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P429 A NOVEL APPROACH THROUGH THE EFFECTS OF TURBULENT FLOW ON THE ENDOTHELIAL CELL SHAPE
78th EAS Congress
Atherosclerosis Supplements 11, no. 2 (2010) 17–108
ultimately macrophage death. Bcl-xL is the most abundantly expressed member of the Bcl-2 gene family in macrophages and plays a protective role against macrophage apoptosis. However, the role of Bcl-xL in atherosclerosis is currently unknown. We therefore specifically inactivated Bcl-xL in macrophages and determined the impact on atherosclerotic lesion formation in an apoEKO background. Bcl-xLKOmac (Bcl-xLflox -LysMcre , apoEKO ) mice fed a Western diet for 27 weeks exhibited advanced lesions in the whole aorta which were 45% larger than those seen in control mice; these changes were associated with elevated liver and plasma cholesterol levels. Analysis of liver tissue by flow cytometry revealed a significant decrease (33%, p < 0.001) in resident macrophages (Kupffer ¨ cells) in Bcl-xLKOmac mice in comparison to controls. Our data suggest that modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-xL may impact the macrophage cell population in the whole body, including Kupffer ¨ cells, the largest pool. Macrophage survival may not only influence atherosclerotic plaque development, but also, lipid and hepatic metabolism. P427 ROLE OF DIFFERENT FORMS OF HDL (Ox-HDL AND nHDL) ON Ox-LDL INDUCED APOPTOSIS IN DIFFERENTIATED MONOCYTES N. Kaur1 , S. Kumari1 , S. Jain1 , S. Majumdar2 , S. Ghosh2 . 1 Department of Internal Medicine, 2 Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh, India Introduction: Macrophages in atherosclerotic lesions have been shown to have cellular characteristic of both necrosis and apoptosis. However, apoptosis of macrophages is beneficial or detrimental during atherosclerosis is not well understood. Objectives: This study examined the role of different forms of HDL (nHDL/OxHDL) on mitochondrial dependent apoptotic pathway induced by Ox-LDL in differentiated monocytes. Methods: Apoptosis was examined in PMA differentiated monocytes obtained from THP-1 cells as well as 30 hyperlowdensitylipoproteinemic and normolowdensitylipoproteinemic subjects which were preincubated with nHDL/Ox-HDL followed by coincubation with Ox-LDL and further the expression of various pro- and anti- apoptotic molecules was studied both mRNA and protein level. Results: We demonstrated that nHDL but not Ox-HDL inhibit Ox-LDL mediated apoptosis in differentiated monocytes. The findings were substantiated in patient and control subject by studying the expression of Bax and Bcl-2 proteins. In the present study, Ox-LDL and Ox-HDL were found to be cytotoxic in differentiated monocytes in a dose dependent manner. HDL is also susceptible to oxidation and this modification of HDL leads to the cytotoxicity in cultured cells. The Ox-HDL also induced apoptosis of differentiated monocytes/macrophages in presence of Ox-LDL via activation of Bax leading to mitochondrial dysfunctioing and release of cytochrome C in the cytosol. Conclusion: HDL is identified as carrier of monocytes/macrophage survival factor and suggests that induction of mitochondrial pathway of apoptosis of monocytes/macrophage by Ox-HDL may represent an important and novel aspect of HDL indicating that modification of lipoprotein like HDL may enhance the process of atherogenesis. P428 SEX PARTICULARITIES IN NITRIC OXIDE AVAILABILITY IN HEALTHY AND HYPERTENSIVE RATS UNDER NORMAL AND STRESS CONDITIONS A. Kuznetsova, O. Semychkina-Glushkovskaya, T. Sindyakova, I. SemyachkinGlushkovskij, Y. Kuznetsova. Biology Department, Saratov State University, Saratov, Russia Aims: The goal of this study was to determine the gender differences in nitric oxide (NO) content in normal and hypertensive (two kidney, one clip) rats at rest and in immobilization stress (IS, 60 min). Methods: Serum NO concentration were measured in blood by a spectrophotometric assay. NO determinations were performed by Gress reaction as NO2 