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Tu-P7:16 Adipobiology of atherosclerosis
188 ~
Tues&ty, June 20, 2006: Poster Session P7 Basic science ( lst part) APELIN AND HEART FUNCTION IN HEMODIALYZED PATIENS: ARE THEY RELATED?
J. Malyszko I , J. Malyszko I , P. Kozminski 2, M. Mysliwiec I . 1Department of Nephrology, Medical Universit, Bialystok, Poland: 2Dialysis Unit, Dzialdowo, Poland Apelin, newly discovered adipocytokine, is produced by white adipose tissue and also expressed in kidney and heart. Increasing evidence suggests a role for the apelin in the pathology of the cardiovascular system. Cardiovascular disease is a major contributor to the mortality and morbidity in patients with chronic renal failure The aim of the study was to assess associations between apelin, coronary artery disease and echocardiographic parameters in hemodialyzed patients. We investigated plasma apelin levels in 82 non-diabetic, clinically stable hemodialyzed patients (38F,44M) with and without coronary artery disease. We observed statistically significant correlations between apelin and echocardiographic parameters: LVIDd-left ventricular internal enddiastolic dimension, LVISd-left ventriculax internal endsystolic dimension, RV- right ventricle, LA-left atrium, RA right atrium, LVPW- LV posterior wall diastole, Ao-aorta, and serum lipids: cholesterol, LDL, triglycerides. In multiple logistic regression analysis the only predictor of apelin was LVIDd. Apelin is significantly lowered in dialyzed patients with coronary artery disease and its level is predicted by cardiac function. Apelin might be involved in the pathophysiology of cardiovascular disease in chronic renal failure. Since apelin is an inotrope in normal and failing hearts, this finding may have a clinical implications for future use of apelin as a novel inotropic agent also for patients with "'uremic caxdiomyopathy'"
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EFFECT OF ALDEHYDES, ARACHIDONIC ACID AND ROSIGLITAZONE ON ADIPOCYTE DIFFERENTIATION
A. Cabre, I. Lazaro, J. Girona, L. Masana. Unitat de Recerea de Lfpids I Arteriosclerosi, h'eis, Hospital UniversitaH Sant Joan, Universitat Rovira I Virgili, Reus, Spabt Objective: Effect of aldehydes, arachidonic acid (AA) and rosiglitazone on morphological changes, lipid droplet accumulation, modulation of adipocyte differentiation markers (PPARg and FABP4) and adipokine expression (adiponectin and RBP4) during adipocyte differentiation (AD). Methods: AD of human preadipocytes was induced in the presence of aldehydes (2,4-decadienal and hexanal), arachidonic acid and rosiglitazone. Lipid accumulation was assessed by Oil Red O staining. Morphological changes of cells, FABP4, PPARg, adiponectin, RBP4, were analyzed by flow citometry and aP2/FABP4 mRNA levels by real time RT-PCR. Results: Aldehydes and rosiglitazone produced an enhancement of lipid droplets accumulation, an increase of size and complexity and positive labelling for PPARg and FABP4 protein. AA produced cell dedifferentiation. Under the same conditions, 2,4-decadienal increased FABP4 mRNA levels more than 4-fold respect to vehicle. During rosiglitazone adipocyte differentiation, adiponectin and RBP4 were expressed following different patterns. While low-fat content adipocytes produced similar amounts of both adipokines, the more mature rich-fat adipocytes showed a relative overexpression of RBP4. Conclusion: The presence of oxidation products may facilitate adipocyte hypertrophy. Mature adipocyte state would lead to an alteration of adipokine secretion pattern prone to insulin resistance.
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ADIPOBIOLOGY OF ATHEROSCLEROSIS
G.N. Chaldakov I , I.S. Stankulov I , P. Atanassova 2 , M. Fiore 3, P.I. Ghenev I , A.B. Tonchev 1 , L. Aloe 3. 1Medical Universi~, Vama, Bulgaria: "-Medical Universi~, Plovdiv, Bulgaria: ~bzstitute of Neurobiology arm Molecular Medicine, CNR, Rome, Italy Objective: Adipose tissue is not solely a fat storage, but an active endocrine and paxacrine organ secreting a variety of molecules conceptually dubbed adipokines. The present study aimed at evaluating the role of epicardial adipose tissue in the pathogenesis of human coronary atherosderosis. Methods: Samples were obtained from autopsies. Left anterior descending coronary arteries aYfected by atherosclerosis (n=12) and control arteries (n=9) all taken with the surrounding epicardial adipose tissue were processed for routine and immunohistochemical analysis, and by an enzyme-linked immunosorbent assay to separately measure nerve growth factor (NGF) levels in the epicardial adipose tissue and the coronary vascular wall tissue.
