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Has Lp(a) any physiological function?
Kostner
Design and Methods: 89 patients (53 men and 46 women, 57±12 years) with CAD were enrolled. Coronary angiography was performed. Measurements of inflammatory cytokines tumor necrosis factor alpha (TNF-c0 and interleukin-l[3 (IL-I[3) and endothelial factors endothelin-1 and 6-ketoPGFla were carried by specific radioimmunoassay and ELISA. Results: The concentration of IL-l[3 and TNF-c~ did not differ significantly between patients with coronary atherosclerosis and controls. In contrast, IL-I[3 and TNF-c~ levels were higher in moderate EH patients than those in control group on 50,4% (p<0,05) and 67,4% (p<0,01) respectively. It has been found the positive correlation between endothelin-1 level and IL-I[3 (r-+0,34, p <0,05), and also negative correlation between TNF-c~ and 6-ketoPGFla (r--0,52, p<0,01). Conclusions: Endothelial dysfunction in patients with CAD with proven coronary atherosclerosis is associated with abnormalities in proinflammatory cytokines profile. These data support the hypothesis that the development of endothelial dysfunction in coronary atherosclerosis is mediated through an underlying inflammatory response. The importance of these changes for the pathogenesis of atherosclerosis and its secondary complications remains to be elucidated. ~35-~ RELATIONSHIP BETWEEN ENDOTHELIAL NITRIC OXIDE SYNTHESIS AND LOW-GRADE CHRONIC INFLAMMATION O.M. Korzh. Ukrainian National Academy of Pharmacy, Kharkou, Ukraine Dysfunction of endothelial vasoreactivity contributes to reduced myocardial blood supply and, therefore, might promote myocardial ischemia. To control vasomotor tone, the endothelium releases a variety of substances such as prostacyclin, hyperpolarizing factor, endothelin and, most importantly, nitric oxide (NO). Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in 47 healthy subjects (mean age 57±7,4 years; body mass index 28±2.1 kg/m2; mean arterial blood pressure 107±8,5 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of N(G)-monomethyl-L-arginine (L-NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a nonspecific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with the percentage decrease in forearm blood flow (FBF) during L-NMMA infusion (r-0,68, P<0,01); and the serum leptin concentration (r-0.65, P<0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to L-NMMA remained significant when age and leptin (t-2,41, P
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purpose; it has been the most popular beverage in Japan and large parts of East Asia where obesity is still rare in comparison to the West. This review lecture will in addition summarise other treatment regimes of TCM, which proved to be very effective in the therapy of obesity. [~-1] HAS Lp(a) ANY PHYSIOLOGICAL FUNCTION? G.M. Kostner. Institute of Medical Biochemistry and Molecular Biology,
University of Graz, Austria Lp(a) is a chimerical lipoprotein consisting of an LDL core and the glycoprotein, apo(a), both of which are covalently linked by a disulfide bridge. The high atherogenicity of Lp(a) not only relates to its large content of cholesteryl esters and the deposition in atherosclerotic plaques, but also to the competitive inhibition of plasminogen action. So far a physiological function of Lp(a) has not been defined. Apo(a) is biosynthesized predominantly in the liver and secreted as a glycoprotein. The assembly with LDL occurs at the cell surface - or even in circulation. There is a small percentage of free apo(a) circulating in blood - yet it is not clear whether this fraction consists of intact apo(a) or of fragments thereof. Although the liver plays the main role in Lp(a) catabolism, the uptake into liver cells appears to be independent of LDL-receptors. Apo(a) is hydrolyzed by tissue metalloproteinases into fragments containing 3 and more K-IV repeats. Part of them is secreted into urine yet peripheral tissues, notably skeleton muscle, take up the majority. The physiological implication of that pathway remains to be elucidated. Among the many specific pathways where Lp(a) interferes with hemostasis and fibrinolysis we have recently published that apo(a) and Lp(a) binds and inactivates tissue factor pathway inhibitor (TFPI) and induces PAI-2 expression in monocytes. We have also shown that apo(a) and small fragments consisting of K-IV Type 1 and 2 interfere with angiogenesis in vitro and possibly also in vivo. Whether or not this may have any physiological implication for tumor growth and invasion remains elusive. [f6--~ A NOVEL EXTRACORPOREAL PLASMA