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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied death of human vascular smooth muscle cells derived from coronary plaques and normal coronary arteries and aorta. Cells from normal arteries underwent death only upon removal of serum growth factors. In contrast, plaque-derived cells died even in high serum conditions, and death increased after serum withdrawal. Death was characteristically by apoptosis in both normal and plaque-derived cells, as determined by time-lapse videomicroscopy, electron microscopy, and DNA fragmentation patterns. IGF-1 and PDGF were identified as potent survival factors in serum, whereas EGF and basic fibroblast growth factor had little effect. Stable expression of bcl-2, a protooncogene that regulates apoptosis in other cell lines, protected smooth muscle cells from apoptosis, although there was no detectable difference in endogenous bcl-2 expression between cells from plaques or normal vessels. We conclude that apoptosis of human vascular smooth muscle cells is regulated by both specific gene products and local cytokines acting as survival factors. Apoptosis may therefore regulate cell mass in the normal arterial wall and the higher rates of apoptosis seen in plaque smooth muscle cells may ultimately contribute to plaque rupture and breakdown and thus to the clinical sequelae of atherosclerosis.
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PMID:Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. 773 91

Lp(a) lipoprotein [Lp(a)] was found in previous studies to be independently associated with early atherosclerosis and its sequelae. Lp(a) in vitro bound to glucosaminoglycans and was easily aggregated at physiological Ca2+ concentration, and small Lp(a) aggregates were phagocytosed by macrophages. Lp(a) was also found to be related to carbohydrate metabolism, and increased Lp(a) levels have been described in diabetic patients with clinical complications and were recently found in rheumatoid arthritis patients. In this study of nondiabetic male patients with documented CAD before 50 years of age and controls, a significant correlation was found between Lp(a) and IGF-1 levels. HLA class II DR13 (DR6) was more frequent and DR15 (DR2) was less frequent in patients than in controls. The calculated relative risk for CAD was 4.0 for DR17 (DR3), but the difference was not significant. These differences seem to be related to high Lp(a) levels. It is suggested that phagocytosis of preferably Lp(a) aggregates can induce an immunological tissue response that may contribute in the pathogenesis of Lp(a)-associated diseases and may be more prominent in combination with some inherited HLA class II haplotypes. Probably due to sex hormone effects, the association may be most pronounced in young males and in older females.
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PMID:Importance of Lp(a) lipoprotein and HLA genotypes in atherosclerosis and diabetes. 798 77

In lesions of atherosclerosis, various cytokines and growth factors, which are generally not expressed in the normal artery, are upregulated. Several of them including PDGF, bFGF, HB-EGF, IGF-1, IL-1 and TGF-beta and TNF play key roles in atherogenesis by stimulating chemotaxis and proliferation of vascular smooth muscle cells and production of extracellular matrix substances such as proteoglycans, collagen and elastic fibers by those cells. Endothelial cells and macrophages are also the targets as well as the sources of those cytokines and growth factors. The production of those cytokines or growth factors are regulated by molecules of each other or by themselves forming a complex cytokine network. Understanding and control of the roles of those cytokines in vascular walls will provide an insight on the mechanism of atherogenesis and contribute to the development of better ways to its prevention.
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PMID:[Roles of cytokines and growth factors in atherogenesis]. 841 65

Endothelin, a vasoconstrictor peptide secreted from endothelial cells, has been thought to play a role in various forms of vascular disease. Diabetes mellitus is well known for its association with accelerated atherosclerosis and microvascular damage. Although the basis for the vessel insult is multifactorial, hyperinsulinemia is thought to contribute by an unknown mechanism. In this study, we sought to determine whether insulin stimulates the production and secretion of ET-1 as a possible basis for the association of hyperinsulinemia and vascular disease. We demonstrated that insulin significantly stimulates the gene expression and secretion of ET-1 from cultured BAEC, and that insulin increases ET-1 mRNA expressed in BBCEC. Insulin caused a maximal twofold inducement above control ET-1 mRNA expression in a dose-related fashion in BAEC. The increased mRNA resulted from increased transcription, as determined by nuclear run-off studies. Increased ET-1 mRNA was seen after 4 h of incubation with insulin: the peak occurred at 6-8 h and persisted for 24 h. Insulin caused as much as a fourfold stimulation of ET-1 secretion from BAEC in a dose-related fashion, including a twofold increase at a physiological concentration (10(-9) M): The increase began at 1 h of incubation and continued for the entire 24-h incubation period. The insulin-induced increases in both ET-1 mRNA and ET-1 protein secretion were significantly attenuated by genistein, a tyrosine kinase inhibitor. This stimulation probably occurred through the insulin receptor, because IGF-1 had no effect on ET-1 gene expression or secretion from these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin stimulates production and secretion of endothelin from bovine endothelial cells. 842 73

