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Potential atherogenic effects of short-term high dose growth hormone treatment in the rat model
Wednesday June 28, 2000: Poster Abstracts P:W24 Hormones and Cardiovascular Disease we compared the influence of MPA and NET on the endothelial synthesis of the vasoactive substances prostacyclin and endothelin. Methods: Prostacyclin synthesis was examined in endothelial cells of human umbilical veins by measuring its stable metabolite 6-keto-prostaglandin F 1~. Endothelin synthesis was measured directly in the medium of the cultured cells. MPA and NET were tested at the concentrations 0.01, 0.1 and 1/zM, the reaction time was 24 h. Results: MPA had no significant effect on the synthesis of prostacyclin and endothelin at all dosages tested compared to the control value. NET significantly stimulated prostacyclin synthesis at all three concentrations and reduces endothelin synthesis at the highest concentration. Condusions: These results indicate a significant difference between the progestins MPA and NET. NET can influence the vasotonus balance by a positive effect on prostacyclin synthesis and inhibition of endothelin whereas MPA reacts neutral in this respect. These investigations might contribute to assess the optimal hormonal study medication for interventional prevention trials like HERS with clinical endpoints.
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and hypertrophying of endothelial cells and abundant pynocytotic vesicles in these cells cytoplasm were detected by electron microscopic observations. Also, the lumen of vessels in GH group was significantly narrowed comparing the control group. In addition, abundant connective tissue was observed surrounding the vessels was observed. Conclusion: 1. Short-term high dose GH treatment influenced on coronary vessels ultra-structural characteristics such as thickening and hypertrophying of endothelial cells. 2. Initiation effects of the GH were observed from second weeks. These finding suggest that short-term high dose GH treatment may triggers endothelial dysfunction leading to premature atherosclerosis process.
I WeP1 5:W24 I Relationship between glucagon in a lipid-glucose load and carotid intlma-media thickness E. Henkel, T. Temelkova-Kurktschiev, W. Leonhardt, M. Hanefeld. Institute
of Clinical Metabolic Research, University Clinic Dresden, Germany
Objective: Type 2 diabetes is associated with an excessively high risk for I
WeP13:W24 [ Low cholesterol synthesis in postmenopausal women with hormone replacement therapy R.A. Raiaratnam, H. Gylling, T.A. Miettinen. Department of Medicine,
University of Helsinki, Helsinki, Finland
Objectives: Cholesterol metabolism and hormone replacement therapy (HRT) are associated with serum cholesterol level, and may have significant implication in the morbidity and mortality of coronary artery disease. Thus, the relation between cholesterol metabolism and HRT was investigated in postmenopausal women. Methods: Cholesterol metabolism was determined by sterol balance technique in 30 random postmenopausal women without hypolipidemic medication. Ten of the women were on, twenty of them off HRT (estradiol 2 mg and medroxyprogesterone 10 mg). Fecal neutral sterols and bile acids were measured with gas liquid chromatography, cholesterol absorption efficiency (CAE) with oral dual isotope feeding technique and sex hormone binding globulin (SHBG) with immunofluorometric assay. Results: The body mass index, dietary intakes of cholesterol and fat and CAE were comparable in the women on or off HRT, but serum levels of follicle stimulating hormone were lower and of SHBG were significantly higher in the women on HRT. The latter women tended to have lower serum cholesterol levels (5.7 4- 0.2 vs 5.9 4- 0.3 mmol/L), but had significantly lower fecal total steroids, mainly due to neutral sterols (9.9 4- 0.8 vs 12.6 4- 0.9 mg/kg/day, P < 0.05), and cholesterol synthesis (10.7 4- 0.6 vs 15.0 4- 1.3 mg/kg/day, P < 0.01) than the women off HRT. Cholesterol synthesis was inversely related to CAE (r = 0.38), and SHBG significantly to HDL cholesterol levels (r = 0.39), CAE (r = 0.36) and cholesterol synthesis (r = -0.42). Conclusions: Inefficient elimination of cholesterol as neutral sterols and low cholesterol synthesis are associated with HRT in postmenopansal women. I
WeP14:W24 1 Potential atherogenic effects of short-term high dose growth hormone treatment in the rat model ~. Co§kun, B. Ersoy, C. ~;ekuri 1 , K. Ozbilgin 3 , M. Yurtseven2 , A. Ona~ 2 .