DELIPIDATION PROCEDURE F O R THE TREATMENT OF ATHEROSCLEROSIS K.M. Kostner1, J.L. Smith2, B.E. Chain 3. JLipidsciences, Greenslopes Private Hospital," 2 University of Queensland," 3Curacel Institute of Medical Research, Queensland, Australia Atherosclerotic cardiovascular disease is the worldwide leading cause of death. Currently available treatments are aimed at reducing elevated plasma lipid concentrations, most particularly LDL- cholesterol. These therapies include dietary restrictions, drugs (mainly statins) and LDL-Apheresis. Unfortunately cardiovascular events continue to occur despite LDL-lowering therapy. This is probably due to the fact that there is other important risk factors in certain patients than LDL-cholesterol. Therefore there is a clear need for additional preventive and therapeutic interventions to complement the results of LDL lowering. One such target for new interventions is HDL and/or its apolipoproteins. We recently developed a Plasma Delipidation Process (PDP), a novel extracorporeal solvent extraction procedure that removes essentially all cholesterol and triglyceride from treated plasma while not affecting important blood constituents including apolipoproteins. PDP is a novel procedure for the potential removal of cholesterol deposited in arterial atherosclerotic lesions. This procedure involves three major steps including: a) partial delipididation of plasma lipoproteins (formation of phospholipidprotein complexes) by a mixture of organic solvents; b) reintroduction of partially delipidated lipoproteins into the plasma compartment of autologous recipients; and c) recombination of partially delipidated lipoproteins with plasma neutral lipids and cholesterol mobilized from various tissues including arteries and arterial atherosclerotic lesions. The delipidated plasma, free of solvent, containing the apolipoproteins is returned/reinfused back to the same subject. PDP has been shown to be safe in several animal models including roosters, pigs, calves and dogs. We could also show regression of induced atherosclerosis in several animal models. A phase I clinical trial is on the way to show that PDP is safe in humans.
73rd EAS Congress
Design and Methods: 89 patients (53 men and 46 women, 57±12 years) with CAD were enrolled. Coronary angiography was performed. Measurements of inflammatory cytokines tumor necrosis factor alpha (TNF-c0 and interleukin-l[3 (IL-I[3) and endothelial factors endothelin-1 and 6-ketoPGFla were carried by specific radioimmunoassay and ELISA. Results: The concentration of IL-l[3 and TNF-c~ did not differ significantly between patients with coronary atherosclerosis and controls. In contrast, IL-I[3 and TNF-c~ levels were higher in moderate EH patients than those in control group on 50,4% (p<0,05) and 67,4% (p<0,01) respectively. It has been found the positive correlation between endothelin-1 level and IL-I[3 (r-+0,34, p <0,05), and also negative correlation between TNF-c~ and 6-ketoPGFla (r--0,52, p<0,01). Conclusions: Endothelial dysfunction in patients with CAD with proven coronary atherosclerosis is associated with abnormalities in proinflammatory cytokines profile. These data support the hypothesis that the development of endothelial dysfunction in coronary atherosclerosis is mediated through an underlying inflammatory response. The importance of these changes for the pathogenesis of atherosclerosis and its secondary complications remains to be elucidated. ~35-~ RELATIONSHIP BETWEEN ENDOTHELIAL NITRIC OXIDE SYNTHESIS AND LOW-GRADE CHRONIC INFLAMMATION O.M. Korzh. Ukrainian National Academy of Pharmacy, Kharkou, Ukraine Dysfunction of endothelial vasoreactivity contributes to reduced myocardial blood supply and, therefore, might promote myocardial ischemia. To control vasomotor tone, the endothelium releases a variety of substances such as prostacyclin, hyperpolarizing factor, endothelin and, most importantly, nitric oxide (NO). Low-grade chronic inflammation, characterized by elevated plasma concentrations of C-reactive protein (CRP), is associated with an increased risk of atherosclerotic cardiovascular disease. Therefore, in the present study, we measured CRP concentration (and leptin concentration as an index of fat mass) in 47 healthy subjects (mean age 57±7,4 years; body mass index 28±2.1 kg/m2; mean arterial blood pressure 107±8,5 mmHg) undergoing measurement of basal endothelial nitric oxide (NO) synthesis using intra-brachial infusions of N(G)-monomethyl-L-arginine (L-NMMA; a substrate inhibitor of endothelial NO synthase) and noradrenaline (a nonspecific control vasoconstrictor). In univariate analysis, CRP concentration was correlated with the percentage decrease in forearm blood flow (FBF) during L-NMMA infusion (r-0,68, P<0,01); and the serum leptin concentration (r-0.65, P<0.05). In multivariate analysis, the relationship between CRP concentration and the FBF response to L-NMMA remained significant when age and leptin (t-2,41, P
