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)

Osteoporosis is the most common metabolic bone disease. A low peak bone mass is regarded a risk factor for osteoporosis. Heredity, physical activity, and nutrition are regarded important measures for the observed variance in peak bone mass. Lp(a) lipoprotein is a well-known risk factor for atherosclerosis. Serum insulin-like growth factor I (IGF-I) has been found to be increased in males with early cardiovascular disease. In this study, we evaluated the association between bone mass, body constitution, muscle strength, Lp(a), and IGF-I in 47 Caucasian male adolescents (mean age, 16.9 yr). Bone mineral density (BMD) and body composition were measured by dual x-ray absorptiometry, muscle strength of thigh using an isokinetic dynamometer, IGF-I by RIA, and Lp(a) by enzyme-linked immunosorbent assay. IGF-I was only associated with Lp(a) (r = 0.38, P < 0.01). Lp(a) was related to total body (r = 0.40, P < 0.01), skull (r = 0.45, P < 0.01), and femoral neck BMD (r = 0.44, P < 0.01). Lp(a) was also related to fat mass (r = 0.34, P < 0.05) and muscle strength (r = 0.30-0.42, P < 0.05). After multiple regression and principal component (PC) analysis, the so-called PC body size (weight, fat mass, lean body mass, and muscle strength) was the most significant predictor of BMD (beta = 0.28-0.51, P < 0.05-0.01), followed by the so-called PC physical activity (beta = 0.28-0.38, P < 0.05-0.01, weight-bearing locations). However, the PC analysis confirmed that Lp(a) was an independent predictor of total body, skull, and femoral neck BMD (beta = 0.33-0.36, P < 0.01). The present investigation confirms that BMD, body size, and muscle strength are closely related and that the level of physical activity is a major determinant of BMD. However, the positive relation of Lp(a), a major risk factor for cardiovascular disease, to BMD has not previously been described. The importance of this observation has to be further investigated.
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PMID:The relation between bone mineral density, insulin-like growth factor I, lipoprotein (a), body composition, and muscle strength in adolescent males. 1048 59

Growth hormone (GH) deficiency and acromegaly may be associated with increased cardiovascular risk. Little is known about alterations in high density lipoproteins (HDL) in these conditions. Lecithin:cholesterol acyl transferase (LCAT) has the ability to esterify free cholesterol (FC) in HDL. Cholesteryl ester transfer protein (CETP) is able to transfer cholesteryl esters (CE) from HDL to very low and low density lipoproteins (VLDL and LDL). During phospholipid transfer protein (PLTP)-mediated HDL remodelling, small pre beta-HDL particles are generated which serve as acceptors for cellular cholesterol and provide the initial LCAT-substrate. We documented plasma lipids, LCAT, CETP and PLTP activity levels as well as plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) in 12 adult men with acquired GH deficiency, 12 acromegalic men and 24 healthy male subjects. All GH deficient and acromegalic patients received conventional hormonal replacement therapy if necessary. VLDL + LDL cholesterol and plasma triglycerides were higher in GH deficient (P < 0.01 and P < 0.05) and acromegalic patients (P < 0.05 and P < 0.01) than in healthy subjects. HDL cholesterol and HDL CE were lower (P < 0.05 for both) and the HDL FC/CE ratio was higher (P < 0.01) in these patient groups compared to healthy subjects. Plasma LCAT, CETP and PLTP activity levels were lower in acromegalic patients (P < 0.01 for all) and CETP activity was lower in GH deficient patients (P < 0.01) compared to healthy subjects. Plasma EST and CET were decreased in both acromegalic (P < 0.01 for both) and GH deficient patients (P < 0.05 for both). Multiple regression analysis demonstrated independent negative relationships of plasma insulin-like growth factor I with plasma LCAT (P = 0.0001), CETP (P = 0.009) and PLTP activity levels (P = 0.021). Plasma LCAT (P = 0.0001) and CETP activity (P = 0.0001) were also negatively associated with (substitution therapy for) adrenal insufficiency. In conclusion, GH deficient and acromegalic patients show abnormalities in HDL, consistent with impaired LCAT action. Decreases in plasma EST and CET in such patients, as well as a low PLTP activity in acromegaly suggest that reverse cholesterol transport may be impaired, contributing to increased cardiovascular risk.
Atherosclerosis 2000 Dec
PMID:Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. 1116 39