concentration after NO3 reduction to NO2 . Results: We found that the basal NO production was greater in females vs. males. The IS resulted in significant increase in circulating NO levels that were more pronounced in females vs. males. The ischemia of renal artery was accompanied by development of hypertension and atrophical decrease in mass of kidney. Actually, the hypertension was attenuated in females compared with males. So, the basal BP levels were higher in hypertensive males vs. hypertensive females. The mass of clipped kidney vs. mass of normal kidney was decreased 8.3-fold in females and 15.8-fold in males. We also found that NO production was depressed in hypertensive rats under normal and stress conditions. Nitice, that severe hypertension in males vs. females was accompanied by more significant decrease in basal and stress NO secretion. Conclusion: The present study shows that there are sex differences in NO availability both normotensive and hypertensive rats under normal and stress conditions. Since NO is a vasorelaxing and important stress-limited factor we hypothesize that there are sex differences in basal and stress NO availability
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may be responsible for man are at greater risk for cardiovascular disease than women. Project GK-P1257. P429 A NOVEL APPROACH THROUGH THE EFFECTS OF TURBULENT FLOW ON THE ENDOTHELIAL CELL SHAPE R. Paeizi, E. Barzanouni, M. Bokaiyan. Mashhad University of Medical Sciences, Mashhad, Iran Turbulent flow is an aggregator of injury and dysfunction of endothelial cells lining which leads to deposition of low density lipoprotein (LDL) into the intima layer of large and medium sized elastic and muscular arteries; chronic deposition of LDL leads to progression of atherosclerosis plaque formation. Clinical evidences show atherosclerosis occurs in bifurcation and curvatures which are concerning regions of our hypothesis due to different flow pattern called turbulent flow; through a new point of view, we approach the possible role of turbulent blood flow and endothelial luminal cell surfaces which induces static electricity on plasma membrane; this static electricity can cause a new arrangement of actin filaments- cell shape determiners − which can induce chronic shifting of cytoskeleton and chronic changing in cell shape. Changing process effects cell-to-cell junction and leads to concordance disruption in lining of endothelial cells. This phenomenon can cause endothelial dysfunction of arterial lining which might cause chronic events that leads to atherosclerosis. Taken together, turbulent flow results in atherosclerosis with induction of static electricity which can help us design more efficient prophylactic and therapeutic strategies. P430 THE BENEFICIAL EFFECT OF MEDITERRANEAN DIET ON METABOLIC SYNDROME: A META-ANALYSIS OF 49 STUDIES AND 175,529 INDIVIDUALS C.-M. Kastorini1 , H. Milionis2 , K. Esposito3 , D. Giugliano3 , J. Goudevenos2 , D.B. Panagiotakos1 . 1 Department of Nutrition-Dietetics, Harokopio University, Athens, 2 School of Medicine, University of Ioannina, Ioannina, Greece, 3 Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy Objective: To systematically review and meta-analyze epidemiological studies and clinical trials that have assessed the effect of a Mediterranean diet on Metabolic syndrome and its components. Design: Systematic review and random effects meta-analysis of epidemiological studies and randomized controlled trials. English language publications in PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials from 1/1/1990 to 31/12/2009; 49 original research studies (35 clinical trials, 2 prospective and 12 cross-sectional), with 175,529 participants, were included in the analysis. Results: The overall effect shows that adherence to the Mediterranean diet is associated with reduced odds of metabolic syndrome (log (OR): −0.36, 95% CI: −0.63 to −0.09). Additionally results from clinical studies (mean difference, 95% CI) indicate the protective