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The lipid lowering effect of yogurt in patients with high total cholesterol level
88
Chanu
sis. Age, hypertension, diabetes, smoking, and hypercholesterolemia were proved to be risk factors of clinically significant coronary artery disease. However, there were only few issues concerning risk factors of insignificant coronary artery atherosclerosis. Methods: 30 patients (16 males) with both negative stress test and angiographically insignificant coronary artery atherosclerosis (luminal stenosis <50%) were enrolled. Average age was 51.7±9.9 years. Risk factors including hypertension, diabetes, hypercholesterolemia, and smoking were checked. Coronary artery atherosclerosis was evaluated using severity and diffuseness score. Association of these probable risk factors and coronary artery atherosclerosis was analyzed. Results: Concerning severity score, the intra-observer correlation was 0.98. Age (Spearman' s rank correlation coefficient-0.657, l~0.001) and hypercholesterolemia (without vs. with, 14.7±4.6 vs. 31.3±5.4, p-0.028) were two significant risk factors With regard to diffuseness score, the intraobserver correlation was 0.982. Age (Spearman' s rank correlation coefficient-0.62, p<0.001) and hypercholesterolemia (without vs. with, 1.8±0.6 vs. 3.9±0.7, p-0.034) were two significant risk factors. Conclusion: From current study, age and hypercholesterolemia were two risk factors of negative stress test and angiographically insignificant coronary artery atherosclerosis. This result suggests that it may be better to treat hypercholesterolemia more aggressively than present practice guideline, especially in aged patients, to postpone the possibility of progression of clinically insignificant coronary artery atherosclerosis to significant coronary artery disease and to reduce the possibility of acute coronary syndrome.
•
EFFECTS OF ATORVASTATIN 10 M G ON TRIGLYCERIDES IN DIABETICS TYPE 2 PATIENTS, A DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY B. Chanu 1, C. Koch2, J.J. Portal 2, H. Laouenan2. IMedecine V, Hopital
Henri Mondor, Creteil," 2Pfizer, Paris, France The present double-blind randomized study compared the effect of 8-weeks treatment with atorvastatin 10 mg (A) versus placebo (P) on TG levels and plasma lipid profile. 126 patients with type 2 diabetes (78 men and 48 women) were randomized into two groups (68 in A, and 58 in P). Mean age-62±8 years, mean glycemia "a jeun"-8.1±2.0 mmol/L, mean BMI-29.6±3.3. Baseline values of lipidic parameters were: TG-2.48±0.94 g/L, LDL-C-1.67±0.24 g/L, HDL-C-0.43±0.09 g/L. Baseline values were not significantly different between the two groups. After 8 W, reductions from baseline in TG levels were significantly different between A and P (-21.9% vs +17.0%, p<0.001; analysis of covariance with baseline value as covariate). A decreased LDL-C (-34.0% vs -0.4%, p<0.001), and increase HDL-C (+5.0% vs + 0.2%, p-0.16). Differences observed were already significant after 4 W of treatment. Significant decreases at 8 W were also found for the other lipidic parameters studied (TC, VLDL-C, VLDL-TG, ApoB, Apo CIII and LpB:CIII). No significant differences in the frequency of adverse effects were found (43% vs 41%). This study demonstrated that A 10 mg significantly and rapidly reduced TG levels, an important risk factor in patients with type 2 diabetes and dyslipidemia. Furthermore, this study showed that A favorably modified the atherogenic lipoprotein profile in these patients.
•1-•
THE LIPID L O W E R I N G EFFECT OF YOGURT IN PATIENTS W I T H H I G H TOTAL CHOLESTEROL LEVEL
T.H. Chao 1, J.H. Chen 1, M.-T. Lin 2, W.C. Tsai 1, Y.H. Li 1, EY. Liu 1.
