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)

Low levels of insulin-like growth factor binding protein-1 (IGFBP-1) have recently been associated with several risk factors for cardiovascular disease. The effects of estrogen replacement therapy (ERT) on plasma IGFBP-1 levels are, however, unclear. A double-blind, placebo-controlled study for 6 months was conducted in 73 hysterectomized postmenopausal women randomized into two groups: oral estradiol (E2) valerate, 2 mg/day (n = 35) and transdermal E2 gel, 1 mg/day (n=38). Plasma IGFBP-1, insulin-like growth factor-I (IGF-I) and lipoprotein(a) (Lp(a)) were determined at baseline, 3 and 6 months. The groups were similar for age and BMI. The baseline levels of estrone (E1), E2, IGFBP-1, IGF-I and Lp(a) did not differ between the groups. During treatment, serum estradiol concentrations increased in both groups. During oral ERT, IGFBP-1 levels increased by 104% (P<0.001), whereas IGF-I levels decreased by 13% (mean, P<0.05). IGF-I and IGFBP-1 levels remained unchanged in the transdermal group. Lp(a) levels decreased by 23% (median, P<0.001) in the oral group, but were unaffected by transdermal therapy. The change in IGFBP-1 concentrations during oral ERT showed an inverse correlation to that in Lp(a) (r = -0.40, P<0.05, Spearman correlation). In conclusion, oral ERT seems to enhance plasma levels of IGFBP-1, which may be one reason for the reduced Lp(a) levels.
Atherosclerosis 2000 Mar
PMID:Insulin-like growth factor binding protein-1 (IGFBP-1) and IGF-I during oral and transdermal estrogen replacement therapy: relation to lipoprotein(a) levels. 1070 27

Despite an improved understanding of the molecular mechanisms of insulin-like growth factor-I (IGF-I) signaling and the recognition that IGF-I mediates many effects in endothelial cells, some of which may be important for atherosclerosis, little is known about the signal transduction pathways that mediate the effects of IGF-I in endothelial cells. To that end, we examined the signaling pathways activated by IGF-I in endothelial cells and their contribution to IGF-I-stimulated endothelial cell migration and nuclear factor (NF)-kappaB-dependent transcription. Treatment of bovine pulmonary artery endothelial cells (PAEC) with IGF-I activated the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK)1/2 and ERK5. In contrast, IGF-I had no effect on either c-Jun amino-terminal kinase or p38 kinase activity. IGF-I also activated phosphatidylinositol (PI) 3-kinase, as reflected by increased phosphorylation of AKT: There was no evidence of cross-talk between the ERK and PI 3-kinase pathways in PAEC. In PAEC transiently transfected with pTK81-NFkappaB-Luc, which contained four copies of the NF-kappaB DNA binding site 5' to a minimal promoter and the luciferase gene, treatment with 50 ng/ml IGF-I increased luciferase activity 1.8-fold. Inhibition of ERK activity using PD98059 and PI 3-kinase activity with LY 294002 abrogated the induction of NF-kappaB-dependent transcription by IGF-I, suggesting that both pathways contribute to the effect of IGF-I on NF-kappaBdependent transcription. In contrast to the effect of tumor necrosis factor-alpha on NF-kappaB activation, Western blot analyses demonstrated that IGF-I had no effect on IkappaB phosphorylation and degradation or nuclear translocation and DNA binding of NF-kappaB. These data suggest a direct of effect of IGF-I on nuclear NF-kappaB. IGF-I also increased endothelial cell migration approximately 2-fold, as demonstrated using a Boyden chamber apparatus. IGF-I-induced endothelial cell migration was inhibited, in part, by LY 294002 but not PD98059. Together, these studies demonstrate that IGF-I activates multiple signaling pathways in endothelial cells with little evidence for cross-talk between the pathways. Moreover, these pathways appear to mediate both overlapping and distinct effects in that activation of both PI 3-kinase and the ERKs contributed to the stimulation of NF-kappaB-dependent transcription by IGF-I, whereas only PI 3-kinase mediated IGF-I-stimulated endothelial cell migration.
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PMID:The role of phosphatidylinositol 3-kinase and the mitogen-activated protein kinases in insulin-like growth factor-I-mediated effects in vascular endothelial cells. 1131 33