role of the Mediterranean diet on metabolic syndrome components: waist circumference: −0.42 cm, 95% CI: −0.82 to −0.02, HDL: 1.17 mg/dL, 95% CI: 0.38 to 1.96, triglycerides: −6.14 mg/dL, 95% CI: −10.35 to −1.93, systolic (SBP): −2.35 mmHg, 95% CI: −3.51 to −1.18 and diastolic blood pressure (DBP): −1.58 mmHg, 95% CI: −2.02 to −1.13, glucose: −3.89 mg/dL, 95% CI: −5.84 to −1.95. Results from epidemiological studies confirm those of clinical trials: waist circumference: −4.87 cm, 95% CI: −6.21 to −3.53, HDL: 2.04 mg/dL, 95% CI: 1.01 to 3.07, triglycerides: −8.63 mg/dL, 95% CI: −14.89 to −2.36, SBP: −2.19 mmHg, 95% CI: −4.91 to 0.54, DBP: −2.34 mmHg, 95% CI: −5.54 to 0.86, glucose: −3.32 mg/dL, 95% CI: −5.90 to −0.74. Conclusions: The present meta-analysis suggests that Mediterranean diet is beneficial not only regarding metabolic syndrome, as a whole, but also its individual components. P431 MIPOMERSEN, AN apo B SYNTHESIS INHIBITOR, PREFERENTIALLY REDUCES SMALL LDL PARTICLE NUMBER AND INCREASES LDL PARTICLE SIZE IN HoFH PATIENTS W. Cromwell1 , R. Santos2 , D. Blom3 , A.D. Marais3 , M.-J. Charng4 , R. Lachmann5 , D. Gaudet6 , J.-L. Tan7 , D. Tribble8 , J. Flaim8 , S. ChasanTaber9 , J. Donovan9 , F. Raal10 . 1 Division of Atherosclerosis and Lipoprotein Disorders, Presbyterian Cardiovascular Institute, Charlotte, NC, USA, 2 Heart ˜ Paulo, Sao ˜ Paulo, Brazil, 3 Division of Institute (inCor), University of Sao Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa, 4 Department of Cardiology, Taipei Veterans Genl Hosp and Natl Yang-Ming Univ, Taipei, Taiwan R.O.C., 5 Charles Dent Metabolic Unit, University College London Hospitals, London, UK, 6 ECOGENE-21 Clinical Research Ctr and Lipid Clinic, Chicoutimi, QC, Canada, 7 Cardiology, National Heart Center, Singapore, Singapore, 8 Isis Pharmaceuticals, Inc., Carlsbad, CA, 9 Genzyme Corporation, Cambridge, MA, USA, 10 Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa Background and Aim: Apolipoprotein B (apo B) is a key component of atherogenic lipoprotein particles VLDL, IDL, and LDL, elevations of which
Atherosclerosis Supplements 11, no. 2 (2010) 17–108
ultimately macrophage death. Bcl-xL is the most abundantly expressed member of the Bcl-2 gene family in macrophages and plays a protective role against macrophage apoptosis. However, the role of Bcl-xL in atherosclerosis is currently unknown. We therefore specifically inactivated Bcl-xL in macrophages and determined the impact on atherosclerotic lesion formation in an apoEKO background. Bcl-xLKOmac (Bcl-xLflox -LysMcre , apoEKO ) mice fed a Western diet for 27 weeks exhibited advanced lesions in the whole aorta which were 45% larger than those seen in control mice; these changes were associated with elevated liver and plasma cholesterol levels. Analysis of liver tissue by flow cytometry revealed a significant decrease (33%, p < 0.001) in resident macrophages (Kupffer ¨ cells) in Bcl-xLKOmac mice in comparison to controls. Our data suggest that modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-xL may impact the macrophage cell population in the whole body, including Kupffer ¨ cells, the largest pool. Macrophage survival may not only influence atherosclerotic plaque development, but also, lipid and hepatic metabolism. P427 ROLE OF DIFFERENT FORMS OF HDL (Ox-HDL AND nHDL) ON Ox-LDL INDUCED APOPTOSIS IN DIFFERENTIATED MONOCYTES N. Kaur1 , S. Kumari1 , S. Jain1 , S. Majumdar2 , S. Ghosh2 . 