- Email: [email protected]
Heterozygosity for ABCAI gene mutations; effects on lipid metabolism
146
Kuboyama
in some metabolic disturbances like insulin resistance and hyperlipidemia has been postulated by some authors. The aim of the study was to evaluate serum concentrations of TNF-c~ and its soluble receptors in the group of postmenopausal women with known risks for atherosclerosis development. Material and Methods: In 103 postmenopausal women groups with hypercholesterolemia, hypertriglycerydemia, hyperlipoproteinemia (a), hyperapolipoproteinemia B, BMI over 25 kg/m2 and obesity, arterial hypertension, glucose intolerance, age > 60 y. and low insulin sensitivity index (IS) were selected. In all women serum TNF-c~, sTNF-RI and sTNF-RII were estimated by IRMA and EASIA kits. PM women with atheromatosis risk factors failed to show the relation between TNF-c~ and fT4 that has been found in women without the risk factors. In the risk groups with a low serum HDL-C the serum concentrations for both soluble receptors appeared to be higher than in women with normal HDL-C serum level. Obesity, low SI index, and high serum Lp(a) have been found to increase serum concentrations of both soluble receptors. Interestingly, women with the higher serum LDL-C did not revealed the higher serum sTNF-RII level. The same was observed for the high LDL/HDL-C relations. The close relation between serum triglycerides and serum TNF-c~ has been confirmed. The lowest serum sTNF-RI in PM women was documented in normal weight and normal HDL-C level. Serum concentration of both soluble receptors strongly refers to: body mass index, serum leptin level, peptyde C and SHBG concentration, fasting insulin level and arterial systolic blood pressure. Moreover serum sTNF-RII level inversely correlates with total cholesterol, IS index and directly with area under the curve of insulin and glucose during OGTT. The partially diverse relations of both soluble receptors to the atheromatosis risk parameters were observed. Conclusion: Serum TNF-c~ and its soluble receptors to some extent may reflect an atheromatic risk in postmenopausal women especially in obese, with poor glucose tolerance, arterial hypertension and in advanced age patients. Thus, the serum TNF-c~, sTNF-RI and sTNF-RII do not indicate all endangered women. ~ - 3 ] THE CHANGE OF COMPOSITION AS WELL AS THE CONCENTRATION OF SERUM Lp(a) CAN BE A SIGN F O R END-STAGE RENAL FAILURE M. Kubo,/ama, M. Ageta, K. Nishihira, Y. Arimura, T. Shigenaga, T. Ishihara, J.-I. Ashitani, Y. Fujiura, N. Kashio, I. Ikushima. Nichinan
Hospital, Miyazaki, Japan High concentration of serum lipoprotein(a) [Lp(a)] is one of risk factors for cardiac events, and is frequently observed in the patients with renal failure. And so, atherogenesis in the patients with renal failure seems to have a relation to Lp(a) metabolism. The aim of this study is to investigate the relation between serum Lp(a) and renal function in Japanese. The 558 patients in our hospital having hypertension, hyperlipidemia, diabetes mellitus and/or chronic renal failure were selected in this study. All patients were divided into three groups by the level of serum creatinine; the control group had lower than 1.2mg/dl, the group 1 had 1.2mg/dl< Cr <5.0mg/dl and the group 2 had higher than 5.0 mg/dl. Serum Lp(a) concentration in the control was 24.2±l.lmg/dl, and that of the group 1 and 2 was 34.4±3.3 and 41.6±3.8mg/dl, respectively. Usually, a low molecular weight (LMW) isoform of apoprotein(a) is observed in the patients with high Lp(a) level. In this study, high concentration of serum Lp(a) with HMW was observed in the group 2. The conflicting results is probably due to the changes of Lp(a) composition. And the LDL particle in these patients with renal faulure became a triglyceride-rich LDL. Furthermore, Lp(a) concentration in the end stage of renal failure was not related to serum LDL and/or apo-B level. Patients with renal failre had high level of serum Lp(a) and the composition was something different from the control. ~]
HETEROZYGOSITY F O R ABCAI GENE MUTATIONS; EFFECTS ON LIPID METABOLISM
J.A. Kuivenhoven, G.K. Hovingh, A. Van Tol, A.H. Smelt, J.C. Fruchart, E. Brinton, J.D. Otvos, A.H. Zwinderman, M.R. Hayden, J.J.R Kastelein The effects of reduced ABCAI function on lipid metabolism were studied in 27 heterozygous carriers of ABCAI gene defects from 4 unrelated families and their age- and sex-matched family controls. Twenty-three subjects were carriers of missense mutations resulting in amino acid substitutions while four subjects were heterozygous for a mutation resulting in a splicing defect. Comparing heterozygotes with controls, no differences were identified for total cholesterol, triglyceride and LDL-c concentrations. However, HDL-c was reduced by 40% (1.4(0.41) mmol/1 vs. 0.92(0.2) mmol/1; p<0.001) reflected
