Swiss, German and French Atherosclerosis Societies
3rd Joint Meeting of the French, German and Swiss Atherosclerosis Societies
Saint-Gervais-Les-Bains, Haute-Savoie, France - January 31 - February 2, 2008
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DEAR COLLEAGUES
We are delighted to invite you to the third Joint Meeting of French, German and Swiss Atherosclerosis Societies, January 31 –February 2, 2008 , which will be held jointly by the “Nouvelle Société Française d’Athérosclérose”, the “Deutsche Atherosklerose Gesellschaft” and the “Swiss Atherosclerosis Society”.
The main topics of this meeting are :
- Lipid metabolism : New Targets for the Prevention of Atherosclerosis
- New approaches in cardiovascular risk assessment
- Hypertension and dyslipidemia
The meeting will take place in a small village of Haute Savoie, at the feet of Mont-Blanc mountain. We hope that the relaxing atmosphere of mountain resort will provide an excellent opportunity for scientific colleagues from different countries to share their recent results and ideas. The number of participants will be limited to 80 persons, including established scientists and students .
The meeting will start with a poster session accompanied by an informal discussion to allow free scientific exchange between the presenting group and the expert audience.
We invite you to present an abstract of your work on the topic of atherosclerosis and its risk factors.
The Abstracts (1 page A4, 2500 characters -spaces non included-, Times New Roman, size 12 p) should be sent by December 20th at the latest by email to Prof. Jacques Bonnet.
We kindly ask you to confirm your participation by sending us the enclosed registration form by email to Prof. Jacques Bonnet .
The managing boards of the three atherosclerosis societies would highly appreciate your participation in this third Joint Meeting.
Don’t hesitate to contact us for any further queries.
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- D r J-F Arnal, P r J Bonnet
| President | Secretary | International Relationship |
|---|---|---|
| Prof Jacques Bonnet University Victor Segalen Bordeaux 2 Hôpital Cardiologique du Haut Lévêque Avenue du Magellan 33600 Pessac Phone : +33 5 57 65 64 90 Fax +33 5 57 65 60 30 |
Marie Françoise Rivière 13, avenue des Arts 94100 Saint-Maur Phone : +33 1 42 83 96 63 Fax : +33 1 42 83 97 01 |
Prof Gérard Siest Université Nancy Henri Poincaré Faculté de Pharmacie 30, rue Lionnois 54000 Nancy Phone : +33 3 83 68 21 70 Fax : +33 3 83 32 13 22 |
PROGRAM
Thursday, January 31, 2008
- 16h00 - 20h00 Registration
- 18h00 - 20h00 Poster session
Chair : Bart Staels, Lille, France and (1german and 1 swiss scientist to be defined) - 19h00 – 21H00 Cocktail
Friday, February 1, 2008
- 9h00 - 12h00 : 1st Symposium : Lipid metabolism : New Targets for the Prevention of Atherosclerosis
Chair : Eric Bruckert (Paris, France), Regine Heller (Jena, Germany),
- Introduction
- 9h00 – 9H30 : Genetics of Hyperchylomicronemia , Philippe Moulin, Christophe Marçais (Lyon, France)
- 9h30 – 10H00 : CETP and PLTP : New targets for atherosclerosis prevention ? , Laurent Lagrost (Dijon, France)
- 10h00 – 10H30 : Genetic approach of atherosclerosis , Martin Hersberger (Zurich, Switzerland)
- 10h30 – 11H00 : Coffee Break
- 11h00 – 11H30 : Nuclear receptor and dyslipidemia , Bart Staels (Lille, France)
- 11h30 – 12H00 : The sphingosine-1-phosphate content of HDL as a novel diagnostic and therapeutic agent in atherosclerosis , Bodo Levkau , (Essen, Germany)
- 12h00 - 18h00 : Free Time
- 18h00 - 20h00 : 2 nd Symposium : New approaches in cardiovascular risk assessment
Chair : Gérard Siest (Nancy, France), Martin Hersberger , (Zurich, Switzerland)
- Introduction
- 18h00 – 18H30 : Coagulation polymorphisms in atherosclerosis , Pierre Morange (Marseille, France)
- 18h30 – 19H00 : Coagulation Factors and Atherosclerosis : New Players, New Territory , Prof. D r . Klaus T. Preissner (Giessen, Germany)
- 19h00 – 19H30 : Chemokines : inflammatory mediators of atherosclerosis , Prof. D r . med. Christian Weber (Aachen, Germany)
- 19h30 – 20H00 : Red wine polyphenolic compounds and endothelium physiopathology , Philippe Gambert (Dijon, France)
- 20h30 Gala Dinner : Restaurant “Le Sérac”
Saturday, February 2, 2008
- 9h00 - 12h00 : 3rd Symposium : Hypertension and dyslipidemia
Chair : Arnold Von Eckardstein (Zurich, Switzerland), Jacques Bonnet (Bordeaux, France)- Introduction
- 9h00 – 9H15 : Cell-derived microparticles as vectors of proteolytic activity : relevance in vascular risk , Eduardo Anglès-Cano (Caen, France)
- 8h15 - 9h30 : Regulation and function of AMP-activated kinase in endothelials cells , Regine Heller , (Jean, Germany)
- 9h30 – 10H00 : The ADVANCE study : a randomized controlled trial that could modify the care to type 2 diabetic patients , Samy Hadjadj (Poitiers, France)
- 10h00 – 10H30 : Type 2 Diabetes, the Metabolic Syndrom, and Cardiovascular Risk in Angiographied Coronary Patients , Christoph Saely , (Feldkirch, Austria)
- 10h30 – 11H00 : Coffee Break
- 11h00 – 11H30 : Implications of the torcetrapib failure for the future of HDL therpy , Arnold Von Eckardstein , (Zurich, Switzerland)
- 11h30 – 11H45 : No effect of C-reactive protein on early atherosclerosis in LDL-R-/-/human C-reactive protein transgenic mice , Karl Lackner , (Mainz, Germany)
- 11h45 – 12h00 : New forms of Autosomal Dominant Hypercholesterolemia , Mathilde Varret , (Paris, France)
- 12H00 : End of the Congress
GENERAL INFORMATION
Arrival
By car
Saint-Gervais-les-Bains can be reached by A40 high way from Geneva or from Macon. From Lyon, take the A41 and join A40.
