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)

The mitogenic and chemotactic potency of platelet-derived growth factor (PDGF) has linked this polypeptide to the pathogenesis of several disease states including atherosclerosis and neoplasia. We have reviewed the recent literature on aspects relating to the structure, distribution and biology of PDGF and its high-affinity cell-surface and intracellular receptors. In addition to platelets, several normal and tumor cells secrete the mitogen in one or more of three possible dimeric configurations. Alternative splicing of exon 6 in PDGF A-chain RNA results in the formation of two protein species with different carboxy-termini. Initially, it was thought that the longer A-chain variant was processed only by transformed cells. However, recent evidence indicates that alternative splicing occurs in several cells which express the A-chain, including early Xenopus embryos. The functional significance of the exon 6 product, a highly basic region spanned by 18 amino acid residues (A194-211), is not precisely clear. We have summarized recent findings which implicate roles for A194-211 in the processing, secretion, and mitogenesis of the A-chain homodimer, nuclear transport signalling, and heparin binding. Thus, alternative splicing could play an important role in the modulation of the functional properties of the PDGF A-chain variants per se and in the complex interactive network of polypeptide growth factors and cytokines.
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PMID:Platelet-derived growth factor and alternative splicing: a review. 128 70

To elucidate the role of oxygen free radicals and lipid peroxidation in the pathogenesis of early hypertension and atherosclerosis, we studied the native distribution of three primary arterial antioxidant enzymes (AEs). Specific immunohistochemical localization of superoxide dismutase (Cu-Zn SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) was examined in the arterial wall of New Zealand White rabbits: six sham-operated normotensive/normolipidemics (NT/NL), seven coarctation-induced hypertensive/normolipidemics (HT/NL), eight normotensive diet-induced hyperlipidemics (NT/HL), and six hypertensive/hyperlipidemics (HT/HL). All three AEs were confined primarily to the endothelium in NT/NL rabbit aortas. However, in HT and HL rabbits a greater proportion of the arterial wall, including the endothelium, inner media, and middle media, displayed immunolocalization of three AEs. Multiple linear-regression analysis revealed that more than 70% of the total variability in the depth of immunolocalization of arterial AEs could be explained by changes in blood pressure and/or total cholesterol. Also, levels of plasma and arterial cholesterol oxides were significantly different (p less than 0.05) in HT and HL rabbits compared with controls, with twofold increases in NT/HLs, threefold increases in HT/NLs, and fourfold increases in HT/HLs. We conclude that intense free-radical activity in the arterial wall of HT and HL animals is one possibility and that this occurs despite the presence of abundant AEs.
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PMID:Immunolocalization of native antioxidant scavenger enzymes in early hypertensive and atherosclerotic arteries. Role of oxygen free radicals. 155 32

Low density lipoprotein modified by oxidation (Ox-LDL) causes adhesion of leukocytes to the endothelium, a feature common in early atherogenesis. Because leukocyte adhesion under various pathophysiological conditions involves superoxide generation, we explored the possibility that superoxide is likewise involved in leukocyte adhesion in response to Ox-LDL. For our studies, we used the dorsal skin fold chamber model for intravital microscopic observation of leukocyte-endothelium interactions in hamsters. We show here that injection of human LDL (4 mg/kg LDL cholesterol oxidatively modified by incubation in 7.5 microM Cu2+ for 18 hours at 37 degrees C) elicited in control hamsters (n = 7) the rolling and adhesion of circulating leukocytes along the endothelium of arterioles and postcapillary venules. This adhesion was significantly attenuated when hamsters were pretreated with bovine copper-zinc-superoxide dismutase (CuZn-SOD, 0.25 mg/kg, n = 7) or heparin (2,000 IU/kg, n = 7). The CuZn-SOD infusion and the heparin-induced release of extracellular SOD from endothelial cell surfaces to plasma resulted in nearly equal plasma SOD activities. Further inhibition of Ox-LDL-induced leukocyte adhesion could not be achieved by increasing the dose of CuZn-SOD to 5 mg/kg (n = 6). Pretreatment of the hamsters with inactivated CuZn-SOD showed no effect. These results indicate that Ox-LDL stimulates leukocyte adhesion through a superoxide-dependent step, and they indicate a possible mechanism by which antioxidants might inhibit the onset of experimental and clinical atherosclerosis.
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PMID:Superoxide-dependent stimulation of leukocyte adhesion by oxidatively modified LDL in vivo. 161 7

