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HMG-CoA reductase inhibitor reduces monocyte adhesion to vascular endothelium under physiological flow conditions
Monday June 26, 2000: Poster Abstracts P: W6 New Aspects of Statin Treatment
42
Conclusion: In individuals without clinical evidence of CVD, BMI was the strongest predictor of circulating oxidized LDL. Treatment of obese patients with atorvastatin decreased levels of circulating oxidized LDL to control values. I
MOP31 :W6 [ No effect of simvastatin treatment on C-reactive protein in patients with familial hypercholesterolemia M.E Mohrschladt l , M.P.M. de Maat 2, R.G.J. Westendorp I , A.H.M. SmeltL
/Leiden University Medical Center, Dept. of General Internal Medicine; 2Gaubius Laboratory, TNO-PG, Leiden, The Netherlands Objective: To evaluate the effect of simvastatin treatment on serum levels of C-reactive protein (CRP) in patients with familial hypercholesterolemia (FH) and to assess the influence of cardiovascular disease (CVD) on CRP concentrations. Methods: We measured baseline CRP levels and lipid profiles in 346 patients with FH (179 females and 167 males), aged 14-81 years (mean age 48 years). CVD was present at baseline in 34% of the patients. We also measured CRP levels and lipid profiles in a second blood sample, collected after one-year treatment with simvastatin (20 mg once daily) in a subgroup of 129 patients. Results: Patients with CVD present at baseline (119 of the 346 patients) had significantly higher baseline CRP levels (2.30 mg/L versus 1.53 mg/L, P < 0.001). Other factors influencing CRP levels were smoking, body mass index, low density cholesterol, and ttiglycerides. In the subgroup of simvastatin treated patients (n = 129) therapy significantly improved lipid profiles. There was a small, but non significant decrease of CRP levels upon therapy. CRP declined from 1.51 mg/L median (IQR 0.76--3.41) at baseline to 1.24 mg/L median (IQR 0.72-2.92) after treatment, (P = 0.33). Conclusions: In patients with FH the presence of CVD is associated with higher CRP concentrations. Simvastatin therapy has no effect on CRP levels in these patients.
MoP32:W6 [ Alleles of high active paraoxonase R/Q192 polymorphisms are associated with HDL-cholesterol increasing effect of pravastatin R. Laaksonen 1.2, R. Malin 3 , T. Janatuinen4 , R. Vesalainen4, J. Knuuti4, T. Lehtimiiki 3. 1Department of Clinical Pharmacology, University of
Helsinki; 2Department of Medicine, University of Tampere; 3Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centrefor Laboratory Medicine, Tampere University Hospital; 4Turku PET Centre, University of Turku, Finland Objectives: To study the effect of human paraoxonase gene (PON) polymorphisms on pravastatin-induced changes in lipids and lipoproteins. Methods: Fifty-one men (aged 35 ± 4 y.) with mild hypereholesterolemia participated in a randomized, placebo-controlled and double-blinded study. They received either placebo or pravastatin (40 mg/day) for six months. PON genotypes, M/L55 and R/QI92, were determined by PCR and restriction enzyme digestion. Subjects were divided into low active groups: QQ (n = 28) or MM, ML (n = 29) and high active groups: LL (n --- 22) or RQ, RR (n = 23). Results: In PON R/QI92 groups pravastatin induced differences between high-and low-active groups in plasma HDL-C (p = 0.079) and in plasma apoA1 (p = 0.018). At baseline HDL-C concentrations were 1.27 ± 0.26 mmol/l and 1.35 ± 0.30 mmol/1 in low and high active groups, respectively. APOAI concentration was at baseline 1.38 g/1 in both groups. At the end of the follow-up mean HDL-C was 1.26 + 0.31 mmol/1 in low-active QQ homozygotes and 1.50 4- 0.13 mmol/l in high-active R-allele carriers (p = 0.038). Corresponding mean apoA1 concentrations were 1.37 4- 0.20 g/1 and 1.57 4- 0.13 g/l (p = 0.012). Similar differences were not seen either in the placebo group or in PON M/L55 genotypes. Serum total cholesterol, LDL-cholesterol and triglyceride concentrations were not affected by PON polymorphisms. Conclusion: This study suggests that PON R/Q192 polymorphisms might influence changes in serum HDL-C and apoAl concentrations during pravastatin treatment.
MOP33:W6 ] HMG-CoA reductase inhibitor reduces rnonocyte adhesion to vascular endothelium under physiological flow conditions M. YoshidaL R.E. Gerszten2, A. Rosenzweig2, M.A. Gimbrone, Jr. 3, Y. Yasukochi I , E Numano 1. 1Tokyo MedDent Univ., Tokyo, Japan; 2Mass.
