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)

Hyperlipidemia has been reported in adults with hypopituitarism, and human (h) GH therapy has been shown to lower plasma cholesterol in patients with hypercholesterolemia. Macrophage cholesterol accumulation is an early event in atherosclerosis, and these cells have been shown to respond to GH and insulin-like growth factor (IGF-I). The present study was aimed at investigating the activity of GH and IGF-I in macrophages, and used murine macrophages as a model system to investigate the effects of GH and IGF-I on cellular uptake and metabolism of low density lipoprotein (LDL). The J-774 murine macrophage cell line was shown to bind hGH, to respond to hGH by an increase in cell IGF-I content, and to have specific high affinity binding sites for IGF-I. Mouse peritoneal macrophages and the J-774 macrophage cell line respond to hGH with a dose-dependent stimulation of cellular association and degradation of LDL as well as an enhanced cholesterol esterification rate. A similar response was observed after in vitro treatment of the cells with IGF-I. Preliminary results in human monocyte-derived macrophages showed similar results. The dependency of the effect of hGH on locally produced IGF-I was shown by abrogation of the hGH effect after adding anti-IGF-I antibody to the culture medium. It is concluded that murine macrophages possess the machinery to bind GH, produce IGF-I, and bind IGF-I. This machinery is used by macrophages, and apparently by other cells, to execute GH-dependent IGF-I-mediated stimulation of cellular uptake and metabolism of LDL. This may provide the explanation for both the elevated plasma LDL concentration in patients with GH deficiency and the effect of GH therapy to reduce plasma LDL levels.
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PMID:Growth hormone and insulin-like growth factor-I increase macrophage uptake and degradation of low density lipoprotein. 161 24

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.
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PMID:The insulin-like growth factors: their putative role in atherogenesis. 171 10

The authors have previously shown that serum from young women receiving the same combined mestranol-norethindrone containing oral contraceptive (OC) preparation accelerated the proliferation of arterial smooth muscle cells (SMC) in tissue culture, and this in vitro effect was not a direct action of either of its estrongenic or progestagenic constituents. To identify the substance(s) which might contribute to this potentially atherogenic action, blood was obtained from 20 OC users, 18-25 years, and control women for the measurment of growth hormone, insulin, somatomedins (insulin-like growth factor IGF-I AND IGF-II), and the platelet alpha-granule constituents platelet-derived growth factor (PDGF), Beta-thromboglobulin, and platelet factor 4 (PF4). No difference was demonstrable between OC users and controls in the levels of any of these growth-promoting hormones, nor in plasma concentrations of any of the platelet alpha-granule proteins. The results indicate that the enhanced mitogenicity found in OC sera is most likely not attributable directly to these hormones or PDGF and may instead result from an in vivo OC-induced alteration in other as yet unidentified mediators of cellular growth.
Atherosclerosis 1985 Aug
PMID:The measurement of arterial smooth muscle cell mitogens in the blood of oral contraceptive users. 293 71

Endothelial cells form the intimal lining of the entire vascular system. The vascular endothelium is continuously and directly bathed by components of the bloodstream and represents the initial fixed anatomical surface with which these components come in contact. In the past decade, the methodologies for studying endothelial cell functions have markedly advanced, enabling direct and detailed study of the vascular endothelium. From such studies, it is now apparent that the vascular endothelium represents an extraordinarily complex network of cells demonstrating a multitude of distinct anatomic, metabolic, and immunologic properties critical to such processes as angiogenesis, atherosclerosis, thrombosis, neoplasia, and a variety of metabolic disorders including homocystinuria and diabetes mellitus. This report will focus on the interactions of insulin and the insulin-like growth factors (IGFs) with vascular endothelium, based on studies with cultured endothelial cells, isolated microvessels, and perfused organ systems. Data will be presented relevant to the following concepts: (1) endothelial cells, in culture and in vivo, have specific receptors for insulin, IGF-I, and IGF-II; (2) insulin, IGF-I, and IGF-II have both distinct and overlapping functions in cultured endothelial cells; (3) cultured endothelial cells process receptor-bound insulin, IGF-I, and IGF-II, by distinct processes; (4) in vivo, capillary endothelial receptors are integrally involved in the transport of intact insulin to subendothelial sites of insulin action; and (5) vascular endothelium has specialized cellular features that are likely to contribute to the unique interactions of endothelial cells with insulin and the IGFs.
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PMID:Insulin, insulin-like growth factors, and vascular endothelium. 297 48