GH deficiency is associated with increased cardiovascular mortality and early manifestations of atherosclerosis. Elevated serum homocyst(e)ine levels have been found to be associated with increased cardiovascular risk. The effect of GH replacement on homocyst(e)ine has not been investigated to date. We evaluated the effect of GH replacement on fasting homocyst(e)inemia in a group of men with adult-onset GH deficiency in a randomized, single blind, placebo-controlled trial. Forty men with adult-onset GH deficiency were randomized to GH or placebo for 18 months, with dose adjustments made according to serum insulin-like growth factor I (IGF-I) levels. Fasting serum homocyst(e)ine, folate, vitamin B12, and total T(3) levels were determined at baseline and 6 and 18 months. Anthropometry, IGF-I levels, insulin, and glucose were measured at 1, 3, 6, 12, and 18 months. Nutritional assessment, body composition, total T(4), thyroid hormone binding index, and free T(4) index were assessed every 6 months. Homocyst(e)ine decreased in the GH-treated group compared with that in the placebo group (net difference, -1.2 +/- 0.6 micromol/L; confidence interval, -2.4, -0.02 micromol/L; P = 0.047). Homocyst(e)ine at baseline was negatively correlated with plasma levels of folate (r = -0.41; P = 0.0087). Total T(3) increased in the GH-treated group vs. that in the placebo group (net difference, 0.17 +/- 0.046 ng/dL; confidence interval, 0.071, 0.26 nmol/L; P = 0.0012). Folate and vitamin B12 levels did not significantly change between groups. Changes in homocyst(e)ine were negatively correlated with changes in IGF-I. For each 1 nmol/L increase in IGF-I, homocyst(e)ine decreased by 0.04 +/- 0.02 micromol/L (P = 0.029). In contrast, changes in homocyst(e)ine did not correlate with changes in folate, vitamin B12, total T(3), C-reactive protein, interleukin-6, or insulin levels. This study shows that GH replacement decreases fasting homocyst(e)ine levels compared with placebo. This may be one of the mechanisms involved in the putative modulation of atherosclerosis and cardiovascular risk by GH replacement.
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PMID:Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial. 1129 77

The aging process is characterized by a number of gradual changes in circulating hormone concentrations as well as a gradual increase in the degree of atherosclerosis. The authors studied whether serum hormone levels are related to atherosclerosis of the carotid artery in independently living, elderly men. In 1996, 403 men (aged 73-94 years) were randomly selected from the general population of Zoetermeer, the Netherlands. Carotid artery intima-media thickness was determined. Serum concentrations of testosterone; estrone; estradiol; dehydroepiandrosterone and dehydroepiandrosterone sulfate; insulin-like growth factor I (IGF-I) (total and free) and its binding proteins IGFBP-1, IGFBP-2, and IGFBP-3; and leptin were measured. After the authors adjusted for age, serum testosterone, estrone, and free IGF-I were inversely related to intima-media thickness. The strength of these relations was as powerful in subjects with as in those without prevalent cardiovascular disease. Serum estradiol; dehydroepiandrosterone sulfate; total IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3; and leptin showed no association. These findings suggest that endogenous testosterone, estrone, and free IGF-I levels may play a protective role in the development of atherosclerosis in aging men.
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PMID:Endogenous hormones and carotid atherosclerosis in elderly men. 1250 87