Saint-Gervais-les-Bains can be reached by A40 high way from Geneva or from Macon. From Lyon, take the A41 and join A40.
By train
From Paris
We advise to take a fast train (TGV) from Gare de Lyon to Bellegarde (direction to Geneva).
Departure : 11.10 A.M. and 1.10 P.M. The travel takes approximately 3h.
The buses will pick up the participants at the Bellegarde railway station at 2.20 and 4.20 P.M. The trip to Saint Gervais takes approximately 1h30 min. Please, do not forget to notify in the registration form if you intend to take the bus.
Trains to Saint-Gervais railway station (Le Fayet) are also available. At Saint-Gervais - Le Fayet, take a taxi (approximately 20 €) or a public bus (Societe Alpes Transports, Phone : +33 4 50 78 05 33).
Reduction coupon is available at the secretariat of the NSFA.
By plane
Geneva International Airport
The buses will pick up the participants at 2 and 4 PM. Please, do not forget to notify in the registration form if you intend to take the bus.
Otherwise, you may use public transportation (information and ticket booking on www.altibus.com ).
Air France is the official carrier of this event.
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Valid for travel from 25/01/2008 to 08/02/2008
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Siège social : 45 rue de Paris, F95704 Roissy Charles de Gaulle cedex, France
FREE TIME
On Friday, February 1, the scientific session will stop at noon and start again at 6 PM.
The lunch tickets will be provided at registration. All other expenses are at the own charge of participants.
| On the slope www.st-gervais.net welcome@st-gervais.net Downhill ski, cross-country ski, snowshoes, snowboard |
In the village www.st-gervais.net Lunch : Restaurants in the village. Balneothermal therapy : A visit to the Mountain balneothermal therapy and Beauty Institute : Relaxing bath Body sculpting (under thermal water or with oils) Sauna / Hammam Price : 67,50 €/pers. Approximately 2 h Inscription is necessary Transportation : The bus will leave at 2 PM from espace Montblanc . Return to the village at 4.30 PM. Tramway de Montblanc (TBM) : A ride to the Prarion station located at the altitude of 1850 m. Inscription is necessary Transportation : The bus will leave at 2 PM from espace Montblanc . |
| 18H Congrès : Espace Mont-Blanc | 18H Congrès : Espace Mont-Blanc |
ABSTRACTS
| Jean-Francois Arnal and Pierre Gourdy |
| INSERM U858, CHU Rangueil, Toulouse, France |
| Whereas hormone therapy may increase the risk of coronary heurt disease and stroke in menopausal women, epidemiological studies (protection in premenopausal women) suggest and experimental studies (prevention of fatty streak development in animals) demonstrate a major atheroprotective action of estradiol. There is also evidence for a thrombogenic effect of oral estrogens. An understanding of the deleterious and beneficial effects of estrogens is thus required. The immuno-inflammatory system plays a key role in the development of fatty streak deposit as well as in the rupture of the atherosclerotic plaque. Whereas estradiol favors an anti-inflammatory effect in vitro (cultured cells), it rather elicits a pro-inflammatory response in vivo involving several subpopulations of the immuno-inflammatory system, which could contribute to plaque destabilization. Endothelium is another important target for estrogens, since estradiol potentiates endothelial nitric oxide and prostacyclin production. The respective actions of estrogens on these cell populations may be influenced by the timing of hormonal therapy initiation, hormone regimens, status of the vessel wall and expression of isoforms of estrogen receptors a and b. A better understanding of the balance between the deleterious and beneficial effects of estrogens is required and should help to improve hormonal therapy safety and to optimize the prevention of cardiovascular disease after menopause. |
| Mathias Burgmaier, Daniel Walcher, Mirjam Ostertag, Helga Bach, Renate Durst, Angelina Hausauer, Vinzenz Hombach, Nikolaus Marx |
| Ulm, Germany |
| Di-peptidyl-peptidase IV inhibitors, which increase glucagon like peptide -1 (GLP-1) blood levels, and GLP-1 receptor agonists have recently become available for the treatment of patients with diabetes mellitus, a high-risk population for the development of diffuse and severe arteriosclerosis. However, it is still unknown whether GLP-1 also has a beneficial effect on atherogenesis. We tested the hypothesis that GLP-1 inhibits chemokine-induced migration of human CD4-positive lymphocytes as an early and critical step in lesion development. The expression of GLP-1 receptor protein was confirmed in human CD4-positive lymphocytes both by western blot analysis of total cell lysates and by immunohistochemical staining of human arteriosclerotic endarterectomy specimen. In-vitro, SDF-1 treatment significantly induced the migration of human CD4-positive lymphocytes by 4.1±3.1 fold (p<0.01 ; n=22) and pretreatment of cells with GLP-1 reduced this effect in a concentration-dependent manner to a 1.6±0.7 fold induction at 1 nmol/L GLP-1 (p<0.01 compared with SDF-1 treated cells ; n=22). Similar effects were obtained when RANTES was used as a stimulus