1 Department of Internal Medicine, 2 Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh, India Introduction: Macrophages in atherosclerotic lesions have been shown to have cellular characteristic of both necrosis and apoptosis. However, apoptosis of macrophages is beneficial or detrimental during atherosclerosis is not well understood. Objectives: This study examined the role of different forms of HDL (nHDL/OxHDL) on mitochondrial dependent apoptotic pathway induced by Ox-LDL in differentiated monocytes. Methods: Apoptosis was examined in PMA differentiated monocytes obtained from THP-1 cells as well as 30 hyperlowdensitylipoproteinemic and normolowdensitylipoproteinemic subjects which were preincubated with nHDL/Ox-HDL followed by coincubation with Ox-LDL and further the expression of various pro- and anti- apoptotic molecules was studied both mRNA and protein level. Results: We demonstrated that nHDL but not Ox-HDL inhibit Ox-LDL mediated apoptosis in differentiated monocytes. The findings were substantiated in patient and control subject by studying the expression of Bax and Bcl-2 proteins. In the present study, Ox-LDL and Ox-HDL were found to be cytotoxic in differentiated monocytes in a dose dependent manner. HDL is also susceptible to oxidation and this modification of HDL leads to the cytotoxicity in cultured cells. The Ox-HDL also induced apoptosis of differentiated monocytes/macrophages in presence of Ox-LDL via activation of Bax leading to mitochondrial dysfunctioing and release of cytochrome C in the cytosol. Conclusion: HDL is identified as carrier of monocytes/macrophage survival factor and suggests that induction of mitochondrial pathway of apoptosis of monocytes/macrophage by Ox-HDL may represent an important and novel aspect of HDL indicating that modification of lipoprotein like HDL may enhance the process of atherogenesis. P428 SEX PARTICULARITIES IN NITRIC OXIDE AVAILABILITY IN HEALTHY AND HYPERTENSIVE RATS UNDER NORMAL AND STRESS CONDITIONS A. Kuznetsova, O. Semychkina-Glushkovskaya, T. Sindyakova, I. SemyachkinGlushkovskij, Y. Kuznetsova. Biology Department, Saratov State University, Saratov, Russia Aims: The goal of this study was to determine the gender differences in nitric oxide (NO) content in normal and hypertensive (two kidney, one clip) rats at rest and in immobilization stress (IS, 60 min). Methods: Serum NO concentration were measured in blood by a spectrophotometric assay. NO determinations were performed by Gress reaction as NO2 concentration after NO3 reduction to NO2 . Results: We found that the basal NO production was greater in females vs. males. The IS resulted in significant increase in circulating NO levels that were more pronounced in females vs. males. The ischemia of renal artery was accompanied by development of hypertension and atrophical decrease in mass of kidney. Actually, the hypertension was attenuated in females compared with males. So, the basal BP levels were higher in hypertensive males vs. hypertensive females. The mass of clipped kidney vs. mass of normal kidney was decreased 8.3-fold in females and 15.8-fold in males. We also found that NO production was depressed in hypertensive rats under normal and stress conditions. Nitice, that severe hypertension in males vs. females was accompanied by more significant decrease in basal and stress NO secretion. Conclusion: The present study shows that there are sex differences in NO availability both normotensive and hypertensive rats under normal and stress conditions. Since NO is a vasorelaxing and important stress-limited factor we hypothesize that there are sex differences in basal and stress NO availability
107
may be responsible for man are at greater risk for cardiovascular disease than women. Project GK-P1257. P429 A NOVEL APPROACH THROUGH THE EFFECTS OF TURBULENT FLOW ON THE ENDOTHELIAL CELL SHAPE R. Paeizi, E. Barzanouni, M. Bokaiyan. Mashhad University of Medical Sciences, Mashhad, Iran Turbulent flow is an aggregator of injury and dysfunction of endothelial cells lining which leads to deposition of low density lipoprotein (LDL) into the intima layer of large and medium sized elastic and muscular arteries; chronic deposition of LDL leads to progression of atherosclerosis plaque formation. Clinical evidences show atherosclerosis occurs in bifurcation and curvatures which are concerning regions of our hypothesis due to different flow pattern called turbulent flow; through a new point of view, we approach the possible role of turbulent blood flow and endothelial luminal cell surfaces which induces static electricity on plasma