The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the differentiated state to the dedifferentiated one is critically involved in the development and progression of atherosclerosis. Although many cytokines and growth factors have been reported as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for visceral SMCs and VSMCs in which both SMCs, when cultured on laminin with insulin-like growth factor-I, show a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level of SMC differentiation marker gene expression. In this study, we searched for critical dedifferentiation factors for these SMCs using our culture system. We found that polar lipids extracted from human serum markedly induced VSMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors to the induction of VSMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced VSMC dedifferentiation is mediated through the coordinated activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Thus, this report demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce VSMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.
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PMID:Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids. 1148 75

Induction of fibronectin (FN) gene expression by platelet-derived growth factor (PDGF) isoforms in rat thoracic aortic smooth muscle cells (SMC) was examined. PDGF-BB enhances FN levels in SMC cultures in a time- and concentration-response fashion. PDGF-AA and PDGF-AB show no effect on FN levels. The effects of insulin and insulin-like growth factor-I (IGF-I) on PDGF-BB-induced FN levels were examined. No additivity of FN levels is observed between PDGF-BB and insulin and/or IGF-I. Experiments also show that PDGF-BB enhances FN mRNA levels, implying that acquisition of additional FN mRNA units accounts for the increase in FN levels. Induction of FN and FN mRNA levels by PDGF-BB could be one of the initial events in vascular SMC proliferation and extracellular matrix expansion, leading to atherosclerosis and hypertension. Copyright 1995 S. Karger AG, Basel
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PMID:Regulation of Fibronectin by Platelet-Derived Growth Factors in Cultured Rat Thoracic Aortic Smooth Muscle Cells. 1172 43

Diabetes causes accelerated atherosclerosis and subsequent cardiovascular disease through mechanisms that are poorly understood. We have previously shown, using a porcine model of diabetes-accelerated atherosclerosis, that diabetes leads to an increased accumulation and proliferation of arterial smooth muscle cells in atherosclerotic lesions and that this is associated with elevated levels of plasma triglycerides. We therefore used the same model to investigate the mechanism whereby diabetes may stimulate smooth muscle cell proliferation. We show that lesions from diabetic pigs fed a cholesterol-rich diet contain abundant insulin-like growth factor-I (IGF-I), in contrast to lesions from non-diabetic pigs. Furthermore, two fatty acids common in triglycerides, oleate and linoleate, enhance the growth-promoting effects of IGF-I in smooth muscle cells isolated from these animals. These fatty acids accumulate predominantly in the membrane phospholipid pool; oleate accumulates preferentially in phosphatidylcholine and phosphatidylethanolamine, whereas linoleate is found mainly in phosphatidylethanolamine. The growth-promoting effects of oleate and linoleate depend on phospholipid hydrolysis by phospholipase D and subsequent generation of diacylglycerol. Thus, concurrent increases in levels of IGF-I and triglyceride-derived oleate and linoleate in lesions may contribute to accumulation and proliferation of smooth muscle cells and lesion progression in diabetes-accelerated atherosclerosis.
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PMID:Oleate and linoleate enhance the growth-promoting effects of insulin-like growth factor-I through a phospholipase D-dependent pathway in arterial smooth muscle cells. 1213 7