To elucidate the role of hyperinsulinemia in the development of atherosclerosis, we evaluated insulin-specific signaling in cultured vascular smooth muscle cells (SMCs) and its desensitization by continuous exposure to insulin. The concentration of unlabeled insulin that inhibited specific [A14-125I]-insulin binding by 50% (IC50) was 0.33 +/- 0.02 nM, which was 100 times less than the IC50 of unlabeled IGF-I. For [125I]-IGF-I binding, the IC50 of unlabeled IGF-I was found to be 6.6 +/- 0.88 nM, which was 100 times less than the IC50 of unlabeled insulin. The binding capacities for insulin and IGF-I were found to be 1.28 +/- 0.86 and 1200 +/- 170 fmol/0.5 mg protein, respectively. Autophosphorylation of the beta-subunit of the insulin receptor was stimulated at above 0.17 nM (24 microU/ml) insulin. Insulin concentrations exceeding 1 nM significantly activated the S6 kinase in a dose-dependent manner. In contrast, 10 nM insulin did not activate MAP kinase nor [3H]thymidine incorporation into DNA, while both were activated by 38% and 44% with 1 microM insulin and by 52% and 67% with 10 nM IGF-I, respectively. By pre-exposing cells to 10 nM insulin for 12 h, the binding capacity for insulin decreased by 34% (P < 0.05), and activation of S6 kinase by insulin almost disappeared, while both IGF-I binding and the activation of S6 kinase by IGF-I were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Feb
PMID:Insulin-specific activation of S6 kinase and its desensitization in cultured rat vascular smooth muscle cells. 775 52

Hyperinsulinemia has been implicated as an independent risk factor for atherosclerosis. We measured the effect of insulin and related hormones on the oxidation of low density lipoproteins (LDL) and superoxide anion production by peripheral blood mononuclear cells (MC). LDL oxidation was measured by the production of thiobarbituric acid reactive substances (TBARS). Insulin and IGF-I at 10(-7) M caused a 33% and 48% increase in TBARS production, respectively. At 10(-6) M the corresponding values were 63% and 67%. Proinsulin and IGF-II at 10(-6) M had no effect. Glucose caused a concentration dependent (up to 10 mM) stimulation of LDL oxidation reaching 85% and 77% at insulin concentrations of 10(-7) M and 10(-6) M, respectively. The stimulatory effect of insulin was confirmed by measurements of other indices of LDL oxidation, i.e. absorbance at 234 nm, trinitrobenzene sulfonic acid reactivity and electrophoretic mobility. Insulin-stimulated LDL oxidation was inhibited by superoxide dismutase (SOD), but insulin had no effect on MC superoxide production. MC were isolated from five subjects before and after a 5 h hyperinsulinemic, euglycemic clamp. Insulin infusion had no effect on TBARS or superoxide production by MC. Our in vitro experiments suggest that high levels of insulin and IGF-I stimulate MC-mediated oxidation of LDL, an effect that is potentially atherogenic.
Atherosclerosis 1994 May
PMID:Stimulation of low-density lipoprotein oxidation by insulin and insulin like growth factor I. 794 63

We have previously reported that C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is produced in vascular endothelial cells (ECs) and acts as an endothelium-derived relaxing peptide. We further demonstrated the detection of the gene transcripts of CNP and atrial natriuretic peptide (ANP) B receptor, a specific receptor for CNP, in human blood vessels. We thus propose the existence of a vascular natriuretic peptide system (NPS). CNP secretion was also demonstrated to be stimulated by various growth factors and cytokines. To clarify the significance of vascular NPS in proliferative vascular complications associated with diabetes, hypertension, or atherosclerosis, in the present study we examined the effect of insulin on CNP secretion from cultured ECs. Insulin at a concentration in the physiological range (10(-10)-10(-7) mol/l) potently suppressed CNP secretion, whereas insulin at the same concentration did not suppress endothelin (ET) secretion from EC. IGF-I had no significant effect on CNP secretion. Insulin, therefore, can be a potent inhibitor of CNP secretion through the activation of insulin receptor. Since CNP has been shown to be a potent inhibitor of vascular smooth muscle cell proliferation, the present study suggests the possibility that attenuated activity of vascular NPS is associated with hyperinsulinemia, which might result in proliferative vascular lesions.
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PMID:Insulin suppresses endothelial secretion of C-type natriuretic peptide, a novel endothelium-derived relaxing peptide. 867 95