Results: NGF level was increased in epicaxdial adipose tissue, whereas significantly decreased in vascular tissue of atherosclerotic coronaries as compared with controls. An increased number of mast cells and increased p75NGF receptor immunostaining were found in both tissues in atherosclerotic samples. Conclusions: We suggest that the up-regulated adipose NGF/NGF receptor expression may be a protective response to injured coronary vascular wall. The epicaxdial adipose tissue surrounding the coronary artery should no longer be stripped, but keep attached and in place, and subject to thorough examination. In effect, adipobiology (Chaldakov et al. Curr Pharm Design 2003; 9: 1023-1031) may offer a novel approach in the study of pathogenesis and therapy of atherosclerosis. Funding: Supported by Medical University, Varna, Bulgaria and by CNR, Rome, Italy.
I Tu-P7:17 I GENETIC VARIABILITY IN BIOTRANSFORMATION A N D ANTIOXIDANT ENZYMES AND THEIR ROLE IN THE PROCESS OF AGING A. Horskfi, C. Mislanovfi, M. Bacekovfi, Z. Hudecovfi, L. Ws61ovfi, M. Dusinskfi. Slovak Medical Universi~, Bratislm,a, Slovak Republic Objective: Aging is a complex process involving systematic depreciation of enzymatic machinery and damage to macromolecules through the action of exogenous and endogenous forces. Development of aging-coupled diseases is influenced by genetic background, notably polymorphisms in genes linked to diseases and genes for defence mechanisms, which can modulate environmental impacts. The aim of study is to investigate the role of selected polymorphisms in aging. Methods: 292 subjects, 151 young and 141 elderly were analysed. Genetic polymorphisms were determined in glutathione S-transferases and superoxide dismutases. DNA damage was measured by the Comet assay and antioxidants were estimated by HPLC. Results: A significant difference was observed in distribution of GSTT1 genotype between young and elderly people (p=0.002). Subjects with deletion in GSTT1 gene had higher levels of g-tocopherol (p=0.002) and decreased levels of DNA strand breaks (p=0.019). Elderly with deleted GSTM1 gene had lower levels of a-tocopherol in plasma. GSTTI* null subjects had lower levels of strand breaks (p= 0.001). Presence of SOD2"16 Ala allele corresponded with decreased retinol (p=0.011). These relations were not found in young. A link between polymorphisms in SOD1 and MDA was found. Young subjects with SOD1 A/A genotype had lower levels of MDA, and MDA depended on BMI (p<0.001). In young with SOD1 A/C, the MDA level depended on g-tocopherol (p=0.011). Conclusions: We supose that healthy aging is paxtialy determined by genetic wxiation in antioxidant and biotransformation genes. Funding: Supported by Slovak STA Agency project No. APVT-21-01320. CHOLESTEROL ABSORPTION IS N O T A ITu-P7:181 INTESTINAL MAJOR DETERMINANT FOR THE AGE-INDUCED I i
INCREASE IN PLASMA CHOLESTEROL IN RATS C. G/ilman, M. Matasconi, P. Parini, B. Angelim M. Rudling. Karolinska Institute, Center for Metabolism, Endocrinology and Diabetology Departnwnt of Medicine, Stoekhohn, Sweden Objective: During aging plasma total and LDL cholesterol increase in both rodents and humans. The balance between dietary input, endogenous synthesis, and cholesterol elimination governs total body cholesterol. A reduced elimination of cholesterol as bile acids (BA) and a decreased receptor-mediated clearance of plasma LDL have been linked to the increase of plasma cholesterol with ageing. This increase may in large part be reversed by treatment with growth hormone (GH). Here, we studied whether the intestinal cholesterol absorption increases with age, and whether any increase could be aYfected by treatment with GH or ezetimibe (EZE). Methods: Male rats, 6 and 18 months, were treated with GH or EZE. Intestinal cholesterol absorption, plasma lipids, BA synthesis, and the gene expression of cholesterol transporters were monitored. Results: Although BA synthesis was reduced and plasma cholesterol was increased in the old animals, intestinal cholesterol absorption could not explain these age-related changes. Accordingly, the mRNA levels of cholesterol transporters, ABCG5, ABCG8 and NPC1L1, were not affected by ageing. Despite improving plasma lipoprotein profile, GH had no effect on cholesterol absorption, while EZE reduced the intestinal cholesterol absorption in both young and old rats. Hepatic LDL-receptors (LDLRs) and scavenger receptor-
XIV bztemational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006
Tues&ty, June 20, 2006: Poster Session P7 Basic science ( lst part) APELIN AND HEART FUNCTION IN HEMODIALYZED PATIENS: ARE THEY RELATED?