hPDGF is the major growth factor of human blood serum. In vivo, it is apparently synthesized by megakaryocytes and is transported in blood stored in the alpha granules of platelets. hPDGF is a heterodimer of two homologous polypeptide chains (PDGF-1(A) and PDGF-2(B] linked together by disulphide bonds. The PDGF-1(A) chain is encoded by a gene localized in chromosome 7 and the PDGF-2(B) chain is encoded by the c-sis proto-oncogene localized in chromosome 22. The hPDGF heterodimer and its two isoforms, the PDGF-1(A) and PDGF-2(B) homodimers, are potent mitogens and chemoattractants for target cells such as diploid fibroblasts, osteoblasts, arterial smooth muscle cells and brain glial cells. The PDGF-1(A) homodimer binds only to its specific receptor alpha, and the hPDGF heterodimer and PDGF-2(B) homodimer bind to both receptors a and b. In addition to their mitogenic action, PDGF stimulates important cellular metabolic activities, including protein, lipid and prostaglandin synthesis. It appears to be an important factor in early development and in vivo appears to modulate tissue regeneration and remodelling during wound healing and osteogenesis. The inappropriate expression of PDGF genes and their mitogenic products has been linked to several proliferative disorders such as fibrosis, atherosclerosis and neoplasia.
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PMID:PDGF: a multifunctional growth factor. 166 77

Endothelin (ET), a peptide originally isolated from the supernatants of cultured endothelial cells, exerts a wide variety of biological effects in different tissues. Endothelial-cell-synthesized ET-1 has been proposed to act in a paracrine manner on adjacent smooth muscle cells (SMC) in vivo, with effects that include both vascular reactivity (vasodilation/vasoconstriction) and mitogenesis. This study, by the use of immunocytochemically characterized SMC (rVSMC) isolated from the aortas of spontaneously hypertensive rats, has investigated a possible autocrine role for ET in regulation of the vasculature. Although quiescent cultures of rVSMC apparently did not constitutively express prepro ET-1mRNA, ET-specific transcripts could be induced by a variety of growth factors (transforming growth factor beta [TGF-beta]; platelet-derived growth factor-AA homodimer [PDGF-A chain]) and vasoactive hormones (angiotensin II [Ang II], arginine-vasopressin, and ET-1 itself). The kinetics for prepro ET-1mRNA induction in rVSMC were characteristically rapid in onset and transient. Down-regulation of protein kinase C by 48 h pretreatment of rVSMC with phorbol ester markedly reduced the subsequent ability of rVSMC to express ET-1 transcripts and secrete ET-1 peptide in response to Ang II. Inducible prepro ET-1mRNA expression was accompanied by a cycloheximide-inhibitable release of ET-1 peptide into the medium of rVSMC. ET-1 peptide was determined by both radioreceptor- and radioimmunoassay. Stimulated rVSMC accumulated ET-1 (approximately 200 pg.10(6) cells-1 x 4 h-1) at levels that attained biological relevance (approximately 10(-10) M). Sep-pak C18 extracts of medium from stimulated rVSMC elicited contraction of isolated endothelium-denuded rat mesenteric resistance vessels, and this response was characteristically protracted and difficult to "wash out." Synthetic (porcine) ET-1 promoted the expression of transcripts for PDGF-A chain, TGF-beta, and thrombospondin in quiescent rVSMC. Such effects of ET-1 on gene expression may be relevant to the mitogenic potential of ET-1 on VSMC. Our findings imply a role for ET-1 in the control of vascular function via both paracrine and autocrine regulatory mechanisms. The expression of prepro ET-1mRNA and peptide biosynthesis by rVSMC may have both short-term (e.g., vasoconstriction) and long-term (e.g., structural remodeling) consequences. A sustained loop of autocrine stimulation by ET-1 in SMC could contribute toward the pathogenesis of vasospasm and/or atherosclerosis.
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PMID:Stimulation of endothelin mRNA and secretion in rat vascular smooth muscle cells: a novel autocrine function. 207 71

Oxygen reactive species are normally formed in cells and play an essential part of the bactericidal activity of phagocytic cells. The damaging effect of these oxygen reactive species is prevented by the endogenous scavengers SOD, glutathione peroxidase, catalase, circulating transferrin, ascorbic acid, and membrane-bound alpha-tocopherol. However, when excess amounts of oxygen radicals and hydrogen peroxide are formed, as in reperfusion injury or trauma, the endogenous scavengers are insufficient to react with these active molecules. Lipid peroxidation is an important part of the formation of oxygen reactive species. Lipid peroxidation, especially peroxidation of LDL, may have a significant role in atherosclerosis. Thus dietary manipulation of PG and TX formation through either feeding cold water fish oils or plant oils containing high amounts of polyunsaturated fatty acids may be a two-edged sword. Also, the dietary manipulation of arachidonic acid through increasing its precursor linoleate may cause a decrease in the immune response as seen in animal experiments. The marine oils may be regarded as a natural aspirin in that formation of PGs of the bisenoic series will be replaced by the PGs of the trienoic series. This results in the formation of TXA3, which is biologically inactive, and PGI3, which is biologically active like PGI2. This may have no physiologic consequences but it is used to illustrate a possible mechanism for the postulated beneficial cardiovascular effects of these oils. The issues and the mechanisms are controversial and frequently highly speculative. The subject is a boon for the lipid biochemist and nutritionist.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Free radicals, arachidonic acid metabolites, and nutrition. 212 35