The long-term goals of our research are to understand the biochemical morbidity surrounding obstructive sleep apnea syndrome to define better the need for treatment and to determine modifiable risk factors for the disease. Our current hypothesis is that sleep-related hypoxemia results in alterations in metabolic regulatory peptides, specifically insulin and insulin-like growth factors (IGF-1 and IGF-2), which are known or suspected factors for obesity and disorders such as hypertension, glucose intolerance, and atherosclerosis. Surveys of clinic populations suggest a relationship between body habitus, parameters of sleep-disordered breathing, indices of oxygenation, and insulin resistance, defined by fasting serum levels of glucose and insulin. Results will provide insight into the role of metabolic regulatory peptides in the pathogenesis of sleep-disordered breathing and the mechanisms for this association.
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PMID:Biochemical morbidity in sleep apnea. 844 24

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.
Atherosclerosis 1995 Nov
PMID: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. 857 32

The mitotic rate of stem cells is a major determinant of cancer risk. Insulin-like growth factors (IGFs) are virtually obligate stimulants of cell turnover in nearly every tissue. IGF activity is subject to rapid modulation by hepatic release of IGF binding protein-1 (IGFBP-1), a factor whose synthesis is suppressed by insulin and increased by glucagon. Up-regulation of IGFBP-1 production can be expected to decrease IGF activity and thereby diminish cancer risk. Measures that sensitize peripheral tissues to insulin, and thereby down-regulate insulin secretion, can be expected to increase IGFBP-1 synthesis, provided that they do not unduly sensitize hepatocytes as well. Prolonged aerobic exercise and caloric restriction also increase IGFBP-1 production. Since IGF-1 suppresses hepatic synthesis of sex hormone binding globulin (SHBG), down-regulation of IGF activity will increase SHBG levels and thus diminish the availability of free sex hormones--an effect that should further decrease cancer risk in sex hormone-responsive tissues. These considerations rationalize many findings in animal and epidemiologic studies, and suggest that non-diabetic insulin resistance may be a significant cancer risk factor. Increased IGF activity associated with insulin resistance may also promote benign hyperplasias-most notably atherosclerosis. Hyperinsulinemia stimulates intimal hyperplasia indirectly, via IGF.
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PMID:Up-regulation of IGF binding protein-1 as an anticarcinogenic strategy: relevance to caloric restriction, exercise, and insulin sensitivity. 916 Feb 83

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

Insulin-like growth factor (IGF)-1 and the type I IGF-1 receptor are important regulators of vascular function that may contribute to cardiovascular disease. We hypothesized that IGF-1 causes endothelial cell dysfunction and expression of neutrophil and monocyte adhesion molecules by enhancing pro-inflammatory cytokine signal transduction. Long-term IGF-1 treatment of endothelial cells potentiated c-Jun and nuclear factor NF-kappaB activation by tumor necrosis factor (TNF)-alpha and enhanced TNF-alpha-mediated adhesion molecule expression. In response to IGF-1 treatment, the expression of kinases in the c-Jun/c-Jun NH(2)-terminal kinase signaling pathway (MEKK1, MEK4, and JNK1/2) was unchanged, but expressions of insulin receptor substrate-1 and Grb2-associated binder-1 (Gab1) were significantly decreased. Because Gab1 is involved in both c-Jun and NF-kappaB activation by TNF-alpha, we focused on Gab1-dependent signaling. Gab1 inhibited c-Jun and NF-kappaB transcriptional activation by TNF-alpha. Interestingly, Gab1 inhibited c-Jun transcriptional activity induced by MEKK3 but not MEKK1 and MEK4. Gab1 associated with MEKK3, and a catalytically inactive form of MEKK3 inhibited TNF-alpha-induced c-Jun and NF-kappaB transcriptional activation, suggesting a critical role for Gab1 and MEKK3 in TNF-alpha signaling. These data demonstrate that Gab1 and MEKK3 play important roles in endothelial cell inflammation via regulating the activation of c-Jun and NF-kappaB. Furthermore, the IGF-1-mediated downregulation of Gab1 expression represents a novel mechanism to promote vascular inflammation and atherosclerosis.
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PMID:Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. 1206 26

The vascular insulin-like growth factor (IGF)-1 system includes the IGFs, the IGF-1 receptor (IGF-1R), and multiple binding proteins. This growth factor system exerts multiple physiologic effects on the vasculature through both endocrine and autocrine/paracrine mechanisms. The effects of IGF-1 are mediated principally through the IGF-1R but are modulated by complex interactions with multiple IGF binding proteins that themselves are regulated by phosphorylation, proteolysis, polymerization, and cell or matrix association. During the last decade, a significant body of evidence has accumulated, indicating that expression of the components of the IGF system are regulated by multiple factors, including growth factors, cytokines, lipoproteins, reactive oxygen species, and hemodynamic forces. In addition, cross-talk between the IGF system and other growth factors and integrin receptors has been demonstrated. There is accumulating evidence of a role for IGF-1 in multiple vascular pathologies, including atherosclerosis, hypertension, restenosis, angiogenesis, and diabetic vascular disease. This review will discuss the regulation of expression of IGF-1, IGF-1R, and IGF binding proteins in the vasculature and summarize evidence implicating involvement of this system in vascular diseases.
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PMID:Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. 1460 34


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