membrane; this static electricity can cause a new arrangement of actin filaments- cell shape determiners − which can induce chronic shifting of cytoskeleton and chronic changing in cell shape. Changing process effects cell-to-cell junction and leads to concordance disruption in lining of endothelial cells. This phenomenon can cause endothelial dysfunction of arterial lining which might cause chronic events that leads to atherosclerosis. Taken together, turbulent flow results in atherosclerosis with induction of static electricity which can help us design more efficient prophylactic and therapeutic strategies. P430 THE BENEFICIAL EFFECT OF MEDITERRANEAN DIET ON METABOLIC SYNDROME: A META-ANALYSIS OF 49 STUDIES AND 175,529 INDIVIDUALS C.-M. Kastorini1 , H. Milionis2 , K. Esposito3 , D. Giugliano3 , J. Goudevenos2 , D.B. Panagiotakos1 . 1 Department of Nutrition-Dietetics, Harokopio University, Athens, 2 School of Medicine, University of Ioannina, Ioannina, Greece, 3 Department of Geriatrics and Metabolic Diseases, Second University of Naples, Naples, Italy Objective: To systematically review and meta-analyze epidemiological studies and clinical trials that have assessed the effect of a Mediterranean diet on Metabolic syndrome and its components. Design: Systematic review and random effects meta-analysis of epidemiological studies and randomized controlled trials. English language publications in PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials from 1/1/1990 to 31/12/2009; 49 original research studies (35 clinical trials, 2 prospective and 12 cross-sectional), with 175,529 participants, were included in the analysis. Results: The overall effect shows that adherence to the Mediterranean diet is associated with reduced odds of metabolic syndrome (log (OR): −0.36, 95% CI: −0.63 to −0.09). Additionally results from clinical studies (mean difference, 95% CI) indicate the protective role of the Mediterranean diet on metabolic syndrome components: waist circumference: −0.42 cm, 95% CI: −0.82 to −0.02, HDL: 1.17 mg/dL, 95% CI: 0.38 to 1.96, triglycerides: −6.14 mg/dL, 95% CI: −10.35 to −1.93, systolic (SBP): −2.35 mmHg, 95% CI: −3.51 to −1.18 and diastolic blood pressure (DBP): −1.58 mmHg, 95% CI: −2.02 to −1.13, glucose: −3.89 mg/dL, 95% CI: −5.84 to −1.95. Results from epidemiological studies confirm those of clinical trials: waist circumference: −4.87 cm, 95% CI: −6.21 to −3.53, HDL: 2.04 mg/dL, 95% CI: 1.01 to 3.07, triglycerides: −8.63 mg/dL, 95% CI: −14.89 to −2.36, SBP: −2.19 mmHg, 95% CI: −4.91 to 0.54, DBP: −2.34 mmHg, 95% CI: −5.54 to 0.86, glucose: −3.32 mg/dL, 95% CI: −5.90 to −0.74. Conclusions: The present meta-analysis suggests that Mediterranean diet is beneficial not only regarding metabolic syndrome, as a whole, but also its individual components. P431 MIPOMERSEN, AN apo B SYNTHESIS INHIBITOR, PREFERENTIALLY REDUCES SMALL LDL PARTICLE NUMBER AND INCREASES LDL PARTICLE SIZE IN HoFH PATIENTS W. Cromwell1 , R. Santos2 , D. Blom3 , A.D. Marais3 , M.-J. Charng4 , R. Lachmann5 , D. Gaudet6 , J.-L. Tan7 , D. Tribble8 , J. Flaim8 , S. ChasanTaber9 , J. Donovan9 , F. Raal10 . 1 Division of Atherosclerosis and Lipoprotein Disorders, Presbyterian Cardiovascular Institute, Charlotte, NC, USA, 2 Heart ˜ Paulo, Sao ˜ Paulo, Brazil, 3 Division of Institute (inCor), University of Sao Lipidology, Department of Medicine, University of Cape Town, Cape Town, South Africa, 4 Department of Cardiology, Taipei Veterans Genl Hosp and Natl Yang-Ming Univ, Taipei, Taiwan R.O.C., 5 Charles Dent Metabolic Unit, University College London Hospitals, London, UK, 6 ECOGENE-21 Clinical Research Ctr and Lipid Clinic, Chicoutimi, QC, Canada, 7 Cardiology, National Heart Center, Singapore, Singapore, 8 Isis Pharmaceuticals, Inc., Carlsbad, CA, 9 Genzyme Corporation, Cambridge, MA, USA, 10 Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa Background and Aim: Apolipoprotein B (apo B) is a key component of atherogenic lipoprotein particles VLDL, IDL, and LDL, elevations of which