by 25% (p<0.001), 28% (p<0.001), 24% (p-0.014), and 34% (p<0.001) reductions in apoAI, LpAI, LpAI:AII, and LpCIII:nonB, respectively. Heterozygotes furthermore presented with reduced ItDL size (p-0.004; by NMR) unchanged apoAII, apoAIV, apoE and apoB but reduced apoCIII (p-0.006). Compared to controls, LCAT activity was reduced in carriers (p<0.001) while LCAT concentrations were unchanged. CETP activities appeared higher in ABCAI heterozygotes (+17%; p-0.005), however, exclusion of one family (n-8) abrogated this effect (p-0.1). ABCAI defects appeared to affect lipoprotein metabolism more in women (n-13; nine 50 yrs or older) than in men (n-14). This is illustrated by larger differences between female carriers and non-carriers than in males, and by the absence of statistically significant effects on HDL size, and LpAI:AII and ApoAI concentrations in male carriers. Moreover, female carriers had larger numbers of LDL particles (p-0.043). In conclusion, heterozygosity for ABCAI defects in 4 families mainly affects HDL metabolism whereby the effects in females are more pronounced. Reduced HDL size and 40% reductions in HDL-c imply an increased risk for atherosclerosis.
~-~
EFFECT OF BLOOD LIPOPROTEINS ON CONTRACTILE FUNCTION OF VESSELS IN RATS
O.K. Kulchitsky, S.N. Novikova, N.V. Sikalo. Institute of Gerontology,
Kiev, Ukraine The tempo and character of atherosclerosis development are determined by both age-related changes in blood content, composition and ratio of lipoproteins (LP), i.e. dyslipoproteinemias, and changes in the vascular tone regulation. The purpose of our work was to analyze the LP effects on contractile function of vessels and to show the possible relationship between these effects and age-related changes of LP composition. Lipoproteins of varying density were isolated from blood plasma by preparative ultracentrifugation. The apolipoprotein composition of LP was estimated electrophoretically in polyacrylamide gel. Contractile force of aortic strips was recorded isometrically using a transducer GCM-IB. Experiments on adult and old rats have shown that blood LP exert a dilatatory effect on isolated segments of the thoracic aorta in animals of different age. In old versus adult animals, the sensitivity of vessels in all LP fractions (LDL,VLDL, HI)L) was lower as a result of age changes in the reactivity of vessels. The capacity of HDL to produce a vasodilatatory effect decreases with age, which may be linked to changes in the lipid and apolipoprotein composition. The results revealed a decrease in the level of phospholipids and an increase in the amount of total cholesterol in HDL observed in old age. The capacities of LDL and VLDL to exert a vascular dilatatory action remained unchaged with age.
~ - - ~ INCREASED P-SELECTIN IN SMOKERS W I T H C H D W.C. Kullich 1, G. Klein 1.2. JLudwig Boltzmann Institute for Rehabilitation
of Internal Diseases," 2Special Hospital~Rehabilitation Centre for Cardiovascular and Rheumatic Diseases, Saalfelden, Austria In the detailed pathogenesis of atherosclerosis in connection to cigarette smoking, significant progress is being made in leading to a better understanding of the relationship between endothelial functions and risk factors. P-selectin (also known as granule membrane glycoprotein-140, GMP-140; PADGEM, CD62, CD62P), expressed on activated endothelial cells and platelets, mediates adhesion of platelets and leucocytes. Our objective was to study whether smoking in patients with coronary heart disease (CHD) influences initial vascular adhesion mechanisms, which are of importance for the development of atherosclerosis, by measuring P-selectin levels. We investigated the P-selectin GMP-140 in 38 patients (24 smoker and 14 nonsmoker) with CHD and a high vascular risk profile (fibrinogen > 300 mg/dl, serum cholesterol > 250 mg/dl) in the mean age of 57±11 years. The P-selectin GMP-140 was measured in plasma samples with a solid phase enzyme immunoassay (Takara Shuzo Co Ltd, Japan). It was interesting that the plasma P-selectin levels in smokers with CHD were significantly higher (134±33 ng/ml) compared to non-smokers with CItD (89±31 ng/ml). Additionally, three times more smokers than non-smokers were found to have increased levels of the known hemostatic risk factor plasminogen activator inhibitor-1. Our results strongly suggest that P-selectins may play an active role in cigarette smoking induced initial mechanisms of endothelial atherosclerosis. P-selectin may act synergistically with other cardiovascular risk factors and may explain the higher risk of atherosclerotic vascular changes.
