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 effect of hypertension on the arterial vascular wall is characterised primarily by morphological changes to the endothelium and hypertrophy of smooth muscle cells within the arterial media. Endothelial dysfunction is manifest through increased permeability to high molecular weight compounds as well as mitogenic and vasoactive substances. At the same time, denudation of the vascular endothelium promotes platelet aggregation and subsequent release of platelet-derived growth factor (PDGF). In conjunction with endothelium- and monocyte-derived growth factors, this mitogen stimulates subintimal smooth muscle cell proliferation and migration and arterial wall thickening, resulting in a haemodynamically important increase in vascular resistance, particularly at the precapillary level. In addition, focal endothelial dysfunction allows entry of lipids into the vascular wall, thereby promoting formation of a lipid-rich fatty streak, the primary 'early' atherosclerotic lesion. Most of these changes, including endothelial injury, subintimal lipid-binding, cellular proliferation and migration, platelet aggregation and PDGF release are common to both hypertensive and early atherosclerotic processes and involve the participation of calcium ions as 'second messengers'. Thus, antihypertensive treatment with calcium antagonists may not only lead to a protective decrease in wall shear stress through a reduction in blood pressure, but may also inhibit those cellular processes within the vascular wall that are responsible for initiating atherosclerosis. Indeed, experimental as well as human studies have demonstrated a beneficial suppressant effect of calcium antagonists on the early stages of atherosclerosis.
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PMID:Hypertension treatment and prevention of new atherosclerotic plaque formation. 753 1

Increased generation of active oxygen species such as H2O2 and O2- may be important in vascular smooth muscle cell growth associated with atherosclerosis and restenosis. In previous work, we showed that H2O2 stimulated vascular smooth muscle cell growth and proto-oncogene expression. In the present study, we compared the effects of H2O2 and O2- on cultured rat aortic vascular smooth muscle cell growth and signal transduction. O2- was generated in a concentration-dependent manner by the naphthoquinolinedione LY83583. Vascular smooth muscle cell growth, as measured by [3H]thymidine incorporation, was stimulated by 200 mumol/L H2O2 (110% increase versus 0.1% serum) and 1 mumol/L LY83583 (175% increase) to levels comparable to 10 ng/mL platelet-derived growth factor (210% increase). Since activation of mitogen-activated protein kinase (MAP kinase) is one of the earliest growth factor signal events, the activity of MAP kinase was measured by changes in mobility on Western blot and by phosphorylation of myelin basic protein. There was a concentration-dependent increase in MAP kinase activity by LY83583 (maximum, 10 mumol/L) but not by H2O2. The time course for activation of MAP kinase by LY83583 showed a maximum at 5 to 10 minutes with return to baseline by 20 minutes. Activation of MAP kinase by LY83583 was protein kinase C dependent. Expression of MAP kinase phosphatase-1 (MKP-1), a transcriptionally regulated redox-sensitive protein tyrosine/threonine phosphatase, was also measured. Although H2O2 induced MKP-1 mRNA to a greater extent than did LY83583, the increased MKP-1 expression could not explain the inability of H2O2 to stimulate MAP kinase, because mRNA levels were not detected until 60 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential activation of mitogen-activated protein kinases by H2O2 and O2- in vascular smooth muscle cells. 754 May 16

Total glycans from the cell layer and the culture medium of human vascular smooth muscle cells (VSMC) that had been cultivated in the presence of platelet-derived growth factor (PDGF) were isolated and purified by gel filtration after Pronase and DNase digestion and alkaliborohydride treatment. Measurements of the content of neutral hexoses and uronic acids revealed that PDGF stimulates total glycan synthesis by proliferating VSMC in a linear fashion from 24 h to 72 h of incubation. In contrast, total glycan synthesis by human fibroblasts, epithelial cells, or endothelial cells was not affected by PDGF, indicating cell-type specificity. Chemical, biochemical, and enzymological characterization of the total glycans synthesized by VSMC showed that PDGF stimulates the secretion of a 340-kDa glycan molecule in a time-dependent manner from 24 h to 72 h. This molecule is highly acidic, shares a common structure with hyaluronic acid, and exhibits a potent antiproliferative activity on VSMC. These results suggest that VSMC in response to PDGF are capable of controlling their own growth and migration by the synthesis of a specific form of hyaluronic acid with antiproliferative potency, which may be involved in the regulation of the local inflammatory responses associated with atherosclerosis.
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PMID:Platelet-derived growth factor stimulates the secretion of hyaluronic acid by proliferating human vascular smooth muscle cells. 756 37