"Celal Bayar University School of Medicine, Department of Pediatry; Cardiology; 3 Histology-Embryology, Manisa; "~lEge University School of Medicine, Department of Histology-Embryology, lzmir, Turkey 2
Recent experimental and clinical studies have suggested an important role for the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis in the regulation of cardiac growth and function. However, the changes of coronary vessels after short-term treatment with GH are not completely investigated. The aim of this study was to evaluate the relationship between growth hormone administration and ultra-structural changes in coronary vessels in rat model. Methods" Recombinant human growth hormone (rt-GH) were administered to rats (group 1) at a dose of 0.3 mg/kg for two weeks (n = 10). Control group (group 2) of rats were exposed to daily subcutaneous injections of saline (n = 10). After this period, coronary vessels were dissected and cross-sectional material prepared for histochemical, immunohistochemical and electronmicroscopic examinations. These prepared sections from control and treated groups were stained with Hematosilen-Eosin for histochemical studies, and with anti-laminin and anti-collagen IV antibodies for immunohistochemical techniques. Results: The slides staining with anti-laminin and anti-collagen IV antibodies were not demonstrated evident differences in vessels basement membrane between the two groups. However, in the GH group, a significant thickening
atherosclerosis. The relevance of the single factors of the insulin-glucose homeostasis is not completely clarified. Glucagon is produced by the a-cells of the pancreas and plays an important role in lipid and carbohydrate metabolism. So far, there are no data on the relationship between glucagon and intima-media thickness (IMT), an accepted marker of atherosclerosis. The aim of this study was to examine the effect of glucagon secretion after a lipid-glucose load on carotid IMT in various glucose tolerance stages. Methods: Male subjects, aged 35 to 70 years, with body mass index between 22 and 33 kg/m 2 were examined. 20 of them had type 2 diabetes mellitus, 16 impaired glucose tolerance and 25 had normal glucose tolerance. All subjects were non-smokers and had fasting triglycerides below 4.6 mmol/1. After an overnight fast they were administered a test drink (93 g fat, 82 g glucose). Blood was drawn in the fasting state and 2, 3, 4 and 6 hours after the load. Carotid IMT was determined by B-mode ultrasound. Results: In univariate analysis a positive correlation was found between IMT and age (p < 0.01), postprandial proinsulin (calculated as area under curve; p < 0.05), plasma triglycerides after removing chylomicra (p < 0.05) and a negative correlation between IMT and fasting glucagon level (p < 0.05). Using multile linear regression analysis age, fasting glucagon and triglycerides in plasma rest were found to be independent determinants of carotid IMT. Conclusions: Our data suggest that glucagon could be involved in atherogenesis.
IWeP16:W24
Dehydroepiandrosterone associated to low density lipoproteins reduces their increased susceptibility with ageing to lipid peroxidation
A. Khalil I , J.-P. Fortin 1, J.-G. Lehoux 2, T. FUltp I ./Ddpartement de m~decine, lnstitut universitaire de g~riatrie de Sherbrooke; 2Ddpartement de biochimie; Universitd de Sherbrooke, Sherbrooke, Canada The incidence of atherosclerosis and its related diseases increase with aging. The aging process may enhance lipoprotein modification, which leads to the increase in the susceptibility of LDL and HDL to oxidation. DHEA the most abundant steroid hormone in humans was shown to have antiatherogenic effects and this hormone is decreasing dramatically with aging. In the present study we were interested to determine the presence of DHEA/DHEAS and the evolution of their contents in HDL and LDL lipoproteins with aging. Moreover, we studied the susceptibility of LDL to oxidation with age in the presence or absence of vitamin E or DHEA. We demonstrated that vitamin E is unable to restore the decreased resistance to oxidation of LDL from elderly subjects to the level of LDL obtained from young subjects. Furthermore, our results provide evidence that DHEA is integrative part of LDL and HDL and disappear to almost non-detectable levels with. The DHEA incorporated in the LDL from elderly subjects increased their resistance to oxidation in a concentration dependent manner, by increasing significantly the lag-phase and decreasing the plateau of conjugated diene, hydroperoxide and TBARS formations. The increased resistance provided by DHEA was higher than that with vitamin E. DHEA seems to act either by protecting Vitamin E from disappearance from LDL under oxidation or to scavenge directly the free radicals produced during the oxidative process. Our results suggest that DHEA exerts an antioxidative effect on LDL, which could have antiatherogenic consequences. Careful clinical trials of DHEA replacement should determine whether this ex vivo effect could be translated into any measurable antiatherogenic (cardio-protective) action.