73rd EAS Congress
Kuboyama
in some metabolic disturbances like insulin resistance and hyperlipidemia has been postulated by some authors. The aim of the study was to evaluate serum concentrations of TNF-c~ and its soluble receptors in the group of postmenopausal women with known risks for atherosclerosis development. Material and Methods: In 103 postmenopausal women groups with hypercholesterolemia, hypertriglycerydemia, hyperlipoproteinemia (a), hyperapolipoproteinemia B, BMI over 25 kg/m2 and obesity, arterial hypertension, glucose intolerance, age > 60 y. and low insulin sensitivity index (IS) were selected. In all women serum TNF-c~, sTNF-RI and sTNF-RII were estimated by IRMA and EASIA kits. PM women with atheromatosis risk factors failed to show the relation between TNF-c~ and fT4 that has been found in women without the risk factors. In the risk groups with a low serum HDL-C the serum concentrations for both soluble receptors appeared to be higher than in women with normal HDL-C serum level. Obesity, low SI index, and high serum Lp(a) have been found to increase serum concentrations of both soluble receptors. Interestingly, women with the higher serum LDL-C did not revealed the higher serum sTNF-RII level. The same was observed for the high LDL/HDL-C relations. The close relation between serum triglycerides and serum TNF-c~ has been confirmed. The lowest serum sTNF-RI in PM women was documented in normal weight and normal HDL-C level. Serum concentration of both soluble receptors strongly refers to: body mass index, serum leptin level, peptyde C and SHBG concentration, fasting insulin level and arterial systolic blood pressure. Moreover serum sTNF-RII level inversely correlates with total cholesterol, IS index and directly with area under the curve of insulin and glucose during OGTT. The partially diverse relations of both soluble receptors to the atheromatosis risk parameters were observed. Conclusion: Serum TNF-c~ and its soluble receptors to some extent may reflect an atheromatic risk in postmenopausal women especially in obese, with poor glucose tolerance, arterial hypertension and in advanced age patients. Thus, the serum TNF-c~, sTNF-RI and sTNF-RII do not indicate all endangered women. ~ - 3 ] THE CHANGE OF COMPOSITION AS WELL AS THE CONCENTRATION OF SERUM Lp(a) CAN BE A SIGN F O R END-STAGE RENAL FAILURE M. Kubo,/ama, M. Ageta, K. Nishihira, Y. Arimura, T. Shigenaga, T. Ishihara, J.-I. Ashitani, Y. Fujiura, N. Kashio, I. Ikushima. Nichinan
Hospital, Miyazaki, Japan High concentration of serum lipoprotein(a) [Lp(a)] is one of risk factors for cardiac events, and is frequently observed in the patients with renal failure. And so, atherogenesis in the patients with renal failure seems to have a relation to Lp(a) metabolism. The aim of this study is to investigate the relation between serum Lp(a) and renal function in Japanese. The 558 patients in our hospital having hypertension, hyperlipidemia, diabetes mellitus and/or chronic renal failure were selected in this study. All patients were divided into three groups by the level of serum creatinine; the control group had lower than 1.2mg/dl, the group 1 had 1.2mg/dl< Cr <5.0mg/dl and the group 2 had higher than 5.0 mg/dl. Serum Lp(a) concentration in the control was 24.2±l.lmg/dl, and that of the group 1 and 2 was 34.4±3.3 and 41.6±3.8mg/dl, respectively. Usually, a low molecular weight (LMW) isoform of apoprotein(a) is observed in the patients with high Lp(a) level. In this study, high concentration of serum Lp(a) with HMW was observed in the group 2. The conflicting results is probably due to the changes of Lp(a) composition. And the LDL particle in these patients with renal faulure became a triglyceride-rich LDL. Furthermore, Lp(a) concentration in the end stage of renal failure was not related to serum LDL and/or apo-B level. Patients with renal failre had high level of serum Lp(a) and the composition was something different from the control. ~]
HETEROZYGOSITY F O R ABCAI GENE MUTATIONS; EFFECTS ON LIPID METABOLISM
J.A. Kuivenhoven, G.K. Hovingh, A. Van Tol, A.H. Smelt, J.C. Fruchart, E. Brinton, J.D. Otvos, A.H. Zwinderman, M.R. Hayden, J.J.R Kastelein The effects of reduced ABCAI function on lipid metabolism were studied in 27 heterozygous carriers of ABCAI gene defects from 4 unrelated families and their age- and sex-matched family controls. Twenty-three subjects were carriers of missense mutations resulting in amino acid substitutions while four subjects were heterozygous for a mutation resulting in a splicing defect. Comparing heterozygotes with controls, no differences were identified for total cholesterol, triglyceride and LDL-c concentrations. However, HDL-c was reduced by 40% (1.4(0.41) mmol/1 vs. 0.92(0.2) mmol/1; p<0.001) reflected
by 25% (p<0.001), 28% (p<0.001), 24% (p-0.014), and 34% (p<0.001) reductions in apoAI, LpAI, LpAI:AII, and LpCIII:nonB, respectively. Heterozygotes furthermore presented with reduced ItDL size (p-0.004; by NMR) unchanged apoAII, apoAIV, apoE and apoB but reduced apoCIII (p-0.006). Compared to controls, LCAT activity was reduced in carriers (p<0.001) while LCAT concentrations were unchanged. CETP activities appeared higher in ABCAI heterozygotes (+17%; p-0.005), however, exclusion of one family (n-8) abrogated this effect (p-0.1). ABCAI defects appeared to affect lipoprotein metabolism more in women (n-13; nine 50 yrs or older) than in men (n-14). This is illustrated by larger differences between female carriers and non-carriers than in males, and by the absence of statistically significant effects on HDL size, and LpAI:AII and ApoAI concentrations in male carriers. Moreover, female carriers had larger numbers of LDL particles (p-0.043). In conclusion, heterozygosity for ABCAI defects in 4 families mainly affects HDL metabolism whereby the effects in females are more pronounced. Reduced HDL size and 40% reductions in HDL-c imply an increased risk for atherosclerosis.