to induce migration. However, GLP-1 had no effect on either cell viability or the expression of the chemokine receptors, as determined by trypan-blue staining and flow cytometry, respectively. A PI-3 kinase activity assay revealed that the effect of GLP-1 on cell migration is mediated by an inhibition of the chemokine-induced PI-3 kinase activity. Further downstream, pretreatment of human CD4-positive lymphocytes with GLP-1 showed in human CD4-positive lymphocytes a significant decrease in SDF-1-induced f-actin formation and ICAM3 translocation. Therefore, human CD4-positive lymphocytes express the GLP-1 receptor and treatment of these cells with GLP-1 inhibits their chemokine-induced migration which is mediated by an inhibition of the PI-3 kinase pathway. These data suggest a novel mechanism how GLP- 1 may modulate vascular disease in patients with type 2 diabetes. |
| Annika Carlsson, PhD. |
| Mercodia AB, Sweden |
| Oxidized low-density lipoprotein (LDL) has gained large interest since the discovery of its association with cardiovascular diseases. In contrast to unmodified LDL, oxidized LDL is shown to be atherogenic and directly involved in the initiation and progression of the atherosclerotic disease process. Atherosclerosis is considered to be an inflammatory disease that may lead to subsequent cardiovascular events. During inflammation a variety of cells produce inflammatory mediators like oxidants as a defense against disease-causing substances. These oxidants may react with lipids of the LDL particle. Formed lipid hydroperoxides then fragment into reactive aldehydes that may substitute lysine residues in the Apolipoprotein B-100 protein part of the LDL particle to generate oxidized LDL. There are different methods described of measuring oxidized LDL, varying in the target antigen. The only method that has been shown to be predictive for future cardiovascular events is the ELISA method based on the murine monoclonal antibody 4E6, specific for oxidatively modified Apolipoprotein B-100 of the LDL particle in human serum or plasma samples. |
| Giovanna CATALAN0¹ ², Emilie DUCHENE¹ ² ³, Zélie JULIA¹ ², Wilfried LE GOFF¹ ² Eric BRUCKERT³, M John CHAPMAN¹ ² and Maryse GUERIN¹ ² |
| ¹INSERM U551, Dyslipoproteinemia and Atherosclerosis, Paris, France ; ²Université Pierre et Marie Curie-Paris 6, UMR S551, Paris, France ; ³Department of Endocrinology, Hopital de la Pitié-Salpêtrière, Paris, France |
| We evaluated the impact of gender differences in both the quantitative and qualitative features of HDL subspecies on cellular free cholesterol (FC) efflux through the SR-BI, ABCA1 or ABCG1 pathways. For that purpose, healthy subjects (30 men and 26 women) matched for age, BMI, triglyceride, apoAl and HDL-cholesterol levels were recruited. We observed a significant elevation (+14% ; p<0.03) in the capacity of whole sera from women to mediate cellular FC efflux via the SR-BI-dependent pathway as compared to sera from men. Such enhanced efflux capacity resulted from significant elevation in plasma levels of large CE-rich HDL2 particles (+20% ; p<0.04), as well as from an enhanced capacity (+14% ; p<0.03) of these particles to mediate cellular FC efflux via SR-BI. By contrast, plasma from men displayed an enhanced FC efflux capacity (+31% ; p<0.001) via the ABCA1 transporter pathway as compared to that from women which result from a 2.4-fold increase in plasma level of pre-β particles (p<0.008). Moreover in women, SR-BI-mediated cellular FC efflux was significantly correlated with plasma HDL-C (r=0.72 ; p<0.0001), whereas this relationship was not observed in men. In conclusion, HDL-C level may not represent the absolute indicator of the efficiency of the initial step of the reverse cholesterol transport. |
| R. Elkaïm¹, M. Dahan², L. Kocgozlu³, S. Werner³, D. Kanter², J. G. Kretz³, H. Tenenbaum² ³ |
| ¹ Parogène, Strasbourg, ² Department of Periodontology, Dental Faculty, University Louis Pasteur, Strasbourg, ³ERT 10-61, interne à l’Unité INSERM U 595, Strasbourg of Vascular Surgery, University Louis Pasteur, Strasbourg, France |
| Objectives : Previous studies have reported different periodontal bacteria in atherosclerotic lesions, but their involvement in plaque formation remains unclear. The aim of the present study was to investigate the presence of 20 periodontal bacteria in atherosclerotic samples and healthy blood vessels (used as controls) and to clarify their relationship in regard to clinical and bacteriological periodontal status. Material and Methods : The day before vascular surgery the patients had a thorough periodontal examination and bacteriological samples were taken from periodontally diseased sites. Atheromatous plaques, internal mammary arteries and saphenous veins were harvested during surgery. A DNA-DNA hybridisation procedure was used to screen periodontal and vascular samples for the 20 selected bacterial species. Results : Periodontal samples from the severe periodontitis group were found to have a higher prevalence and biomass of bacterial species than the moderate periodontitis group. In vessel samples, the prevalence of the same 20 bacterial species analyzed together was similar in the two groups, except for saphenous veins. Conclusion : The presence of periodontal pathogens in atherosclerotic plaques and in apparently healthy vessels appeared to reflect a higher level of bacteremia rather than infection of endothelial cells. |