Gen. Hosp., Charlestown; 3Brigham and Women's Hosp., Boston, USA Objective: To critically assess the direct effect of HMG-CoA-RI upon monocyte-endothelial interaction under physiological flow conditions. Methods: A monocytic cell line U937 was incubated in the presence of cerivastatin for 48 hrs. Adhesive interactions of statin-treated U937 cells were then analyzed using activated (IL-I# 10 U/ml, 4 hrs), human umbilical vein endothelial cells (HUVEC) under laminar flow conditions. Flow cytometric analysis of U937 cells was carried out using mAbs against CDI la, CDI lb, CD18 and VLA-4. F-actin content of U937 after cerivastatin was quantified using FITC-labeled phalloidin. Results: Preincubation of U937 with cerivastatin significantly decreased U937 adhesion to activated HUVEC (40.3 4- 12.9 vs 5.3 ± 1.5 adherent U937 celIs/HPF, P < 0.005). Interestingly, U937 rolling on activated HUVEC was not significantly decreased. FACS analysis of U937 after cerivastatin treatment revealed down regulation of CDI la, CD18, and VLA4. Cerivastatin-induced changes in U937 adhesion was reversed by treatment with 10 IzM mevalonic acid, suggesting that mevalonate pathway is involved in this effect. We also quantitated the F-actin content of U937 after cerivastatin treatment. Cerivastatin significantly reduced F-actin content in U937 (147 + 15.8 vs 26 422.5 RFU, P < 0.005), that was completely reversed when co-incubated with mevalonic acid. Conclusion: We conclude that cerivastatin reduces monocyte adhesion to vascular endothelium under physiological flow condition via down regulation of members of the integrin family of adhesion molecules. The effect of cerivastatin on U937 may involve the inhibition of actin polymerization. Our findings have potentially important implications for lipid-independent effect of HMG-CoA-RI that may be beneficial in patients with atherosclerosis. I
I MoP34:W6 I A new method to evaluate the lipid Ioweringeffect of drugs on lipoprotein metabolism using agarose gel electrophoresis H. Kurata I , K. UtsunomiyaI , T. Kido 2, K. Taniguchi 1, M. Terashima 1 N. K--~mata3 , R. Tobiyama3, T. Nakazato 3, H. Itakura 2, K. Kondo4, ' N. Tajima I . Ijikei Univ. School of Med.; 2National Institute of Health and
Nutrition; 3Helena Laboratory; 40chanomizu Univ., Tokyo, Japan Objective: In this study, we report an easy method to measure plasma lipid levels and evaluate lipid lowering effect of drugs on fipoprotein metabolism in detail using agarose gel electrophoresis (Rapid Electrophoresis System; REP/Helena Laboratories). Methods: Fasting blood was sampled from hyperlipidemic patients at the beginning and 1-6 months after administration of lipid lowering agents. 1 /xl of serum was applied on agarose gel and electrophoreised at 400 V for 15 minutes. After electrophoresis, cholesterol and trigryceride in each lipoprotein fraction were measured after densitometric scanning the intensity of the stained lipoproteins. Results: HMG-CoA reductase inhibitors was significantly decreased LDL-C level, together with increasing HDL-C level, and VLDL-TG level and Ch/TG ratio in VLDL were significantly decreased by additional EPA treatment, in type IIb hyperlipoproteinemic patients VLDL-TG, VLDL-C, LDL-C and LDL-TG levels were significantly decreased by hezafibrate treatment in type IV and V patients. Moreover, the electrophoretic mobilities of their LDL were improved by some HMG-CoA reductase inhibitor and bezafibrate treatment. Conclusions: The analysis using agarose gel electrophoresis brings us to fugher and detailed recognition about lipoprotein metabolism. Effects of fluvastatin on angiotensin II induced superoxide IMoP35:W6 j formation in human aortic smooth muscle cell M. Kugi I , A. Matsunaga l , W. Huang l , H. Hart 1, J. Ono 2, K. Arakawa 1, J. Sasaki I . 1Department of Internal Medicine; 2Department of Laboratory
Medicine, Fukuoka University, Fukuoka, Japan Objective: The effects of fluvastatin on formation of superoxide in human aortic smooth muscle cells by angiotensin II (Ang II) were investigated. Methods: Different concentration of fluvastatin, simvastatin and trolox which is a water-soluble et-tocopherol derivative were added in the culture
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000