J. Malyszko I , J. Malyszko I , P. Kozminski 2, M. Mysliwiec I . 1Department of Nephrology, Medical Universit, Bialystok, Poland: 2Dialysis Unit, Dzialdowo, Poland Apelin, newly discovered adipocytokine, is produced by white adipose tissue and also expressed in kidney and heart. Increasing evidence suggests a role for the apelin in the pathology of the cardiovascular system. Cardiovascular disease is a major contributor to the mortality and morbidity in patients with chronic renal failure The aim of the study was to assess associations between apelin, coronary artery disease and echocardiographic parameters in hemodialyzed patients. We investigated plasma apelin levels in 82 non-diabetic, clinically stable hemodialyzed patients (38F,44M) with and without coronary artery disease. We observed statistically significant correlations between apelin and echocardiographic parameters: LVIDd-left ventricular internal enddiastolic dimension, LVISd-left ventriculax internal endsystolic dimension, RV- right ventricle, LA-left atrium, RA right atrium, LVPW- LV posterior wall diastole, Ao-aorta, and serum lipids: cholesterol, LDL, triglycerides. In multiple logistic regression analysis the only predictor of apelin was LVIDd. Apelin is significantly lowered in dialyzed patients with coronary artery disease and its level is predicted by cardiac function. Apelin might be involved in the pathophysiology of cardiovascular disease in chronic renal failure. Since apelin is an inotrope in normal and failing hearts, this finding may have a clinical implications for future use of apelin as a novel inotropic agent also for patients with "'uremic caxdiomyopathy'"
~
EFFECT OF ALDEHYDES, ARACHIDONIC ACID AND ROSIGLITAZONE ON ADIPOCYTE DIFFERENTIATION
A. Cabre, I. Lazaro, J. Girona, L. Masana. Unitat de Recerea de Lfpids I Arteriosclerosi, h'eis, Hospital UniversitaH Sant Joan, Universitat Rovira I Virgili, Reus, Spabt Objective: Effect of aldehydes, arachidonic acid (AA) and rosiglitazone on morphological changes, lipid droplet accumulation, modulation of adipocyte differentiation markers (PPARg and FABP4) and adipokine expression (adiponectin and RBP4) during adipocyte differentiation (AD). Methods: AD of human preadipocytes was induced in the presence of aldehydes (2,4-decadienal and hexanal), arachidonic acid and rosiglitazone. Lipid accumulation was assessed by Oil Red O staining. Morphological changes of cells, FABP4, PPARg, adiponectin, RBP4, were analyzed by flow citometry and aP2/FABP4 mRNA levels by real time RT-PCR. Results: Aldehydes and rosiglitazone produced an enhancement of lipid droplets accumulation, an increase of size and complexity and positive labelling for PPARg and FABP4 protein. AA produced cell dedifferentiation. Under the same conditions, 2,4-decadienal increased FABP4 mRNA levels more than 4-fold respect to vehicle. During rosiglitazone adipocyte differentiation, adiponectin and RBP4 were expressed following different patterns. While low-fat content adipocytes produced similar amounts of both adipokines, the more mature rich-fat adipocytes showed a relative overexpression of RBP4. Conclusion: The presence of oxidation products may facilitate adipocyte hypertrophy. Mature adipocyte state would lead to an alteration of adipokine secretion pattern prone to insulin resistance.
~
ADIPOBIOLOGY OF ATHEROSCLEROSIS
G.N. Chaldakov I , I.S. Stankulov I , P. Atanassova 2 , M. Fiore 3, P.I. Ghenev I , A.B. Tonchev 1 , L. Aloe 3. 1Medical Universi~, Vama, Bulgaria: "-Medical Universi~, Plovdiv, Bulgaria: ~bzstitute of Neurobiology arm Molecular Medicine, CNR, Rome, Italy Objective: Adipose tissue is not solely a fat storage, but an active endocrine and paxacrine organ secreting a variety of molecules conceptually dubbed adipokines. The present study aimed at evaluating the role of epicardial adipose tissue in the pathogenesis of human coronary atherosderosis. Methods: Samples were obtained from autopsies. Left anterior descending coronary arteries aYfected by atherosclerosis (n=12) and control arteries (n=9) all taken with the surrounding epicardial adipose tissue were processed for routine and immunohistochemical analysis, and by an enzyme-linked immunosorbent assay to separately measure nerve growth factor (NGF) levels in the epicardial adipose tissue and the coronary vascular wall tissue.