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
205
and hypertrophying of endothelial cells and abundant pynocytotic vesicles in these cells cytoplasm were detected by electron microscopic observations. Also, the lumen of vessels in GH group was significantly narrowed comparing the control group. In addition, abundant connective tissue was observed surrounding the vessels was observed. Conclusion: 1. Short-term high dose GH treatment influenced on coronary vessels ultra-structural characteristics such as thickening and hypertrophying of endothelial cells. 2. Initiation effects of the GH were observed from second weeks. These finding suggest that short-term high dose GH treatment may triggers endothelial dysfunction leading to premature atherosclerosis process.
I WeP1 5:W24 I Relationship between glucagon in a lipid-glucose load and carotid intlma-media thickness E. Henkel, T. Temelkova-Kurktschiev, W. Leonhardt, M. Hanefeld. Institute
of Clinical Metabolic Research, University Clinic Dresden, Germany
Objective: Type 2 diabetes is associated with an excessively high risk for I
WeP13:W24 [ Low cholesterol synthesis in postmenopausal women with hormone replacement therapy R.A. Raiaratnam, H. Gylling, T.A. Miettinen. Department of Medicine,
University of Helsinki, Helsinki, Finland
Objectives: Cholesterol metabolism and hormone replacement therapy (HRT) are associated with serum cholesterol level, and may have significant implication in the morbidity and mortality of coronary artery disease. Thus, the relation between cholesterol metabolism and HRT was investigated in postmenopausal women. Methods: Cholesterol metabolism was determined by sterol balance technique in 30 random postmenopausal women without hypolipidemic medication. Ten of the women were on, twenty of them off HRT (estradiol 2 mg and medroxyprogesterone 10 mg). Fecal neutral sterols and bile acids were measured with gas liquid chromatography, cholesterol absorption efficiency (CAE) with oral dual isotope feeding technique and sex hormone binding globulin (SHBG) with immunofluorometric assay. Results: The body mass index, dietary intakes of cholesterol and fat and CAE were comparable in the women on or off HRT, but serum levels of follicle stimulating hormone were lower and of SHBG were significantly higher in the women on HRT. The latter women tended to have lower serum cholesterol levels (5.7 4- 0.2 vs 5.9 4- 0.3 mmol/L), but had significantly lower fecal total steroids, mainly due to neutral sterols (9.9 4- 0.8 vs 12.6 4- 0.9 mg/kg/day, P < 0.05), and cholesterol synthesis (10.7 4- 0.6 vs 15.0 4- 1.3 mg/kg/day, P < 0.01) than the women off HRT. Cholesterol synthesis was inversely related to CAE (r = 0.38), and SHBG significantly to HDL cholesterol levels (r = 0.39), CAE (r = 0.36) and cholesterol synthesis (r = -0.42). Conclusions: Inefficient elimination of cholesterol as neutral sterols and low cholesterol synthesis are associated with HRT in postmenopansal women. I
WeP14:W24 1 Potential atherogenic effects of short-term high dose growth hormone treatment in the rat model ~. Co§kun, B. Ersoy, C. ~;ekuri 1 , K. Ozbilgin 3 , M. Yurtseven2 , A. Ona~ 2 .