Both growth hormone (GH) and insulin-like growth factor I (IGF-I) are involved in heart development and in maintenance of cardiac structure and performance. Cardiovascular disease has been reported to reduce life expectancy in both GH deficiency (GHD) and GH excess. Patients with GHD suffer from a cluster of abnormalities associated with increased cardiovascular risk, including abnormal body composition, unfavorable lipid profile, increased fibrinogen and C-reactive protein levels, insulin resistance, early atherosclerosis and endothelial dysfunction, and impaired left ventricular (LV) performance (i.e., reduced diastolic filling and impaired response to peak exercise). Long-term GH replacement therapy reverses most of these abnormalities. More consistently, GH replacement reduces body fat and visceral adipose tissue, reduces low-density lipoprotein cholesterol and triglyceride levels, and improves endothelial function. GH replacement also reduces intima media thickness at major arteries and improves LV performance, but these results have been observed only in small series of patients treated on a short-term basis. This review discusses the roles of GHD and GH replacement therapy in the development of cardiovascular disease.
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PMID:Beginning to end: cardiovascular implications of growth hormone (GH) deficiency and GH therapy. 1669 Mar 38

Epidemiological studies have reported associations between a range of cardiovascular risk factors such as smoking and intima-media thickness (IMT). Some reports indicate that the maternal tobacco smoking causes disturbances of the endocrine status of the foetus. There are several potential mechanisms by which insulin-like growth factor I (IGF-I) could modify atherosclerotic processes either locally or in a systemic manner. The aim of this study was to investigate the influence of maternal smoking on neonatal aortic IMT (aIMT), serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels. Aortic intima-media thickness was measured in 28 neonates whose mothers smoked during the pregnancy and 28 control neonates. Mean and weight-adjusted aIMT were significantly greater in the neonates whose mothers smoked (0.455 +/- 0.009 mm and 0.151 +/- 0.005 mm/kg, respectively) than in controls (0.403 +/- 0.029 mm and 0.118 +/- 0.014 mm/kg, respectively). Birth-weight of newborns whose mothers smoked was less than that of the controls. The decreases in serum IGF-I and IGFBP-3 observed in the infants whose mothers smoked were non-significant. Mean aIMT was negatively associated with birth-weight and IGF-I level. In conclusion, neonates whose mothers smoked have significantly increased aIMT. It might play a role in the pathogenesis of atherosclerosis in adult life.
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PMID:Influence of maternal smoking on neonatal aortic intima-media thickness, serum IGF-I and IGFBP-3 levels. 1720 79

The aim of the present study was to evaluate the plasma endothelin-1 (ET-1) and total homocysteine (tHcy) levels as biochemical markers of endothelial dysfunction and atherosclerosis in patients with active and cured acromegaly in order to assess the relationship between the secretory status of growth hormone (GH)/insulin-like growth factor I (IGF-I) and ET-1/tHcy levels. The patients were divided in two subgroups: 1) patients with active disease (n = 30); and 2) patients with nonactive cured acromegaly (n = 21). Plasma ET-1 levels were directly determined by a highly sensitive enzyme immunoassay and plasma tHcy concentrations were measured by a fluorescence polarization immunoassay. In active acromegaly subjects, plasma ET-1 levels were 1.24 +/- 0.2 pmol/L, significantly higher than in both nonactive acromegalics (0.39 +/- 0.1 pmol/L) and age-matched healthy controls (0.49 +/- 0.2 pmol/L) (P < 0.001). Plasma tHcy concentrations, however, did not differ significantly in all studied groups: nonactive acromegalics: 9.54 +/- 4.42 micromol/L; active acromegalics: 9.0 +/- 3.14 micromol/L; and control subjects: 9.96 +/- 2.95 micromol/L (P > 0.05). In conclusion, our study demonstrated that elevated ET-1 levels probably contributed to premature atherosclerosis and cardiovascular disease and represent a new risk factor for endothelial dysfunction and early vascular complications in acromegaly. We propose that GH and IGF-I secretory status are important determinants of plasma ET-1 but not tHcy levels.
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PMID:Increased plasma endothelin level as an endothelial marker of cardiovascular risk in patients with active acromegaly: a comparison with plasma homocysteine. 1990 21