In nonhuman primates (Macaca nemestrina) treated with the antioxidant probucol during diet-induced hypercholesterolemia, intimal lesion area in the thoracic aorta was decreased, with increased resistance of plasma LDL to oxidation. The cellular and molecular changes associated with the decrease in lesion size in the probucol-treated hypercholesterolemic animals are quantitatively evaluated in this study. Lesions from the probucol-treated animals appear less mature and have altered lipid distribution. Abundant lipid-laden smooth muscle cells are found in the intima and media of the probucol-treated animals, with fewer medial lipid-laden macrophages, compared with lesions at similar sites in the control hypercholesterolemic animals. In both the control and probucol-treated animals, macrophages are the predominant cells in most lesions, but the ratio of macrophages to smooth muscle cells is decreased in the lower thoracic and upper abdominal aortic sites in the probucol-treated animals. Lesions at all aortic sites in the probucol-treated animals have a 35% to 80% reduction in the percentage of cells in cell cycle traverse, as indicated by immunostaining for proliferating cell nuclear antigen (% PCNA-positive). In both groups, macrophages and smooth muscle cells are PCNA-positive, but the majority (> 60%) are macrophages. No difference in % PCNA-positive cells is seen in the iliac arteries, where the most advanced lesions were present at the time probucol administration was initiated. Limited Northern analysis of growth-regulatory molecules possibly involved in the cellular changes associated with lesions shows a 30% to 50% decrease in mRNA levels of platelet-derived growth factor (PDGF) B-chain, PDGF beta-receptor, colony-stimulating factor type 1, and monocyte chemotactic protein 1. Thus, a potential role for an antioxidant such as probucol in the treatment of atherosclerosis may be to alter the early inflammatory fibroproliferative processes of the disease. Whether these effects are directly related to the antioxidant properties or some other activity of probucol is not yet known.
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PMID:Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. II. Cellular composition and proliferation. 758 37

1. The effects of A02011-1, a pyrazole derivative, on the proliferation of rat vascular smooth muscle cells (VSMCs) were examined. 2. A02011-1 (1-100 microM) concentration-dependently inhibited [3H]-thymidine incorporation into DNA in rat VSMCs that were synchronized by 48 h serum depletion and then re-stimulated by addition of foetal calf serum (FCS, 10%), platelet-derived growth factor (PDGF, 10 ng ml-1), 5-hydroxytryptamine (10 microM) or ADP (10 microM). The inhibitory effect of A02011-1 was fully reversible. However, FCS-induced [3H]-thymidine incorporation into rat endothelial cells was unaffected by A02011-1. 3. The concentration of A02011-1 necessary for inhibition of the FCS-induced proliferation was similar to that necessary for adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. Adenylyl cyclase activity was increased in A02011-1-treated VSMCs, whereas cyclic AMP-specific phosphodiesterase activity was unchanged. 4. A02011-1 was equipotent with forskolin but was more potent than 8-bromo-cyclic AMP against FCS (10%)-induced proliferation. 5. The antiproliferative action of A02011-1 was mimicked by 8-bromo-cyclic AMP, a membrane-permeable cyclic AMP analogue and was antagonized by 2',5'-dideoxyadenosine, an adenylyl cyclase inhibitor and by Rp-cyclic AMPS, a competitive inhibitor of cyclic AMP-dependent protein kinase (PKA) type I and II. 3-Isobutyl-1-methylxanthine (IBMX) caused significant potentiation of the antiproliferative activity of A02011-1. However, Rp-8-bromo-cyclic GMPS and staurosporine did not affect the antiproliferative activity of A02011-1. 6. A02011-1 still inhibited the FCS-induced DNA synthesis even when added 10-18h after restimulation of the serum-starved VSMCs with 10% FCS. Flow cytometry in synchronized cells revealed an acute blockade of FCS-inducible cell cycle progression at a point in the G,/S phase in A02011-1-treated cells. The inhibition of proliferation by A0201 1-1 was shown to be independent of cell damage,as documented by several criteria of cell viability.7. These results indicate that A0201 1-1 inhibition of VSMC proliferation was mediated by cyclic AMP and was due to a delay in the progression from the G1 into S phase of the cell cycle. A02011-1 did not cause cell toxicity and may thus hold promising potential for the prevention of atherosclerosis or vascular diseases.
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PMID:Antiproliferative effects of A02011-1, an adenylyl cyclase activator, in cultured vascular smooth muscle cells of rat. 762 Jul 13