"Celal Bayar University School of Medicine, Department of Pediatry; Cardiology; 3 Histology-Embryology, Manisa; "~lEge University School of Medicine, Department of Histology-Embryology, lzmir, Turkey 2
Recent experimental and clinical studies have suggested an important role for the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis in the regulation of cardiac growth and function. However, the changes of coronary vessels after short-term treatment with GH are not completely investigated. The aim of this study was to evaluate the relationship between growth hormone administration and ultra-structural changes in coronary vessels in rat model. Methods" Recombinant human growth hormone (rt-GH) were administered to rats (group 1) at a dose of 0.3 mg/kg for two weeks (n = 10). Control group (group 2) of rats were exposed to daily subcutaneous injections of saline (n = 10). After this period, coronary vessels were dissected and cross-sectional material prepared for histochemical, immunohistochemical and electronmicroscopic examinations. These prepared sections from control and treated groups were stained with Hematosilen-Eosin for histochemical studies, and with anti-laminin and anti-collagen IV antibodies for immunohistochemical techniques. Results: The slides staining with anti-laminin and anti-collagen IV antibodies were not demonstrated evident differences in vessels basement membrane between the two groups. However, in the GH group, a significant thickening
atherosclerosis. The relevance of the single factors of the insulin-glucose homeostasis is not completely clarified. Glucagon is produced by the a-cells of the pancreas and plays an important role in lipid and carbohydrate metabolism. So far, there are no data on the relationship between glucagon and intima-media thickness (IMT), an accepted marker of atherosclerosis. The aim of this study was to examine the effect of glucagon secretion after a lipid-glucose load on carotid IMT in various glucose tolerance stages. Methods: Male subjects, aged 35 to 70 years, with body mass index between 22 and 33 kg/m 2 were examined. 20 of them had type 2 diabetes mellitus, 16 impaired glucose tolerance and 25 had normal glucose tolerance. All subjects were non-smokers and had fasting triglycerides below 4.6 mmol/1. After an overnight fast they were administered a test drink (93 g fat, 82 g glucose). Blood was drawn in the fasting state and 2, 3, 4 and 6 hours after the load. Carotid IMT was determined by B-mode ultrasound. Results: In univariate analysis a positive correlation was found between IMT and age (p < 0.01), postprandial proinsulin (calculated as area under curve; p < 0.05), plasma triglycerides after removing chylomicra (p < 0.05) and a negative correlation between IMT and fasting glucagon level (p < 0.05). Using multile linear regression analysis age, fasting glucagon and triglycerides in plasma rest were found to be independent determinants of carotid IMT. Conclusions: Our data suggest that glucagon could be involved in atherogenesis.
IWeP16:W24
Dehydroepiandrosterone associated to low density lipoproteins reduces their increased susceptibility with ageing to lipid peroxidation
A. Khalil I , J.-P. Fortin 1, J.-G. Lehoux 2, T. FUltp I ./Ddpartement de m~decine, lnstitut universitaire de g~riatrie de Sherbrooke; 2Ddpartement de biochimie; Universitd de Sherbrooke, Sherbrooke, Canada The incidence of atherosclerosis and its related diseases increase with aging. The aging process may enhance lipoprotein modification, which leads to the increase in the susceptibility of LDL and HDL to oxidation. DHEA the most abundant steroid hormone in humans was shown to have antiatherogenic effects and this hormone is decreasing dramatically with aging. In the present study we were interested to determine the presence of DHEA/DHEAS and the evolution of their contents in HDL and LDL lipoproteins with aging. Moreover, we studied the susceptibility of LDL to oxidation with age in the presence or absence of vitamin E or DHEA. We demonstrated that vitamin E is unable to restore the decreased resistance to oxidation of LDL from elderly subjects to the level of LDL obtained from young subjects. Furthermore, our results provide evidence that DHEA is integrative part of LDL and HDL and disappear to almost non-detectable levels with. The DHEA incorporated in the LDL from elderly subjects increased their resistance to oxidation in a concentration dependent manner, by increasing significantly the lag-phase and decreasing the plateau of conjugated diene, hydroperoxide and TBARS formations. The increased resistance provided by DHEA was higher than that with vitamin E. DHEA seems to act either by protecting Vitamin E from disappearance from LDL under oxidation or to scavenge directly the free radicals produced during the oxidative process. Our results suggest that DHEA exerts an antioxidative effect on LDL, which could have antiatherogenic consequences. Careful clinical trials of DHEA replacement should determine whether this ex vivo effect could be translated into any measurable antiatherogenic (cardio-protective) action.
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000