42
Conclusion: In individuals without clinical evidence of CVD, BMI was the strongest predictor of circulating oxidized LDL. Treatment of obese patients with atorvastatin decreased levels of circulating oxidized LDL to control values. I
MOP31 :W6 [ No effect of simvastatin treatment on C-reactive protein in patients with familial hypercholesterolemia M.E Mohrschladt l , M.P.M. de Maat 2, R.G.J. Westendorp I , A.H.M. SmeltL
/Leiden University Medical Center, Dept. of General Internal Medicine; 2Gaubius Laboratory, TNO-PG, Leiden, The Netherlands Objective: To evaluate the effect of simvastatin treatment on serum levels of C-reactive protein (CRP) in patients with familial hypercholesterolemia (FH) and to assess the influence of cardiovascular disease (CVD) on CRP concentrations. Methods: We measured baseline CRP levels and lipid profiles in 346 patients with FH (179 females and 167 males), aged 14-81 years (mean age 48 years). CVD was present at baseline in 34% of the patients. We also measured CRP levels and lipid profiles in a second blood sample, collected after one-year treatment with simvastatin (20 mg once daily) in a subgroup of 129 patients. Results: Patients with CVD present at baseline (119 of the 346 patients) had significantly higher baseline CRP levels (2.30 mg/L versus 1.53 mg/L, P < 0.001). Other factors influencing CRP levels were smoking, body mass index, low density cholesterol, and ttiglycerides. In the subgroup of simvastatin treated patients (n = 129) therapy significantly improved lipid profiles. There was a small, but non significant decrease of CRP levels upon therapy. CRP declined from 1.51 mg/L median (IQR 0.76--3.41) at baseline to 1.24 mg/L median (IQR 0.72-2.92) after treatment, (P = 0.33). Conclusions: In patients with FH the presence of CVD is associated with higher CRP concentrations. Simvastatin therapy has no effect on CRP levels in these patients.
MoP32:W6 [ Alleles of high active paraoxonase R/Q192 polymorphisms are associated with HDL-cholesterol increasing effect of pravastatin R. Laaksonen 1.2, R. Malin 3 , T. Janatuinen4 , R. Vesalainen4, J. Knuuti4, T. Lehtimiiki 3. 1Department of Clinical Pharmacology, University of
Helsinki; 2Department of Medicine, University of Tampere; 3Laboratory of Atherosclerosis Genetics, Department of Clinical Chemistry, Centrefor Laboratory Medicine, Tampere University Hospital; 4Turku PET Centre, University of Turku, Finland Objectives: To study the effect of human paraoxonase gene (PON) polymorphisms on pravastatin-induced changes in lipids and lipoproteins. Methods: Fifty-one men (aged 35 ± 4 y.) with mild hypereholesterolemia participated in a randomized, placebo-controlled and double-blinded study. They received either placebo or pravastatin (40 mg/day) for six months. PON genotypes, M/L55 and R/QI92, were determined by PCR and restriction enzyme digestion. Subjects were divided into low active groups: QQ (n = 28) or MM, ML (n = 29) and high active groups: LL (n --- 22) or RQ, RR (n = 23). Results: In PON R/QI92 groups pravastatin induced differences between high-and low-active groups in plasma HDL-C (p = 0.079) and in plasma apoA1 (p = 0.018). At baseline HDL-C concentrations were 1.27 ± 0.26 mmol/l and 1.35 ± 0.30 mmol/1 in low and high active groups, respectively. APOAI concentration was at baseline 1.38 g/1 in both groups. At the end of the follow-up mean HDL-C was 1.26 + 0.31 mmol/1 in low-active QQ homozygotes and 1.50 4- 0.13 mmol/l in high-active R-allele carriers (p = 0.038). Corresponding mean apoA1 concentrations were 1.37 4- 0.20 g/1 and 1.57 4- 0.13 g/l (p = 0.012). Similar differences were not seen either in the placebo group or in PON M/L55 genotypes. Serum total cholesterol, LDL-cholesterol and triglyceride concentrations were not affected by PON polymorphisms. Conclusion: This study suggests that PON R/Q192 polymorphisms might influence changes in serum HDL-C and apoAl concentrations during pravastatin treatment.
MOP33:W6 ] HMG-CoA reductase inhibitor reduces rnonocyte adhesion to vascular endothelium under physiological flow conditions M. YoshidaL R.E. Gerszten2, A. Rosenzweig2, M.A. Gimbrone, Jr. 3, Y. Yasukochi I , E Numano 1. 1Tokyo MedDent Univ., Tokyo, Japan; 2Mass.