Insulin-like growth factor I and II (IGF-I and -II)--two 7.65- and 7.47-kDA polypeptides belonging to the somatomedine family--are regular constituents of human blood plasma. Both factors exert mitogenic activity on a variety of cell types including arterial smooth muscle cells. In the present study, the effect of IGF-I and -II on cultured bovine coronary smooth muscle cells (cSMC) was assessed. Human recombinant IGF-I and IGF-II added to cSMC cultured in a medium containing 10% fetal bovine serum (FBS) decreased the cell number and [3H]thymidine incorporation in a dose dependent fashion up to 40% and 43% compared to control cells (100%). At the same time, the expression of basic fibroblast growth factor (bFGF) increased from 60 pg/5 x 10(4) cells (control) to 75 (IGF-I) and 113 pg/5 x 10(4) cells (IGF-II). In parallel with enhanced bFGF expression, the bFGF receptor content per cell and the [35S]sulfate incorporation into extracellular and cell-associated proteoglycans also increased under the influence of IGF-I and -II. In contrast, with low serum concentration (0.1% FBS) the addition of IGF-I and -II to bovine cSMC cultures resulted in a slight increase in cell number, protein content and [3H]thymidine incorporation as described in previous studies. These results suggest that the mitogenic activity of IGF-I and -II towards coronary smooth muscle cells depends on culture conditions. In the presence of 10% fetal bovine serum that mimics in vivo conditions, IGF-I and -II did not necessarily act as mitogenic factors but inhibited the proliferation of cSMC in vitro possibly by modulating antagonizing the action of other growth factors. Irrespective of the inhibition of cell division, the cellular bFGF, the bFGF receptor and the bFGF activity-related proteoheparan sulfate were overexpressed under the influence of IGF.
Atherosclerosis 1996 May
PMID:Human recombinant insulin-like growth factor I and -II stimulate the expression of basic fibroblast growth factor but suppress the division of bovine coronary smooth muscle cells. 876 88

Metalloproteinase-like, disintegrin-like, and cysteine-rich proteins (MDCs) are potential novel regulators of cell-cell and cell-matrix interactions, as well as of matrix degradation. We have asked whether MDCs are expressed in cultured diploid vascular cells, and have identified MDC 15 in human aortic smooth muscle (SMC) and umbilical vein endothelium (HUVEC). MDC 15 mRNA is expressed at higher levels in HUVECs than in SMCs. In cultured SMCs, MDC 15 mRNA levels are not regulated by PDGF or IGF-I or by adherence to different extracellular matrices. Nor is regulation of MDC 15 mRNA levels observed in HUVEC monolayers at different cell densities, after multi-scratch wounding, or after treatment with TNF-alpha, LPS, or thrombin. However, differences in proteolytic processing of MDC 15 are observed in different HUVEC strains. In contrast to cultured arterial cells, MDC 15 protein is not expressed in vivo in normal vessels, but is up-regulated in lesions of atherosclerosis. These findings suggest that MDC 15 may be a potential regulator of vascular cell function and may be involved in the development of lesions of atherosclerosis.
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PMID:Expression of a disintegrin-like protein in cultured human vascular cells and in vivo. 903 60

Acromegaly is associated with changes in lipoprotein metabolism and an excess in cardiovascular mortality. We have examined low density lipoprotein (LDL) subfraction distribution in 24 patients with active acromegaly and in controls matched for age, sex and body mass index. LDL was subfractionated by density gradient ultracentrifugation. The concentration of small dense LDL-III was significantly higher in the acromegalic patients compared to the controls (94.2 +/- 44.9 versus 67.2 +/- 30.4 mg/dl, P < 0.05) and there was a concomitant reduction in the intermediate subfraction LDL-II (124.8 +/- 31.3 versus 149.9 +/- 30.0 mg/dl, P < 0.05). Univariate analysis showed that both growth hormone (GH) and insulin-like growth factor (IGF)-I correlated with LDL-III and inversely with LDL-II. Acromegalic patients were found to have lower hepatic lipase (HL) and lipoprotein lipase (LPL) activities than controls (HL: 13.29 +/- 6.56 versus 21.58 +/- 7.27 micromol FFA released/ml/h, P < 0.001: LPL: 7.22 +/- 3.04 versus 11.53 +/- 7.85 micromol FFA released/ml/h, P < 0.05) whereas plasma cholesteryl ester transfer protein (CETP) activity was significantly increased (8.15 +/- 1.81 versus 5.54 +/- 1.86 pmol/microl/h, P < 0.001). Both GH and IGF-I were significantly associated with HL, LPL and CETP activities. Multivariate analysis on this relatively small sample size showed that in normal subjects, triglyceride and HL activity were the major determinants of LDL-III. In contrast, GH and HDL were the main determinants in acromegaly, accounting for 32 and 24% in the variability of LDL-III respectively. In conclusion, GH excess has a direct effect on LDL subfraction distribution.
Atherosclerosis 1997 Feb 28
PMID:LDL subfractions in acromegaly: relation to growth hormone and insulin-like growth factor-I. 906 18


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