The growth-promoting effects of insulin-like growth factor-I (IGF-I) appear to be different in vascular smooth muscle cells from various segments of the arterial tree. Little information exists on human coronary artery smooth muscle cells (CoSMC), the primary elements of coronary atherosclerosis and post-angioplasty restenosis. In this study we determined the effects of IGF-I on cultured human CoSMC. Type I IGF receptors (IGF-R) were present on CoSMC as assessed by affinity cross-linking of 125I-IGF-I to monolayer cultures. IGF-I was a weak mitogen, 1.5-fold increase in [3H]thymidine incorporation, for CoSMC. However, IGF-I had a potent motility effect on CoSMC with a 314+/-12% increase in cell migration (P<0.001), comparable to that of 5% FBS. IGF-I-stimulated motility was partially inhibited by alphaIR-3, a specific IGF-R inhibitor (P<0.05). Addition of kistrin, a disintegrin, or LM609, a specific alpha(V)beta(3) integrin neutralizing antibody, abolished IGF-I-stimulated migration (P<0.001). This study indicates that IGF-I is a potent motility agent for human CoSMC via the alpha(V)beta(3) integrin receptor, but exerts little mitogenic effect. Because CoSMC migration plays a crucial role in atherosclerosis and restenosis, IGF-I blockade has the potential to limit lumen reduction.
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PMID:Effects of insulin-like growth factor-I on cultured human coronary artery smooth muscle cells. 1293 45

Inflammatory processes, marked in part by the acute phase reactant C-reactive protein (CRP) and insulin resistance are implicated in atherogenesis. Low insulin-like growth factor-I (IGF-I) and IGF binding protein-1 (IGFBP-1) concentrations are closely associated with insulin resistance. We examined CRP in ethnic groups with differing risk for cardiovascular disease and type 2 diabetes and its relationship with insulin sensitivity (Homeostasis model assessment (HOMA)-S) and the IGF system. European (n=155), Pakistani (n=108) and African-Caribbean (African Caribbean) (n=177) origin participants were randomly sampled from population registers. All underwent basic anthropometry, glucose tolerance testing and measurement of insulin sensitivity, CRP and other metabolic variables. CRP was significantly lower in African Caribbean men and women than in other ethnic groups. Across all groups CRP correlated negatively with (HOMA-S) (rho=-0.29, P<0.001). Regression analysis which included ethnicity and body mass index (BMI) showed that low HOMA-S (beta=-0.17, P<0.001) and low IGFBP-1 (beta=-0.14, P<0.001) were independently and inversely associated with CRP, but the effect was modified by obesity. In obese subjects insulin sensitivity was not associated with CRP. However, for the whole population, a 2.7 mg/l increase in CRP was associated with a 50% (95% confidence interval (CI) 10-210%) greater risk of WHO defined metabolic syndrome, independent of IGF-I (odds ratio (OR) 0.46 (95% CI 0.22-0.96)), IGFBP-1 (OR 0.58 (0.44-0.76)), female sex (OR 0.43 (0.22-0.84)), NEFA (OR 1.06 (1.03-1.09)) and Pakistani ethnicity. High CRP (as a measure of chronic subclinical inflammation), low IGF-I and low IGFBP-1 are independently associated with the presence of the metabolic syndrome and with insulin resistance. In obese subjects insulin sensitivity is not associated with changes in CRP whilst in non-obese subjects CRP independently contributes to variation in HOMA-S.
Atherosclerosis 2003 Sep
PMID:C-reactive protein and the insulin-like growth factor (IGF)-system in relation to risk of cardiovascular disease in different ethnic groups. 1295 85

Vascular dementia (VaD) and Alzheimer's disease (AD) are the most common causes of dementia in the elderly. The aim of this study was to investigate carotid atherosclerosis, serum lipid profiles, and atherogenic hormone levels in nondiabetic Japanese men with VaD or AD. Carotid artery intima-media thickness (IMT) and plaque, serum lipid and lipoprotein profiles, including low-density lipoprotein (LDL) particle size, as well as insulin-like growth factor-I (IGF-I, somatomedin C) and testosterone levels, were determined in 34 patients with AD, 37 patients with VaD, and 63 healthy male controls. Age, body mass index, systolic and diastolic blood pressure, and fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), triglyceride, high-density lipoprotein (HDL)-cholesterol, and apolipoproteins (apo) A-I, B, and E levels did not differ significantly among the 3 groups. However, the mean value of carotid IMT, the frequency of atherosclerotic plaque deposition, the serum levels of LDL-cholesterol, lipoprotein(a), and lipid peroxides, and the incidence of small dense LDL (particle diameter </= 25.5 nm) were increased significantly in VaD patients compared with AD patients or controls. VaD patients had a close reverse correlation between carotid IMT and LDL particle diameter, which were statistically proven independent risk factors for VaD. In contrast, AD patients had significantly lower serum levels of IGF-I and testosterone than either VaD patients or controls. Our results indicate that VaD is associated with atherogenic dyslipidemia, in particular, small dense LDL and carotid atherosclerosis, whereas AD is associated with hyposomatomedinemia and hypogonadism rather than atherosclerosis.
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PMID:Small dense low-density lipoprotein and carotid atherosclerosis in relation to vascular dementia. 1504 95