JDepartment of Internal Medicine, College of Medicine, National Cheng Kung University; 2Department of Biochemistry, College of Medicine, National Cheng Kung University, Tainan, Taiwan Controversies have existed for decades on the lipid-lowering effect of fermented milk. The effect of yogurt with probiotic lactic acid bacteria on the lipid profile and oxidative stress are poorly understood. We prospectively enrolled 12 healthy volunteers with only dyslipidemia (total cholesterol (TC) ~> 200 mg/dl or total triglyceride (TG) ~> 200 mg/dl). All subjects received 400 ml commercial yogurt (Uni-President, Taiwan), containing 100 million Acidophilus B. lactis per ml, daily for 4 weeks. Baseline and postintervention lipid profiles and glutathione peroxidase (GP) were measured. Ingestion of yogurt decreased TC by 5.4% (260±60 vs 246±47 mg/dl, p-0.051) and LDL cholesterol by 7.6% (170±56 vs 157±46 mg/dl, p-0.069) with insignificant reduction of TG and HDL cholesterol. Reduction of TC by yogurt was more significant in the subgroup with high TC level (~> 240 mg/dl) (297±50 vs 274±35 mg/dl. P-0.041). HDL cholesterol levels
were also decreased with treatment (61±13 vs 58±13 mg/dl, p-0.013) in this subgroup. GP levels were not significantly changed after ingestion of yogurt. However, plasma levels of GP were increased significantly among subjects with reduced TG levels after ingestion of yogurt (7575±1911 vs 8446±1698 ng/ml, p-0.029). Our data suggest that yogurt has borderline hypocholesterolemic effect among dyslipidemic subjects. For patients with high TC levels, yogurt is an effective hypocholesterolemic adjuvant. Ingestion of yogurt improves oxidative stress among TG responders. The mechanism responsible for the beneficial effects requires further investigation. ~H-~ INDUCTION OF VASCULAR ENDOTHELIAL CELL APOPTOSIS THROUGH THE PLATELET-ACTIVATING FACTOR RECEPTOR IN HYPERCHOLESTEROLEMIA C.-H. Chen, T. Jiang, J.-H. Yang, W. Jiang, H.L Pownall, C.M. Ballantyne, J. Lu, P.D. Henry, C.-Y. Yang. Baylor College of Medicine, Houston, TX,
USA Apoptosis of vascular endothelial cells (EC) plays a critical role in the initiation and progression of atherosclerosis. LDL oxidized in vitro is documented for its proapoptotic effects on EC in culture. To identify circulating LDL species that may exhibit similar effects in hyperlipidemia, we subfractionated LDL isolated from hypercholesterolemic, normotriglyceridemic patients (n-8) and normolipidemic control subjects (n-8) by fast protein liquid chromatography. The procedure yielded 5 subfractions, L1 to L5, in all patient samples, but only 3 subfractions, L1 to L3, in the control group. L5, the most electronegative subfraction, was distinguished by an increased oxidizability and a higher lipid to protein ratio. In bovine aortic EC cultures, L5 effectively induced apoptosis in a concentration-dependent manner, as assayed by standard methods. L4 had a milder effect, whereas L1 to L3 had none. The L5 effect was sensitive to Gi inhibitor pertussis toxin (PTX). Blocking the Gi-coupled platelet-activating factor (PAF) receptor with its antagonist WEB 2086 or degrading PAF-like lipids contained in L5 by a recombinant PAF acetylhydrolase abolished L5 effects. L5-induced apoptosis was accompanied by a transcriptional downregulation of the anti-apoptotic fibroblast growth factor 2 (FGF2), which was also sensitive to PTX and WEB 2086. FGF2 supplementation prevented apoptosis in L5-exposed cells. We conclude that L5 induces EC apoptosis by a mechanism that involves FGF2 downregulation through the PAF receptor. The effects may be mediated by PAF-like lipids contained in this particular LDL subfraction that circulates in patients with hypercholesterolemia. [ ] - - ~ OXIDIZED LDL-INDUCED VASCULAR ENDOTHELIAL C E L L APOPTOSIS INVOLVES CERAMIDE-MEDIATED A K T DEPHOSPHORYLATION: PROTECTIVE ROLE OF FGF20VEREXPRESSION J. Lu 1, S. Suzuki2, H.J. Sail 2, W. Jiang 1, RD. Henry 1, J.-H. Yang 1, J.D. Morrisett 1, C.-H. Chen 1. IBaylor College of Medicine," 2University of