Background. Elevated serum total cholesterol (TC) and triglycerides (TG) are risk factors for atherosclerosis and ischemic heart disease. Adult growth hormone deficiency (AGHD) is associated with elevated TC and TG. Many treatment protocols for AGHD use relatively high doses of growth hormone (GH) given at low frequency, which is associated with increased incidences of edema, joint pains, and carpal tunnel syndrome. We have treated > 2200 patients using a low-dose high frequency (LDHF) dosing regimen of GH which results in similar beneficial subjective responses, and fewer of the side-effects associated with the higher-dosage treatment at a substantial cost savings. Clinically, in addition to increased insulin-like growth factor I (IGF-I), we observed lower TG and TC levels and no elevation of prostate specific antigen levels in treated patients. Methods. A retrospective analysis of IGF-I, TG, TC, and PSA data from our patient population was performed to test our hypothesis that positive objective responses of IGF-I, TG, and TC occur and that elevation of PSA does not occur in response to LDHF dosing regimen of GH. The mean duration of treatment of the analyzed data ranged from 181 to 259 days. Results. The mean plasma IGF-I level rose significantly (p<.00001) to a level 37% greater than baseline with treatment. TC and TG decreased significantly (p<.001) in those patients with elevated baseline values, and did not change significantly in those with normal baseline values. PSA concentrations decreased non-significantly during treatment, and few cases of edema, joint pain, or carpal tunnel were reported. Conclusions. Treatment of AGHD using the LDHF dosing regimen of GH resulted in significant increases in IGF-I, significant reductions in TC and TG levels in patients with elevated baseline values, no increase in PSA concentrations, and fewer side effects than other dosing regimens.
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PMID:Retrospective analysis of the effects of low-dose, high frequency human growth hormone on serum lipids and prostate specific antigen. 2360 76

Diabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulin-like growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is down-regulated, and cells become resistant to insulin. Under these conditions, the IGF-I receptor signals through an alternate scaffold protein, SHPS-1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS-1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS-1 expression in VSMCs in non-diabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF-I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up-regulated in IRS-1-/- mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild-type mice during hyperglycemia. These findings illuminate a new function of IRS-1: that of maintaining cells in their normal, differentiated state. Because IRS-1 is down-regulated in states of insulin resistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications.
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PMID:Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation. 2800 60

We have previously reported that overexpression of human insulin-like growth factor binding protein (IGFBP)-1 in mice leads to vascular insulin sensitization, increased nitric oxide bioavailability, reduced atherosclerosis, and enhanced vascular repair, and in the setting of obesity improves glucose tolerance. Human studies suggest that low levels of IGFBP-1 are permissive for the development of diabetes and cardiovascular disease. Here we seek to determine whether loss of IGFBP-1 plays a causal role in the predisposition to cardiometabolic disease. Metabolic phenotyping was performed in transgenic mice with homozygous knockout of IGFBP-1. This included glucose, insulin, and insulin-like growth factor I tolerance testing under normal diet and high-fat feeding conditions. Vascular phenotyping was then performed in the same mice using vasomotor aortic ring studies, flow cytometry, vascular wire injury, and angiogenesis assays. These were complemented with vascular phenotyping of IGFBP-1 overexpressing mice. Metabolic phenotype was similar in IGFBP-1 knockout and wild-type mice subjected to obesity. Deletion of IGFBP-1 inhibited endothelial regeneration following injury, suggesting that IGFBP-1 is required for effective vascular repair. Developmental angiogenesis was unaltered by deletion or overexpression of IGFBP-1. Recovery of perfusion following hind limb ischemia was unchanged in mice lacking or overexpressing IGFBP-1; however, overexpression of IGFBP-1 stimulated hindlimb perfusion and angiogenesis in insulin-resistant mice. These findings provide new insights into the role of IGFBP-1 in metabolic and vascular pathophysiology. Irrespective of whether loss of IGFBP-1 plays a causal role in the development of cardiometabolic disorders, increasing IGFBP-1 levels appears effective in promoting neovascularization in response to ischemia.
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PMID:IGFBP-1 in Cardiometabolic Pathophysiology-Insights From Loss-of-Function and Gain-of-Function Studies in Male Mice. 3219 Aug 1


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