Gen. Hosp., Charlestown; 3Brigham and Women's Hosp., Boston, USA Objective: To critically assess the direct effect of HMG-CoA-RI upon monocyte-endothelial interaction under physiological flow conditions. Methods: A monocytic cell line U937 was incubated in the presence of cerivastatin for 48 hrs. Adhesive interactions of statin-treated U937 cells were then analyzed using activated (IL-I# 10 U/ml, 4 hrs), human umbilical vein endothelial cells (HUVEC) under laminar flow conditions. Flow cytometric analysis of U937 cells was carried out using mAbs against CDI la, CDI lb, CD18 and VLA-4. F-actin content of U937 after cerivastatin was quantified using FITC-labeled phalloidin. Results: Preincubation of U937 with cerivastatin significantly decreased U937 adhesion to activated HUVEC (40.3 4- 12.9 vs 5.3 ± 1.5 adherent U937 celIs/HPF, P < 0.005). Interestingly, U937 rolling on activated HUVEC was not significantly decreased. FACS analysis of U937 after cerivastatin treatment revealed down regulation of CDI la, CD18, and VLA4. Cerivastatin-induced changes in U937 adhesion was reversed by treatment with 10 IzM mevalonic acid, suggesting that mevalonate pathway is involved in this effect. We also quantitated the F-actin content of U937 after cerivastatin treatment. Cerivastatin significantly reduced F-actin content in U937 (147 + 15.8 vs 26 422.5 RFU, P < 0.005), that was completely reversed when co-incubated with mevalonic acid. Conclusion: We conclude that cerivastatin reduces monocyte adhesion to vascular endothelium under physiological flow condition via down regulation of members of the integrin family of adhesion molecules. The effect of cerivastatin on U937 may involve the inhibition of actin polymerization. Our findings have potentially important implications for lipid-independent effect of HMG-CoA-RI that may be beneficial in patients with atherosclerosis. I
I MoP34:W6 I A new method to evaluate the lipid Ioweringeffect of drugs on lipoprotein metabolism using agarose gel electrophoresis H. Kurata I , K. UtsunomiyaI , T. Kido 2, K. Taniguchi 1, M. Terashima 1 N. K--~mata3 , R. Tobiyama3, T. Nakazato 3, H. Itakura 2, K. Kondo4, ' N. Tajima I . Ijikei Univ. School of Med.; 2National Institute of Health and
Nutrition; 3Helena Laboratory; 40chanomizu Univ., Tokyo, Japan Objective: In this study, we report an easy method to measure plasma lipid levels and evaluate lipid lowering effect of drugs on fipoprotein metabolism in detail using agarose gel electrophoresis (Rapid Electrophoresis System; REP/Helena Laboratories). Methods: Fasting blood was sampled from hyperlipidemic patients at the beginning and 1-6 months after administration of lipid lowering agents. 1 /xl of serum was applied on agarose gel and electrophoreised at 400 V for 15 minutes. After electrophoresis, cholesterol and trigryceride in each lipoprotein fraction were measured after densitometric scanning the intensity of the stained lipoproteins. Results: HMG-CoA reductase inhibitors was significantly decreased LDL-C level, together with increasing HDL-C level, and VLDL-TG level and Ch/TG ratio in VLDL were significantly decreased by additional EPA treatment, in type IIb hyperlipoproteinemic patients VLDL-TG, VLDL-C, LDL-C and LDL-TG levels were significantly decreased by hezafibrate treatment in type IV and V patients. Moreover, the electrophoretic mobilities of their LDL were improved by some HMG-CoA reductase inhibitor and bezafibrate treatment. Conclusions: The analysis using agarose gel electrophoresis brings us to fugher and detailed recognition about lipoprotein metabolism. Effects of fluvastatin on angiotensin II induced superoxide IMoP35:W6 j formation in human aortic smooth muscle cell M. Kugi I , A. Matsunaga l , W. Huang l , H. Hart 1, J. Ono 2, K. Arakawa 1, J. Sasaki I . 1Department of Internal Medicine; 2Department of Laboratory
Medicine, Fukuoka University, Fukuoka, Japan Objective: The effects of fluvastatin on formation of superoxide in human aortic smooth muscle cells by angiotensin II (Ang II) were investigated. Methods: Different concentration of fluvastatin, simvastatin and trolox which is a water-soluble et-tocopherol derivative were added in the culture
Xllth International Symposium on Atherosclerosis, Stockholm, Sweden, June 25-29, 2000