Texas Houston Medical School, Houston, TX, USA Apoptosis of vascular endothelial cells (EC) plays a critical role in atherothrombosis and modified lipoproteins are considered proapoptotic. We recently demonstrated that copper-oxidized LDL (oxLDL) induces EC apoptosis in part by downregulating the anti-apoptotic fibroblast growth factor 2 (FGF2). FGF2 acts in part by stimulating phosphatidylinositol3-kinase (PI3K) that phosphorylates Akt (protein kinase B); phosphorylated Akt inhibits apoptosis by deactivating downstream apoptotic targets. Because ceramide is a documented intracellular apoptosis mediator, we investigated the interaction between the FGF2-PI3K-Akt axis and ceramide in EC exposed to oxLDL. In bovine aortic EC cultures, oxLDL (50 microg/mL) induced marked apoptosis at 24 hours, as assessed by nuclear staining, DNA laddering, and flow cytometry. The apoptosis was accompanied by Akt dephosphorylation. Addition of membrane permeable C2-ceramide to the cultures produced oxLDL-like effects. Intracellular ceramide can be synthesized from sphingosine by ceramide synthase or derived from sphingomyelin through hydrolysis by sphingomyelinases. OxLDL-induced Akt dephosphorylation and apoptosis were attenuated by a ceramide synthase inhibitor (fumonisin B-l) and two sphingomyelinase inhibitors (desipramine and chlorpromazine). Overexpressing FGF2 in cells by infection with adenoviruses that contained a FGF2-sense cDNA prevented oxLDL or ceramide-induced Akt dephosphorylation and the associated apoptosis. Cells infected with FGF2-antisense viruses exhibited marked apoptosis and Akt dephosphorylation. The results suggest that oxLDL-induced EC apoptosis involves ceramide formation through ceramide synthase and sphingomyelinases, which contributes to Akt dephosphorylation. The Akt-dependent
73rd EAS Congress
Chanu
sis. Age, hypertension, diabetes, smoking, and hypercholesterolemia were proved to be risk factors of clinically significant coronary artery disease. However, there were only few issues concerning risk factors of insignificant coronary artery atherosclerosis. Methods: 30 patients (16 males) with both negative stress test and angiographically insignificant coronary artery atherosclerosis (luminal stenosis <50%) were enrolled. Average age was 51.7±9.9 years. Risk factors including hypertension, diabetes, hypercholesterolemia, and smoking were checked. Coronary artery atherosclerosis was evaluated using severity and diffuseness score. Association of these probable risk factors and coronary artery atherosclerosis was analyzed. Results: Concerning severity score, the intra-observer correlation was 0.98. Age (Spearman' s rank correlation coefficient-0.657, l~0.001) and hypercholesterolemia (without vs. with, 14.7±4.6 vs. 31.3±5.4, p-0.028) were two significant risk factors With regard to diffuseness score, the intraobserver correlation was 0.982. Age (Spearman' s rank correlation coefficient-0.62, p<0.001) and hypercholesterolemia (without vs. with, 1.8±0.6 vs. 3.9±0.7, p-0.034) were two significant risk factors. Conclusion: From current study, age and hypercholesterolemia were two risk factors of negative stress test and angiographically insignificant coronary artery atherosclerosis. This result suggests that it may be better to treat hypercholesterolemia more aggressively than present practice guideline, especially in aged patients, to postpone the possibility of progression of clinically insignificant coronary artery atherosclerosis to significant coronary artery disease and to reduce the possibility of acute coronary syndrome.
