0/33, 0%, P = 0.013). Approximately 46% (22/48) of the subjects with gout were hypertriglyceridaemic (with a serum triglyceride greater than 2.1 mmol/l). Of the 22 patients in this subgroup, 5 (23%) had the uncommon S1S2 genotype, which was also a significantly greater proportion than among the normotriglyceridaemic controls (P = 0.015). These data suggest that the hypertriglyceridaemia associated with primary gout may have a genetic basis. In contrast, we found no differences in the frequencies of restriction fragment length polymorphisms of the genes for apoproteins AI, AII and CII.

Apoproteins↗
PubMed1986

A DNA polymorphism of the apoprotein AII gene in hypertriglyceridaemia.

A polymorphism of the apolipoprotein AII gene (on chromosome 1) was investigated using genomic hybridisation analysis. The two common alleles at this locus were defined by MspI restriction fragments of 3.0 kilobase pairs (M3.0) and 3.7 kilobase pairs (M3.7) respectively. The M3.7 allele was significantly more common (P less than 0.02) in Caucasian subjects who were normo-lipaemic (34%, 20/59) than in those who were hypertriglyceridaemic (16%, 16/98). Serum triglyceride levels were measured in 126 Caucasian subjects with different combinations of disease-associated alleles at the ApoAII and ApoCIII gene loci. Mean serum triglyceride levels were found to be significantly higher (P less than 0.05) in subjects with disease-associated alleles of both the ApoCIII and ApoAII genes, compared with subjects with a disease-associated allele of one or neither locus.

Alleles↗
PubMed1986

Haplotypes of the human apoprotein AI-CIII-AIV gene cluster in coronary atherosclerosis.

Restriction fragment length polymorphisms of the apoprotein AI-CIII-AIV gene cluster (on the long arm of chromosome 11) were investigated in a group of Caucasian survivors of myocardial infarction, using genomic hybridisation analysis. Four common haplotypes were identified at this locus, M1P1S1, M2P1S1, M1P2S1, and M2P1S2; where M1 and M2 are the common and uncommon alleles defined using the restriction enzyme MspI, P1 and P2 are the common and uncommon alleles defined by the enzyme PstI, and S1 and S2 are the common and uncommon alleles defined by the enzyme SstI. Seven genotype combinations were observed of approximate frequencies; a/a 0.70 (33/47), a/d 0.15 (7/47), a/b 0.04 (2/47), d/d 0.04 (2/47), a/c 0.02 (1/47), b/c 0.02 (1/47), and c/d 0.02 (1/47). In contrast the corresponding values for normotriglyceridaemic Caucasian controls, without a personal or family history of atherosclerotic heart disease were; 0.83 (40/48), 0.02 (1/48), 0.06 (3/48), 0, 0.04 (2/48), 0.04 (2/48), and 0. The relative incidence of the d haplotype, characterised by the presence of a cleavage site for the enzyme SstI in the fourth exon of the ApoCIII gene, was significantly higher in the patient group (P less than 0.01). However, because of the tight linkage between the polymorphic loci studied, it was not possible to identify haplotypes associated with any greater risk of premature atherosclerosis than when the SstI polymorphism was considered in isolation.

Adult↗