Previous studies revealed altered levels of the circulating insulin-like growth factor-I (IGF-I) and of its binding protein-3 (IGFBP-3) in subjects with coronary atherosclerosis, metabolic syndrome and premature atherosclerosis. Hyperlipidemia is a powerful risk factor of atherosclerosis. We expected IGF-I and IGFBP-3 alterations in subjects with moderate/severe hyperlipidemia but without any clinical manifestation of atherosclerosis. Total IGF-I and IGFBP-3 were assessed in 56 patients with mixed hyperlipidemia (MHL; cholesterol >6.0 mmol/l, triglycerides >2.0 mmol/l), in 33 patients with isolated hypercholesterolemia (IHC; cholesterol >6.0 mmol/l, triglycerides <2.0 mmol/l), and in 29 healthy controls (cholesterol<6.0 mmol/l, triglycerides<2.0 mmol/l). The molar ratio of IGF-I/IGFBP-3 was used as a measure of free IGF-I. IHC subjects differed from controls by lower total IGF-I (164+/-60 vs. 209+/-73 ng/ml, p=0.01) and IGF-I /IGFBP-3 ratio (0.14+/-0.05 vs. 0.17+/-0.04, p=0.04). Compared to controls, MHL subjects had lower total IGF-I (153+/-54 ng/ml, p=0.0002) and IGFBP-3 (2.8+/-0.6 mg/ml, p<0.0001), but higher IGF-I/IGFBP-3 ratio (0.25+/-0.06, p<0.0001). Differences remained significant after the adjustment for clinical and biochemical covariates, except for triglycerides. Patients with both IHC and MHL have lower total IGF-I compared to controls. The mechanism is presumably different in IHC and MHL. Because of prominent reduction of IGFBP-3 in patients with MHL, they have reduced total IGF-I despite the actual elevation IGF-I/IGFBP-3 ratio as a surrogate of free IGF-I.
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PMID:Hyperlipidemia is associated with altered levels of insulin-like growth factor-I. 1805 85

We investigated the relationship between serum dehydroepiandrosterone-sulfate (DHEA-S) and insulin-like growth factor-I (IGF-I) to various parameters for atherosclerosis in type 2 diabetes. The levels of DHEA-S and IGF-I are known to decrease with aging and thereby might be associated with an increased risk of cardiovascular disease. One hundred forty-eight men and 106 postmenopausal women with type 2 diabetes were assessed in a cross-sectional study. Serum DHEA-S and IGF-I concentrations were measured and brachial-ankle pulse wave velocity (baPWV) and ultrasonographically-evaluated intima-media thickness (IMT) were assessed. Although simple regression analysis showed that log(DHEA-S) and IGF-I in men and log(DHEA-S) in women were significantly and inversely correlated with baPWV and IMT, only log(DHEA-S) in women was still significantly and inversely correlated with these atherosclerotic parameters after multiple regression analysis was adjusted for age, duration of diabetes, BMI, HbA(1C), systolic blood pressure, LDL-Cholesterol (C), serum creatinine, and smoking (Brinkman index). Serum DHEA-S level seemed to be associated with atherosclerosis in diabetic postmenopausal women independent of age, body stature, diabetic status, and other atherosclerotic risk factors, and might be a useful addition to other parameters for assessing the risk of atherosclerosis in this population.
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PMID:Serum DHEA-S level is associated with the presence of atherosclerosis in postmenopausal women with type 2 diabetes mellitus. 1849 2


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