•
EFFECTS OF ATORVASTATIN 10 M G ON TRIGLYCERIDES IN DIABETICS TYPE 2 PATIENTS, A DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED STUDY B. Chanu 1, C. Koch2, J.J. Portal 2, H. Laouenan2. IMedecine V, Hopital
Henri Mondor, Creteil," 2Pfizer, Paris, France The present double-blind randomized study compared the effect of 8-weeks treatment with atorvastatin 10 mg (A) versus placebo (P) on TG levels and plasma lipid profile. 126 patients with type 2 diabetes (78 men and 48 women) were randomized into two groups (68 in A, and 58 in P). Mean age-62±8 years, mean glycemia "a jeun"-8.1±2.0 mmol/L, mean BMI-29.6±3.3. Baseline values of lipidic parameters were: TG-2.48±0.94 g/L, LDL-C-1.67±0.24 g/L, HDL-C-0.43±0.09 g/L. Baseline values were not significantly different between the two groups. After 8 W, reductions from baseline in TG levels were significantly different between A and P (-21.9% vs +17.0%, p<0.001; analysis of covariance with baseline value as covariate). A decreased LDL-C (-34.0% vs -0.4%, p<0.001), and increase HDL-C (+5.0% vs + 0.2%, p-0.16). Differences observed were already significant after 4 W of treatment. Significant decreases at 8 W were also found for the other lipidic parameters studied (TC, VLDL-C, VLDL-TG, ApoB, Apo CIII and LpB:CIII). No significant differences in the frequency of adverse effects were found (43% vs 41%). This study demonstrated that A 10 mg significantly and rapidly reduced TG levels, an important risk factor in patients with type 2 diabetes and dyslipidemia. Furthermore, this study showed that A favorably modified the atherogenic lipoprotein profile in these patients.
•1-•
THE LIPID L O W E R I N G EFFECT OF YOGURT IN PATIENTS W I T H H I G H TOTAL CHOLESTEROL LEVEL
T.H. Chao 1, J.H. Chen 1, M.-T. Lin 2, W.C. Tsai 1, Y.H. Li 1, EY. Liu 1.
JDepartment of Internal Medicine, College of Medicine, National Cheng Kung University; 2Department of Biochemistry, College of Medicine, National Cheng Kung University, Tainan, Taiwan Controversies have existed for decades on the lipid-lowering effect of fermented milk. The effect of yogurt with probiotic lactic acid bacteria on the lipid profile and oxidative stress are poorly understood. We prospectively enrolled 12 healthy volunteers with only dyslipidemia (total cholesterol (TC) ~> 200 mg/dl or total triglyceride (TG) ~> 200 mg/dl). All subjects received 400 ml commercial yogurt (Uni-President, Taiwan), containing 100 million Acidophilus B. lactis per ml, daily for 4 weeks. Baseline and postintervention lipid profiles and glutathione peroxidase (GP) were measured. Ingestion of yogurt decreased TC by 5.4% (260±60 vs 246±47 mg/dl, p-0.051) and LDL cholesterol by 7.6% (170±56 vs 157±46 mg/dl, p-0.069) with insignificant reduction of TG and HDL cholesterol. Reduction of TC by yogurt was more significant in the subgroup with high TC level (~> 240 mg/dl) (297±50 vs 274±35 mg/dl. P-0.041). HDL cholesterol levels
were also decreased with treatment (61±13 vs 58±13 mg/dl, p-0.013) in this subgroup. GP levels were not significantly changed after ingestion of yogurt. However, plasma levels of GP were increased significantly among subjects with reduced TG levels after ingestion of yogurt (7575±1911 vs 8446±1698 ng/ml, p-0.029). Our data suggest that yogurt has borderline hypocholesterolemic effect among dyslipidemic subjects. For patients with high TC levels, yogurt is an effective hypocholesterolemic adjuvant. Ingestion of yogurt improves oxidative stress among TG responders. The mechanism responsible for the beneficial effects requires further investigation. ~H-~ INDUCTION OF VASCULAR ENDOTHELIAL CELL APOPTOSIS THROUGH THE PLATELET-ACTIVATING FACTOR RECEPTOR IN HYPERCHOLESTEROLEMIA C.-H. Chen, T. Jiang, J.-H. Yang, W. Jiang, H.L Pownall, C.M. Ballantyne, J. Lu, P.D. Henry, C.-Y. Yang. Baylor College of Medicine, Houston, TX,