| Miguel Frias, Richard James, Christine Gerber-Wicht, Ursula Lang |
| Division of Endocrinology, Diabetology and Nutrition, University Hospital, Geneva, Switzerland |
| Objective : High-density lipoprotein (HDL) has been reported to have cardioprotective properties independent from its cholesterol transport activity. We have investigated modulating the composition of reconstituted HDL (rHDL) as a means of expanding its cardioprotective effects. The influence of rHDL and native HDL on Stat3, the transcription factor playing an important role in myocardium adaptation to stress, was analyzed in ventricular cardiomyocytes. Methods and Results : In neonatal rat ventricular cardiomyocytes, Stat3 activation and phosphorylation were determined by electrophoretic mobility shift assay and Western blots. HDL induces a concentration- and time-dependent increase in Stat3 activation. It also enhances extracellular signal regulated kinases (ERK1/2) and p38 MAP kinase (MAPK) phosphorylation. The ERK1/2 inhibitor U0126 abolishes HDL-induced Stat3 activation whereas the p38 MAPK blocker SB203580 bas no significant effect. The HDL constituent sphingosine-1-phosphate (S1P) and rHDL containing S1P have a similar strong stimulatory action on Stat3, ERK1/2 and p38 MAPK as native HDL. S1P-free rHDL has a much weaker effect. Experiments with agonists and antagonists of SI P receptor subtypes indicate that HDL and S 1 P activate Stat3 mainly through the S 1 P2 receptor. Conclusion : In ventricular cardiomyocytes, addition of S1P to rHDL enhances its therapeutic potential by improving its capacity to activate Stat3. Activation of Stat3 occurs mainly through S1P2 and requires stimulation of ERK1/2 but not p38 MAPK. The study underlines the therapeutic potential of tailoring rHDL to confront particular clinical situations. |
| A Fougerat¹, S Gayral¹, P Gourdy², A Schambourg², JF Arnal², MP Wymann³, M Douillon¹, M Laffargue¹ |
| ¹INSERM U563, CHU Purpan, Toulouse, France ; ²INSERM U589, CHU Rangueil, Toulouse, France ; ³ University of Basel, Switzerland |
| The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase γ(PI3Kγ) is thought to be a key player in various inflammatory, autoimmune and allergic processes. These properties as well as the expression of PI3Kγ in cardiovascular system suggest that PI3Kγ plays a role in atherosclerosis. Our results demonstrate that a specific PI3Kγ inhibitor, AS605240 (Merck-Serono), is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg kg -1 daily) significantly decreased early atherosclerotic lesions in apolipoprotein E-deficient (ApoE -/- ) mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor-deficient (LDLR -/- ) mice on atherogenic diet. Furthermore, PI3Kγ levels were elevated in both human and mouse atherosclerotic lesions especially in macrophage and T lymphocyte rich regions suggesting that immune PI3Kγ could be responsible for the pharmacological effects observed. Comparison of LDLR -/- mice transplanted with wild type or PI3Kγ-deficient bone marrow demonstrated that functional PI3Kγ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting PI3Kγ activity was accompanied by decreased macrophage and T cell infiltration as well as increased plaque stabilization. These data identify PI3Kγ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation such as fatty streak constitution, cellular composition and final fibrous cap establishment. |
| Philipp Heinz, Daniel Walcher, Katharina Heß, Kerstin Petscher, Dusica Vasic, Ulrich Kintscher, Markus Clemenz, Martin Hartge, Katrin Raps, Vinzenz Hombach, Nikolaus Marx |
| Ulm, Germany |
| Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin-Il type 1 receptor (AT1R) blocker with PPARγ-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARγ in this context. CD4-positive lymphocytes express both, the AT1R as well as PPARγ. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 4.5±3.4 fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner (from 4.5±3.4 to a 1.8±1.2 fold induction at 10 µmol/L Telmisartan ; p<0.05 compared to SDF-1-treated cells, n=17). In addition, telmisartan also reduced RANTES-induced cell migration, suggesting an effect independent of the chemotactic stimulus employed. Moreover, three différent PPARγ activators, rosiglitazone, pioglitazone, as well as GW 1929 had similar effects, while eprosartan, a non-PPARγ-activating AT1R blocker did not affect chemokine-induced lymphocyte migration. Telmisartan’s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, telmisartan inhibited f-actin formation as well as ICAM3 translocation. Blockade of the AT1R by high concentrations of eprosartan did not alter the effect of telmisartan on cell migration, while transfection of CD4-positive lymphocytes with PPARγ siRNA abolished telmisartan’s effect, suggesting that telmisartan acts via PPARγ. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARγ. These data provide a novel mechanism how telmisartan modulates lymphocyte activation by its PPARγ-activating properties. |