143
purpose; it has been the most popular beverage in Japan and large parts of East Asia where obesity is still rare in comparison to the West. This review lecture will in addition summarise other treatment regimes of TCM, which proved to be very effective in the therapy of obesity. [~-1] HAS Lp(a) ANY PHYSIOLOGICAL FUNCTION? G.M. Kostner. Institute of Medical Biochemistry and Molecular Biology,
University of Graz, Austria Lp(a) is a chimerical lipoprotein consisting of an LDL core and the glycoprotein, apo(a), both of which are covalently linked by a disulfide bridge. The high atherogenicity of Lp(a) not only relates to its large content of cholesteryl esters and the deposition in atherosclerotic plaques, but also to the competitive inhibition of plasminogen action. So far a physiological function of Lp(a) has not been defined. Apo(a) is biosynthesized predominantly in the liver and secreted as a glycoprotein. The assembly with LDL occurs at the cell surface - or even in circulation. There is a small percentage of free apo(a) circulating in blood - yet it is not clear whether this fraction consists of intact apo(a) or of fragments thereof. Although the liver plays the main role in Lp(a) catabolism, the uptake into liver cells appears to be independent of LDL-receptors. Apo(a) is hydrolyzed by tissue metalloproteinases into fragments containing 3 and more K-IV repeats. Part of them is secreted into urine yet peripheral tissues, notably skeleton muscle, take up the majority. The physiological implication of that pathway remains to be elucidated. Among the many specific pathways where Lp(a) interferes with hemostasis and fibrinolysis we have recently published that apo(a) and Lp(a) binds and inactivates tissue factor pathway inhibitor (TFPI) and induces PAI-2 expression in monocytes. We have also shown that apo(a) and small fragments consisting of K-IV Type 1 and 2 interfere with angiogenesis in vitro and possibly also in vivo. Whether or not this may have any physiological implication for tumor growth and invasion remains elusive. [f6--~ A NOVEL EXTRACORPOREAL PLASMA DELIPIDATION PROCEDURE F O R THE TREATMENT OF ATHEROSCLEROSIS K.M. Kostner1, J.L. Smith2, B.E. Chain 3. JLipidsciences, Greenslopes Private Hospital," 2 University of Queensland," 3Curacel Institute of Medical Research, Queensland, Australia Atherosclerotic cardiovascular disease is the worldwide leading cause of death. Currently available treatments are aimed at reducing elevated plasma lipid concentrations, most particularly LDL- cholesterol. These therapies include dietary restrictions, drugs (mainly statins) and LDL-Apheresis. Unfortunately cardiovascular events continue to occur despite LDL-lowering therapy. This is probably due to the fact that there is other important risk factors in certain patients than LDL-cholesterol. Therefore there is a clear need for additional preventive and therapeutic interventions to complement the results of LDL lowering. One such target for new interventions is HDL and/or its apolipoproteins. We recently developed a Plasma Delipidation Process (PDP), a novel extracorporeal solvent extraction procedure that removes essentially all cholesterol and triglyceride from treated plasma while not affecting important blood constituents including apolipoproteins. PDP is a novel procedure for the potential removal of cholesterol deposited in arterial atherosclerotic lesions. This procedure involves three major steps including: a) partial delipididation of plasma lipoproteins (formation of phospholipidprotein complexes) by a mixture of organic solvents; b) reintroduction of partially delipidated lipoproteins into the plasma compartment of autologous recipients; and c) recombination of partially delipidated lipoproteins with plasma neutral lipids and cholesterol mobilized from various tissues including arteries and arterial atherosclerotic lesions. The delipidated plasma, free of solvent, containing the apolipoproteins is returned/reinfused back to the same subject. PDP has been shown to be safe in several animal models including roosters, pigs, calves and dogs. We could also show regression of induced atherosclerosis in several animal models. A phase I clinical trial is on the way to show that PDP is safe in humans.
73rd EAS Congress