~-~
EFFECT OF BLOOD LIPOPROTEINS ON CONTRACTILE FUNCTION OF VESSELS IN RATS
O.K. Kulchitsky, S.N. Novikova, N.V. Sikalo. Institute of Gerontology,
Kiev, Ukraine The tempo and character of atherosclerosis development are determined by both age-related changes in blood content, composition and ratio of lipoproteins (LP), i.e. dyslipoproteinemias, and changes in the vascular tone regulation. The purpose of our work was to analyze the LP effects on contractile function of vessels and to show the possible relationship between these effects and age-related changes of LP composition. Lipoproteins of varying density were isolated from blood plasma by preparative ultracentrifugation. The apolipoprotein composition of LP was estimated electrophoretically in polyacrylamide gel. Contractile force of aortic strips was recorded isometrically using a transducer GCM-IB. Experiments on adult and old rats have shown that blood LP exert a dilatatory effect on isolated segments of the thoracic aorta in animals of different age. In old versus adult animals, the sensitivity of vessels in all LP fractions (LDL,VLDL, HI)L) was lower as a result of age changes in the reactivity of vessels. The capacity of HDL to produce a vasodilatatory effect decreases with age, which may be linked to changes in the lipid and apolipoprotein composition. The results revealed a decrease in the level of phospholipids and an increase in the amount of total cholesterol in HDL observed in old age. The capacities of LDL and VLDL to exert a vascular dilatatory action remained unchaged with age.
~ - - ~ INCREASED P-SELECTIN IN SMOKERS W I T H C H D W.C. Kullich 1, G. Klein 1.2. JLudwig Boltzmann Institute for Rehabilitation
of Internal Diseases," 2Special Hospital~Rehabilitation Centre for Cardiovascular and Rheumatic Diseases, Saalfelden, Austria In the detailed pathogenesis of atherosclerosis in connection to cigarette smoking, significant progress is being made in leading to a better understanding of the relationship between endothelial functions and risk factors. P-selectin (also known as granule membrane glycoprotein-140, GMP-140; PADGEM, CD62, CD62P), expressed on activated endothelial cells and platelets, mediates adhesion of platelets and leucocytes. Our objective was to study whether smoking in patients with coronary heart disease (CHD) influences initial vascular adhesion mechanisms, which are of importance for the development of atherosclerosis, by measuring P-selectin levels. We investigated the P-selectin GMP-140 in 38 patients (24 smoker and 14 nonsmoker) with CHD and a high vascular risk profile (fibrinogen > 300 mg/dl, serum cholesterol > 250 mg/dl) in the mean age of 57±11 years. The P-selectin GMP-140 was measured in plasma samples with a solid phase enzyme immunoassay (Takara Shuzo Co Ltd, Japan). It was interesting that the plasma P-selectin levels in smokers with CHD were significantly higher (134±33 ng/ml) compared to non-smokers with CItD (89±31 ng/ml). Additionally, three times more smokers than non-smokers were found to have increased levels of the known hemostatic risk factor plasminogen activator inhibitor-1. Our results strongly suggest that P-selectins may play an active role in cigarette smoking induced initial mechanisms of endothelial atherosclerosis. P-selectin may act synergistically with other cardiovascular risk factors and may explain the higher risk of atherosclerotic vascular changes.
73rd EAS Congress