| Petra Keul, Susann Lucke, Karin von Wnuck Lipinski, Gerd Heusch, Bodo Levkau |
| Institute of Pathophysiology, Universitätsklinikum Essen, University of Duisburg-Essen |
| Objective- Sphingosine-l-phosphate (S1P) is a biologically active sphingolipid that regulates a multitude of physiological processes such as immunity, angiogenesis, regulation of vascular tone, inflammation and cardioprotection. SI P mediates its effects through engagement of its 5 cognate G protein-coupled receptors S1P Methods and Results- Atherosclerotic lesion formation and composition was examined in 12 male ApoE -/- // S1P 3 -/- and 10 ApoE -/- mice fed a normal chow diet for 45 weeks. The brachiocephalic artery (BCA) was serially sectioned according to the method of Cavalieri, and lesion volume and composition were determined. While there was no différence in plaque volume, macrophage content in the lesion was reduced by 76.1 % in ApoE -/- // S1P 3 -/- vs. ApoE -/- mice (6.6± 1.1 % vs. 27.3±2.7%, p< 0.001). In contrast, lesional smooth muscle cell (SMC) content was increased by 74.4% in ApoE -/- // S1P 3 -/- vs. ApoE-/- mice (7.3±1.0% vs. 4.2±0.6%, p<0.01). Collagen content was not altered. Serum lipid levels and peripheral blood cell counts were similar. To test if macrophage recruitment to inflammation sites was impaired by S1P 3 deficiency, we used a model of sterile peritonitis caused by the irritant thioglycolate. Four days after injection, there was a dramatic decrease in macrophage cell counts in the peritoneum by 82.6% in S1P 3 -/- mice vs. C57BL/6 controls (2.2±1.3 vs. 12.4±2.3*10 6 per cavity, p<0.001). In addition, the inflammatory cytokine mRNA expression profile of the S1P 3 -deficient peritoneal macrophages was strongly altered : MCP-1 and TNFα gene expression were downregulated by 67% and 75%, respectively, while IFNγ gene expression was upregulated by 329%. No changes were observed in the expression of CCR-2, IL-1a, IL-6, IL-10, MIP-1α, MIP-1β, and GM-CSF. Conclusions- The S1P3 receptor plays a major role in the recruitment of monocyte/macrophages to inflammation sites and atherosclerotic lesions by altering macrophage cytokine expression. |
| Krämer BF, Seizer P, Gawaz M, Lindemann S |
| Medizinische Klinik, Abteilung Kardiologie und Kreislauferkrankungen Eberhard. Karls -Universität Tübingen, Germany |
| Background : So far, a platelet that was adherent to fibrinogen was regarded a static cell without further movements. Movement of adherent platelets was not discussed by the scientific audience so far. Methods and Results : 2-dimensional gel-electrophoresis of platelets revealed that fibrinogen-adherent platelets synthesize or modify multiple proteins. Most of these proteins include cytoskeletal proteins and proteins of the migration apparatus. We concluded that platelet might be able to migrate on a surface platelets are able to adhere to. To demonstrate platelet migration platelets were adhered to a fibrinogen-coated coverslip and exposed to a continuous flow under high shear rates that are usual for the arterial vascular system. All non-adherent platelets were removed from the experiment. Inside the dense layer of platelets some of these platelets started to migrate through the whole slide. These platelets were still tightly adherent, otherwise they would have been swept away by the continuous flow. We found, that these migrating platelets underwent cytoskeletal rearrangement and formed pseudopodia. These platelets migrate towards a cytokine concentration gradient. To prove this hypothesis we developed a SDF-1 (stromal cell derived factor-1 ; 10µg/ml) source that constantly released SDF-1 and thereby generated a gradient. Platelets were adhered to the coverslip around the SDF-1 source. After a few minutes of incubation, about 30% of these firm adherent platelets started to move towards the SDF-1 source. They formed pseudopodia into the direction of migration. The platelets were actively migrating for several hours in this in¬vitro setting. When the SDF-1 source was removed, platelets migrated without a specific direction. Without a SDF-1 source, pseudopodia formation was distributed uniformely around the platelet surface without polarization of the celL Also, with SDF-1 present but blockade of the CXCR4 receptor, which is the specific receptor for SDF-1, platelet migration followed the same pattern like without the SDF-1 gradient. Conclusion : Platelets that adhere to fibrinogen are not irreversibly fixed on their surface. They are able to move into a specific direction that is given by a SDF-1 source. By this mechanism, platelets might be able to migrate into a platelet clot to further stabilize the hemostatic plug. . Moreover, they might be able. SDF-1 and platelet migration might be a physiological mechanism to cover arterial lesions and further play a role in the recruitment of platelets to the site of vascular lesions or inflammation. |
| Peter Seizer, Moritz Schött, Björn Krâmer, Harald Langer, Boris Bigalke, Meinrad Gawaz, Andreas E. May |
| Medizinische Klinik III, Klinikum der Eberhard Karls-Universität Tübingen, Germany |