Results: NGF level was increased in epicaxdial adipose tissue, whereas significantly decreased in vascular tissue of atherosclerotic coronaries as compared with controls. An increased number of mast cells and increased p75NGF receptor immunostaining were found in both tissues in atherosclerotic samples. Conclusions: We suggest that the up-regulated adipose NGF/NGF receptor expression may be a protective response to injured coronary vascular wall. The epicaxdial adipose tissue surrounding the coronary artery should no longer be stripped, but keep attached and in place, and subject to thorough examination. In effect, adipobiology (Chaldakov et al. Curr Pharm Design 2003; 9: 1023-1031) may offer a novel approach in the study of pathogenesis and therapy of atherosclerosis. Funding: Supported by Medical University, Varna, Bulgaria and by CNR, Rome, Italy.
I Tu-P7:17 I GENETIC VARIABILITY IN BIOTRANSFORMATION A N D ANTIOXIDANT ENZYMES AND THEIR ROLE IN THE PROCESS OF AGING A. Horskfi, C. Mislanovfi, M. Bacekovfi, Z. Hudecovfi, L. Ws61ovfi, M. Dusinskfi. Slovak Medical Universi~, Bratislm,a, Slovak Republic Objective: Aging is a complex process involving systematic depreciation of enzymatic machinery and damage to macromolecules through the action of exogenous and endogenous forces. Development of aging-coupled diseases is influenced by genetic background, notably polymorphisms in genes linked to diseases and genes for defence mechanisms, which can modulate environmental impacts. The aim of study is to investigate the role of selected polymorphisms in aging. Methods: 292 subjects, 151 young and 141 elderly were analysed. Genetic polymorphisms were determined in glutathione S-transferases and superoxide dismutases. DNA damage was measured by the Comet assay and antioxidants were estimated by HPLC. Results: A significant difference was observed in distribution of GSTT1 genotype between young and elderly people (p=0.002). Subjects with deletion in GSTT1 gene had higher levels of g-tocopherol (p=0.002) and decreased levels of DNA strand breaks (p=0.019). Elderly with deleted GSTM1 gene had lower levels of a-tocopherol in plasma. GSTTI* null subjects had lower levels of strand breaks (p= 0.001). Presence of SOD2"16 Ala allele corresponded with decreased retinol (p=0.011). These relations were not found in young. A link between polymorphisms in SOD1 and MDA was found. Young subjects with SOD1 A/A genotype had lower levels of MDA, and MDA depended on BMI (p<0.001). In young with SOD1 A/C, the MDA level depended on g-tocopherol (p=0.011). Conclusions: We supose that healthy aging is paxtialy determined by genetic wxiation in antioxidant and biotransformation genes. Funding: Supported by Slovak STA Agency project No. APVT-21-01320. CHOLESTEROL ABSORPTION IS N O T A ITu-P7:181 INTESTINAL MAJOR DETERMINANT FOR THE AGE-INDUCED I i
INCREASE IN PLASMA CHOLESTEROL IN RATS C. G/ilman, M. Matasconi, P. Parini, B. Angelim M. Rudling. Karolinska Institute, Center for Metabolism, Endocrinology and Diabetology Departnwnt of Medicine, Stoekhohn, Sweden Objective: During aging plasma total and LDL cholesterol increase in both rodents and humans. The balance between dietary input, endogenous synthesis, and cholesterol elimination governs total body cholesterol. A reduced elimination of cholesterol as bile acids (BA) and a decreased receptor-mediated clearance of plasma LDL have been linked to the increase of plasma cholesterol with ageing. This increase may in large part be reversed by treatment with growth hormone (GH). Here, we studied whether the intestinal cholesterol absorption increases with age, and whether any increase could be aYfected by treatment with GH or ezetimibe (EZE). Methods: Male rats, 6 and 18 months, were treated with GH or EZE. Intestinal cholesterol absorption, plasma lipids, BA synthesis, and the gene expression of cholesterol transporters were monitored. Results: Although BA synthesis was reduced and plasma cholesterol was increased in the old animals, intestinal cholesterol absorption could not explain these age-related changes. Accordingly, the mRNA levels of cholesterol transporters, ABCG5, ABCG8 and NPC1L1, were not affected by ageing. Despite improving plasma lipoprotein profile, GH had no effect on cholesterol absorption, while EZE reduced the intestinal cholesterol absorption in both young and old rats. Hepatic LDL-receptors (LDLRs) and scavenger receptor-
XIV bztemational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006