USA Apoptosis of vascular endothelial cells (EC) plays a critical role in the initiation and progression of atherosclerosis. LDL oxidized in vitro is documented for its proapoptotic effects on EC in culture. To identify circulating LDL species that may exhibit similar effects in hyperlipidemia, we subfractionated LDL isolated from hypercholesterolemic, normotriglyceridemic patients (n-8) and normolipidemic control subjects (n-8) by fast protein liquid chromatography. The procedure yielded 5 subfractions, L1 to L5, in all patient samples, but only 3 subfractions, L1 to L3, in the control group. L5, the most electronegative subfraction, was distinguished by an increased oxidizability and a higher lipid to protein ratio. In bovine aortic EC cultures, L5 effectively induced apoptosis in a concentration-dependent manner, as assayed by standard methods. L4 had a milder effect, whereas L1 to L3 had none. The L5 effect was sensitive to Gi inhibitor pertussis toxin (PTX). Blocking the Gi-coupled platelet-activating factor (PAF) receptor with its antagonist WEB 2086 or degrading PAF-like lipids contained in L5 by a recombinant PAF acetylhydrolase abolished L5 effects. L5-induced apoptosis was accompanied by a transcriptional downregulation of the anti-apoptotic fibroblast growth factor 2 (FGF2), which was also sensitive to PTX and WEB 2086. FGF2 supplementation prevented apoptosis in L5-exposed cells. We conclude that L5 induces EC apoptosis by a mechanism that involves FGF2 downregulation through the PAF receptor. The effects may be mediated by PAF-like lipids contained in this particular LDL subfraction that circulates in patients with hypercholesterolemia. [ ] - - ~ OXIDIZED LDL-INDUCED VASCULAR ENDOTHELIAL C E L L APOPTOSIS INVOLVES CERAMIDE-MEDIATED A K T DEPHOSPHORYLATION: PROTECTIVE ROLE OF FGF20VEREXPRESSION J. Lu 1, S. Suzuki2, H.J. Sail 2, W. Jiang 1, RD. Henry 1, J.-H. Yang 1, J.D. Morrisett 1, C.-H. Chen 1. IBaylor College of Medicine," 2University of
Texas Houston Medical School, Houston, TX, USA Apoptosis of vascular endothelial cells (EC) plays a critical role in atherothrombosis and modified lipoproteins are considered proapoptotic. We recently demonstrated that copper-oxidized LDL (oxLDL) induces EC apoptosis in part by downregulating the anti-apoptotic fibroblast growth factor 2 (FGF2). FGF2 acts in part by stimulating phosphatidylinositol3-kinase (PI3K) that phosphorylates Akt (protein kinase B); phosphorylated Akt inhibits apoptosis by deactivating downstream apoptotic targets. Because ceramide is a documented intracellular apoptosis mediator, we investigated the interaction between the FGF2-PI3K-Akt axis and ceramide in EC exposed to oxLDL. In bovine aortic EC cultures, oxLDL (50 microg/mL) induced marked apoptosis at 24 hours, as assessed by nuclear staining, DNA laddering, and flow cytometry. The apoptosis was accompanied by Akt dephosphorylation. Addition of membrane permeable C2-ceramide to the cultures produced oxLDL-like effects. Intracellular ceramide can be synthesized from sphingosine by ceramide synthase or derived from sphingomyelin through hydrolysis by sphingomyelinases. OxLDL-induced Akt dephosphorylation and apoptosis were attenuated by a ceramide synthase inhibitor (fumonisin B-l) and two sphingomyelinase inhibitors (desipramine and chlorpromazine). Overexpressing FGF2 in cells by infection with adenoviruses that contained a FGF2-sense cDNA prevented oxLDL or ceramide-induced Akt dephosphorylation and the associated apoptosis. Cells infected with FGF2-antisense viruses exhibited marked apoptosis and Akt dephosphorylation. The results suggest that oxLDL-induced EC apoptosis involves ceramide formation through ceramide synthase and sphingomyelinases, which contributes to Akt dephosphorylation. The Akt-dependent
73rd EAS Congress