| Foam cell-derived matrix metalloproteinases (MMPs) such as MMP-9 and MT1-MMP are thought to induce plaque rupture. However, the key mechanism of MMP regulation within the plaque has not been clarified, yet. By using a novel model of foam cell formation from CD34-positive cells and platelets, we have studied EMMPRIN expression during foam cell differentiation and its functional relevance. Methods and Results : Human CD34 + -progenitor cells were freshly derived from umbilical veins and were coincubated with platelets (2x10 8 /ml) for 12 days resulting in large, lipid-loaden CD68 positive foam cells as confirmed by immunocytochemistry, flow cytometry and confocal and electron microscopy. While CD34 + -cells did not express EMMPRIN or MT1-MMP, foam cells strongly expressed EMMPRIN on the cell surface [flow cytometry, immunocytochemistry]. While EMMPRIN expression was associated with strong MT1-MMP expression [flow cytometry] and with MMP-9 secretion (SDS-Page gelatin zymography), gene silencing of EMMPRIN by small interfering RNA (siRNA) prohibited the expression of MT1-MMP and of MMP-9 during the differentiationprocess. Notably, control-siRNA had no effect on MT1-MMP or MMP-9, and MMP-2 was not affected during cell differentiation and by EMMPRIN gene silencing. Comparable results were obtained using monocyte-derived foam cells. Furthermore we could show that EMMPRIN regulated MMPs are functional relevant for migration of monocytes derived foam cells through « matrigel » and that EMMPRIN is involved in cytokine release of foam cells. Moreover we can show by immunofluorescence microscopy that activation of EMMPRIN involves NF-kappa-B. Conclusion : CD34 + -progenitor cells differentiate into foam cells upon coincubation with platelets. During this différentiation process, EMMPRIN becomes expressed on the cells surface and is required for MMP-9 secretion and MT1-MMP expression. EMMPRIN thus represents a promising target to modify foam cell activity and te, prevent plaque rupture. |
| Dusica Vasic¹, Christina Babiak¹, Paulina Poletek¹, Stephan Rosenkranz², Helga Bach¹, Susanne Betz¹, Renate Durst¹, Miriam Grüb¹, Nikolaus Marx¹, Daniel Walcher¹ |
| ¹ Department of Internal Medicine II, Cardiology, University of Ulm Medical Center, Germany ; ² Department of Internal Medicine III, University of Cologne, Germany |
| Background - Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus and recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (SMCs) prolifération and evaluated intracellular signaling pathways involved. Methods and Results - Stimulation of human or rat SMCs with C-peptide induced cell prolifération in a concentration-dependent manner with a maximal 2.6±0.8 fold induction at 10 nmol/L human C-peptide (p<0.05 compared with unstimulated cells ; n=9) and a 1.8±0.2 fold induction at 0.5 nmol/L rat C-peptide (p<0.05 compared with unstimulated cells ; n=7), respectively, as shown by [H3] thymidin incorporation. Similar mitogenic action of C-peptide was shown by KI-67 immunoflourescence staining. The proliferative effect of C-peptide on SMCs was inhibited by PP2, an inhibitor of scr-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide-induced SMC prolifération. In addition, PP2 and LY294002 inhibited ERK1/2 phosphorylation. Conclusions - Our results demonstrate that C-peptide induces SMC prolifération through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus. |
| A. Zerrad Saadi, P. Thérond, M. Couturier, S. Chantepie. M.J. Chapman and A. Kontush |
| INSERM Unit 551, UPMC-Paris 6, Hôpital de la Pitié, Paris, France |
| Plasma levels of HDL cholesterol are inversely correlated with cardiovascular risk. HDL possess multiple anti-atherogenic properties, including capacity to protect LDL from oxidative stress. HDL particles are highly heterogeneous with five major subfractions, HDL2b, 2a, 3a, 3b and 3c, which differ in physico-chemical properties and biological activity ; small HDL3c possess potent antioxidative activity which is impaired in dyslipidemic subjects with insulin resistance at high cardiovascular risk, as occurs in Type 2 diatetes. HDL transport several proteins and enzymes possessing antioxidative activity, including apolipoprotein A-I (apo A-I), lecithin:cholesterol acyltransferase (LCAT) and platelet-activating factor-acetyl hydrolase (PAF-AH). ApoA-I can reduce lipid hydroperoxides (LOOH) to corresponding redox-inactive hydroxides, whereas LCAT and PAF-AH are implicated in the hydrolysis of oxidised phospholipids by HDL. Importantly, apo A-I, LCAT and PAF-AH are specifically enriched in small, dense HDL3. It remains however indeterminate as to how individual HDL components might function in a concerted manner to protect LDL from oxidation. We evaluated molecular mechanisms implicated in the HDL-mediated protection of LDL from oxidative stress using density gradient ultracentrifugal fractionation and HPLC. Our experimental strategy involved isolation of large, light HDL2 and small, dense HDL3 from normolipidemic donors, oxidation of LDL+HDL2 vs LDL+HDL3 mixtures and reisolation of LDL, HDL2 and HDL3. LDL oxidation was induced by a low flux of aqueous free radicals (AAPH). Accumulation of phosphatidylcholine (PC) and cholesteryl ester (CE) hydroperoxides (PCOOH and CEOOH) and concomitant consumption of non-oxidised PC and CE