Vascular smooth muscle cells (VSMC) are the principal cellular component of the blood vessel wall. Atherosclerosis, hypertension, and angiogenesis are associated with abnormal VSMC growth. Angiotensin II is hypertrophic for cultured adult rat aortic VSMC, whereas platelet-derived growth factor and serum are hyperplastic. To identify changes in specific proteins associated with either hyperplastic or hypertrophic growth, high resolution two-dimensional gel electrophoresis was performed on extracts from quiescent rat aortic VSMC and from VSMC exposed for 24 h to growth factors (10% fetal calf serum, platelet-derived growth factor, or angiotensin II). 12 proteins were up-regulated and 5 down-regulated by treatment with growth factors. Eight of the up-regulated and one of the down-regulated proteins were identified by internal protein microsequencing from electroblotted two-dimensional gels or by co-electrophoresis of purified proteins in two-dimensional gels. Four of the proteins up-regulated by growth factors were identified as mediators of protein folding. These were heat shock proteins, HSP-60 and HSP-70, protein disulfide isomerase, and protein disulfide isomerase isozyme Q-2. Additional proteins were identified as elongation factor EF-1 beta, a component of the protein synthesis apparatus, and calreticulin, another putative molecular chaperone. Vimentin and actin were also up-regulated, whereas an isoform of myosin heavy chain was down-regulated. Hyperplastic and hypertrophic growth were accompanied by similar changes in protein expression, suggesting that both types of growth require up-regulation of the protein synthesis and folding machinery.
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PMID:Components of the protein synthesis and folding machinery are induced in vascular smooth muscle cells by hypertrophic and hyperplastic agents. Identification by comparative protein phenotyping and microsequencing. 767 76

Histamine in serum and arterial tissue contributes to the pathogenesis of atherosclerosis and the formation of coronary artery vasospasm. As the effect of histamine at a given site will be mediated by its specific receptors, we investigated by in situ hybridization and Northern blot analysis the expression and localization of human histamine H1 receptor mRNA in the arterial wall and in cultured human aortic intimal smooth muscle cells (SMC) and immortalized SMC (ISS10) and endothelial cells (SE1). In situ hybridization showed that SMC and endothelial cells expressed H1 receptor mRNA in vivo and that the expression was increased in SMC in the thickened intima of atherosclerotic foci in both the aorta and coronary artery. By Northern blot analysis, we also detected histamine H1 receptor mRNA in cultured SMC, ISS10, and SE1 and found that platelet-derived growth factor stimulated SMC to increase their expression of the mRNA in vitro. These results suggest that up-regulation of histamine H1 receptor expression by platelet-derived growth factor plays an important role in the initiation and progression of cardiovascular diseases.
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PMID:Expression of the histamine H1 receptor gene in relation to atherosclerosis. 771 64

Lipoprotein lipase (LPL), which is secreted by the two predominant cell types in atherosclerotic plaque, macrophages and smooth muscle cells, may be involved in atherosclerosis by generating atherogenic remnant lipoproteins. We investigated the effects of platelet-derived growth factor (PDGF)-BB on the synthesis of LPL by human monocyte-derived macrophages. These cells were cultured in the presence of PDGF-BB for 8 days, after which the enzyme activity, mass, and mRNA levels of LPL were determined. The effect of PDGF-BB was time-dependent and dose-dependent at concentrations of 1 to 10 ng/mL. At 10 ng/mL PDGF-BB enhanced twofold to 2.3-fold the secretion of LPL, and a pulse-labeling study with [35S]methionine revealed that 10 ng/mL PDGF-BB significantly increased the synthesis of LPL. Northern blotting analysis showed that the LPL mRNA level increased dose dependently in macrophages treated with PDGF-BB, and 10 ng/mL PDGF-BB enhanced twofold the expression of LPL mRNA. The protein kinase C inhibitor staurosporine suppressed the effect of PDGF-BB on LPL activity. These results indicate that PDGF-BB stimulated transcription of the LPL gene in human monocyte-derived macrophages through protein kinase C activation and resulted in an increased synthesis of LPL. Therefore, we hypothesize that the augmented synthesis of LPL by PDGF-BB modulates atherosclerosis by influencing lipoprotein metabolism in the vascular wall.
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PMID:Effects of platelet-derived growth factor on the synthesis of lipoprotein lipase in human monocyte-derived macrophages. 774 65

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.
Atherosclerosis 1995 Feb
PMID:Vitamin E inhibits the intimal response to balloon catheter injury in the carotid artery of the cholesterol-fed rat. 775 53

Vascular medial smooth muscle cells migrate, proliferate and transform to foam cells in the process of atherosclerosis. We have reported that the intimal smooth muscle cells express proto-oncogene c-fms, a characteristic gene of monocyte-macrophages, which is not normally expressed in medial smooth muscle cells. In the present study, we demonstrated that combinations of platelet-derived growth factor (PDGF)-BB and either epidermal growth factor (EGF) or fibroblast growth factor (FGF) induced high expression of c-fms in normal human medial smooth muscle cells to the level of intimal smooth muscle cells or monocyte-derived macrophages, whereas c-fms expression by PDGF-BB alone was 1/10 and both EGF and FGF had no independent effect on c-fms expression. By contrast, interferon (IFN)-gamma and macrophage colony-stimulating factor (M-CSF) suppressed the induction of c-fms expression. These results indicate that multiple growth factors and cytokines may play a role in the phenotypic transformation of medial smooth muscle cells to intimal smooth muscle cells in atherosclerotic lesions by altering c-fms expression.
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PMID:Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic medial smooth muscle cells. 788 62


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