There is direct evidence that there is an increase of concentration of oxidizing species and oxidized products in plasma of human diabetics. The extent of this increase seems to reflect a predilection to diabetic damage. 1. A high concentration of lipid hydroperoxide in plasma was observed in diabetic patients and it's levels correlated well with the degree of diabetic nephropathy. 2. Lipid peroxide causes membrane injury of endothelial cells. The addition of anti-oxidant inhibited cell injury markedly. 3. Malondialdehyde and protein (lysin-residual or low density lipoprotein) made conjugates to change the antigenicity. This results shows the possibility that atherosclerosis as diabetic complication may be caused by immunological reactions with modified proteins for example, oxidized LDL and so on. 4. SOD activity in erythrocytes of diabetic patient was extremely decreased compared with non diabetics, but no difference was observed by the ELISA method with monoclonal antibody. Glycosylation had been expected to occur in various kinds of proteins. The inactivation of SOD may be caused by non enzymatic glycosylation, because negative correlation was observed between the activity of SOD and GHb in erythrocytes. This inactivation of SOD may play an important role in the pathogenesis of diabetic complications. From these results, it was suggested that both free radical reactions and non enzymatic glycosylation may play important roles not only in the development of diabetes but also in its complications.
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PMID:[Free radicals and diabetes mellitus]. 220 Sep 13

As part of a study to determine the effect of 150 mg zinc/day on plasma lipoproteins, healthy young female (n = 26; mean age 27 years) and male (n = 21; mean age 28 years) volunteers took part in a double-blind cross-over trial lasting 12 weeks. During 6 weeks of supplementation, plasma Zn rose significantly in both groups, indicating compliance. Plasma total cholesterol remained unchanged in both males and females. However, mean LDL-cholesterol decreased from 2.38 to 2.17 mmol/l in females and there was a trend for total HDL-cholesterol to be redistributed in that HDL2 rose and HDL3 fell slightly. In parallel with these changes in females, Zn supplements reduced the ferroxidase activity of serum caeruloplasmin (from 13.0 to 11.3 U/ml) and the antioxidant activity of erythrocyte superoxide dismutase (E-SOD) (from 4557 to 3638 U/g Hb) and CuZn E-SOD (from 2184 to 1672 U/g Hb). Plasma Cu and haematocrit were unaffected. No such changes were seen in males in either lipoproteins or these indicators of Cu status. Since the females were lighter than the males but received the same dose, a dose-response effect rather than a sex difference cannot be ruled out. Overall, Zn supplements significantly decrease a major risk factor for CHD in females but reduced their Cu status.
Atherosclerosis 1988 Apr
PMID:The effect of zinc supplements on lipoproteins and copper status. 336 92

Oxidised LDL has been implicated in the pathogenesis of atherosclerosis. Macrophages can oxidatively modify low-density lipoprotein (LDL) in vitro. The mechanisms of this oxidation process are presently unclear. In this study, we have investigated the effects of compounds and enzymes widely used to quench or scavenge active oxygen species to try to identify the oxidative species involved in this process. The data obtained suggest that hydrogen peroxide may possibly play a role in LDL oxidation by macrophages, whereas singlet oxygen and hydroxyl radicals may not. The role of superoxide anions was uncertain because copper-zinc superoxide dismutase (Cu/Zn-SOD) and manganese SOD (Mn-SOD), widely used to determine superoxide-dependency in other systems may be unsuitable in this particular system. Cu/Zn-SOD at high concentrations displayed a variability in its effects, sometimes augmenting LDL oxidation and sometimes inhibiting it. In the experiments in which Cu/Zn-SOD augmented LDL oxidation, heat inactivation of the enzyme decreased the augmentation; in the experiments in which Cu/Zn-SOD inhibited LDL oxidation, it retained its inhibitory effect after heat inactivation. Mn-SOD always inhibited modification even after heat inactivation. We have therefore concluded that superoxide involvement in LDL oxidation by macrophages is still uncertain and the uncertainty will remain until a suitable probe is found.
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PMID:The effects of free radical scavengers on the oxidation of low-density lipoproteins by macrophages. 781 8

We describe a second Italian family with primary Lipoprotein Lipase deficiency. A new mutation in exon 8 causes a Leu365- > Val change resulting in severe mass reduction and loss of enzyme activity. We suggest that this change interferes with the correct folding and stability of the protein and impairs the assembly of the active homodimer. The procedures applied are useful to screen a large sample of population for genetic variants and allow the clear identification of asymptomatic heterozygous subjects at risk from atherosclerosis disease.
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PMID:A new Italian case of lipoprotein lipase deficiency: a Leu365- > Val change resulting in loss of enzyme activity. 813 97


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