was evaluated in LDL and HDL by HPLC with chemiluminescent and UV detection. Measurements of CEOOH and PCOOH revealed a decrease in hydroperoxide formation in the presence of HDL2b+2a and HDL3b+3c at the end of the lag and the propagation phases of oxidation (T1 and T2 respectively) as compared to LDL alone. This reduction was more pronounced for PCOOH (-51% with HDL2b+2a and -55% with HDL3b+3c at T2) as compared to CEOOH. In LDL re-isolated from LDL+HDL mixtures, we observed diminished content of LOOH as compared to LDL oxidised alone. This effect was more pronounced at T2 (-51% in the presence of HDL2b+2a and -73% in the presence of HDL3b+3c) than at TL In parallel, the consumption of CE in the oxidised LDL was decreased up to -26% by HDL2 and up to -61% by HDL3. HDL re-isolated from LDL+HDL mixtures accumulated LOOH, particularly CEOOH. Such accumulation was more pronounced in HDL2b+2a than in HDL3b+3c. We conclude that the potent capacity of small dense HDL3 to reduce LDL oxidation is related to reduced LOOH accumulation in both LDL and HDL, potentially reflecting potent capacity of small HDL3 to inactivate LOOH, primarily in the form of PCOOH. A. Gerrad-Saadi gratefully acknowledges the award of a PhD fellowship by the NSFA . Keys words : LDL. HDL. Lipid hydroperoxide. Phosphatidylcholine. cholesteryl esters. |
| Bodo Levkau |
| Instiute of Pathophysiology, University of Duisburg-Essen, Germany |
| Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that plays a major role in a plethora of biological processes such as inflammation, immunity and angiogenesis. S1P is released from platelets, leukocytes, and endothelial cells into the plasma, where it is mainly associated with HDL. Over the last years, others and we have attributed several of the beneficial effects ascribed to HDL to the S1P content it carries. Such effects are nitric oxide-dependent vasodilation, angiogenesis, survival and protection against post-ischemic inflammatation during myocardial ischemia/reperfusion injury. S1 P signals via G protein-coupled receptors, named S1P 1 to S1P 5 . Their differential expression and function in vascular and hematopoetic cells imply them as attractive targets for the pharmacological therapy of atherosclerosis. Indeed, S1P analogues engaging several of the S1P receptors such as the immunomodulatory drug FTY720 were recently shown to prevent atherosclerosis in rodent models, making them functional HDL mimetics in vivo. In addition, by being responsible for part of the beneficial HDL effects, the S1P content of HDL may serve as a marker of the biological « quality » of HDL. |
| Klaus T Preissner |
| Depart. Biochemistry, Faculty of Medicine, Justus-Liebig-University, Giessen, Germany |
| Several studies have established a pathomechanistic link between (dsyregulated) haemostasis / blood coagulation and the development of atherosclerosis. This is truc for the early onset of this chronic disease and its progression, and is particularly valid in the acute attack phase following plaque rupture with subsequent occlusive thrombus formation. Thus, anti-platelet and anticoagulant treatments are well established in their benefit for the therapy of atherosclerosis. Our recent findings demonstrate that extracellular nucleic acids, derived from injured as well as from stimulated vascular cells, may serve as temporary template for promotion of tissue factor-dependent and contactphase-related coagulation. Différent serine proteases are activated in a nucleic acid-dependent manner, and due to cytokine-RNA interactions, various molecular relations between coagulation and atherosclerosis will be possible. These data are discussed in light of finding new therapeutic modalities for the therapy of atherosclerosis at différent stages of the disease. |
| Eduardo ANGLES-CANO |
| Inserm U919. Serine Proteases in Neurovascular Pathology. GIP Cyceron, Caen, France |
| Cell-derived microparticles (MP) are membrane microvesicles, 0.1-1 µm in size, shed by cells on activation or during apoptosis in a variety of pathological conditions. MPs of blood or endothelial cell origin display molecular signatures that allow their identification and functional characterization. In addition, cell-derived microparticles participate in the dissemination of biological activities : they provide tissue factor and a procoagulant phospholipids surface, they may also express various bioactive components derived from the parent cell (growth factors, membrane receptors, mRNA or transcription factors) that may influence the biology of target cells. We have recently shown (Blood 2007, 110 : 2432-2439) that MPs derived from cells that express plasminogen activators may generate, disseminate and transfer plasmin proteolytic activity. MP-bound plasmin is a powerful proteolytic enzyme that in cells is responsible for pericellular proteolysis (degradation of matrix and membrane proteins, activation of metalloproteinases and growth factors) and fibrinolysis if in contact with fibrin. In other words, cell-derived microparticles serve as a surface for the generation of plasmin, which is of critical importance in the control of vascular homeostasis including cell migration and angiogenesis. Preliminary results obtained in patients with vascular risk indicate that cell-derived microparticles are involved in plasmin generation in vivo and may therefore participate in the pathophysiology of thrombotic states. |
| N. Stahmann¹, A. Woods², D. Carling², R. Heller¹ |
| ¹Institute of Molecular Cell Biology, Friedrich-Schiller-University of Jena, Jena, Germany and ² Cellular Stress Group, MRC Clinical Science Centre, Imperial College, Hammersmith Hospital, London, United Kingdom |
| AMP-activated protein kinase (AMPK) has been shown to act as a sensor of cellular energy state and to be involved in the regulation of cellular homeostasis and signaling. AMPK has also been suggested to contribute to the activation of endothelial NO synthase (eNOS) via phosphorylation of its residue serine 1177. AMPK is controlled by upstream kinases which have recently been identified as LKB 1 or Ca ++ /calmodulin-dependent protein kinase kinase-β (CaMKKβ). The aim of this study was to investigate whether endothelial agonists such as thrombin or VEGF activate AMPK in human umbilical vein endothelial cells, to identify the underlying signaling pathways and to explore the role of AMPK in endothelial function. Thrombin (1 U/ml, 0.25 - 15 min) and VEGF (50 ng/ml, 0.5 - 30 min) led to a time-dependent AMPK activation which was measured in cell lysates by phosphorylation of the AMPK residue threonine 172 and in AMPKα1 immunoprecipitates by phosphorylation of a specific substrate peptide. AMPK activation by both stimuli was reduced by the phospholipase C inhibitor U-73122, the intracellular Ca ++ chelator BAPTA and the CaMKK inhibitor STO-609. Accordingly, downregulation of CaMKKbeta but not of LKB1 by RNA interference decreased thrombin- or VEGF-induced AMPK activation indicating that CaMKKβ was the responsible upstream kinase. Thrombin and VEGF led to phosphorylation of acetyl-CoA carboxylase (ACC), a downstream target of AMPK involved in the regulation of ATP supply. On the contrary, neither CaMKKβ- nor AMPKα1-downregulation by specific siRNAs nor CaMKK inhibition by STO-609 affected the thrombin or VEGF response on eNOS phosphorylation. Our data identify thrombin and VEGF as new stimuli for CaMKKβ-mediated AMPK activation. We propose that AMPK-mediated ACC phosphorylation is important to balance energy metabolism after cell stimulation and to provide ATP for energy-requiring processes. Our data do not support a role of AMPK in eNOS phosphorylation suggesting that AMPK affects angiogenic functions of endothelial cells independent of eNOS. |
| Michael Torzewski¹, Kurt Reifenberg², Fei Cheng¹, Elena Wiese², Ines Küpper², Jeanine Crain², Sucharit Bhakdi³ and Karl J. Lackner¹ |
| ¹Institute of Clinical Chemistry and Laboratory Medicine, ²Central Laboratory Animal Facility, ³lnstitute of Medical Microbiology and Hygiene, Johannes Gutenberg University Mainz, Mainz, Germany |
| The association between increased concentrations of C-reactive protein (CRP) and future cardiovascular events is well established. However, today it is unclear whether this clinical observation represents an epiphenomenon or whether the pentraxin may actively promote the development of atherosclerosis. Experimental studies with knockout mice with a defect in apolipoprotein E(ApoE -/- ) have been used to investigate the role of CRP in atherogenesis, but the results obtained have been contradictory so far. Since knockout mice with a defect in low density lipoprotein receptor (LDLR -/- ) may represent a better model of atherogenesis compared to ApoE -/- animals, we undertook experiments to investigate the atherogenic potential of CRP using LDLR -/- knockout mice. We crossbred CRP transgenic animals expressing the human CRP pentraxin (huCRP) to LDLR -/- mice, fed the resulting double mutants a pro-atherogenic Western type diet (WTD) for 4, 8 or 12 weeks, respectively, and quantitated atherosclerotic lesion development. Significant differences of lesion size or lesion composition could not detected between the huCRP-positive LDLR -/- mice and the huCRP-negative LDLR -/- controls corroborating the contention that CRP does not play a pathogenetic role in early murine atherogenesis. |
| Mathilde Varret, Marianne Abifadel, Jean-Pierre Rabès and Catherine Boileau |
| Paris, France |
| Autosomal Dominant Hypercholesterolemia (ADH) is characterized by isolated elevation of plasmatic LDL cholesterol associated with high risk of premature cardiovascular complications. Over 1000 mutations in the LDLR gene and 9 mutations in the APOB gene have been implicated. We have shown further heterogeneity with the discovery of missense mutations in the PCSK9 gene resulting in ADH. Différent studies have tried to evaluate the respective contribution of mutations in each gene to the disease. Numerous reports give evidence for the existence of a greater level of genetic heterogeneity in ADH, and the involvement of still unknown genes. We now report a large French ADH family in which involvement of these three genes was excluded and named the pathology HCHOLA4. Our aim is to identify the new disease gene and to define the associated pathophysiology. A whole-genome scan, using 232 polymorphic microsatellite markers, located the HCHOLA4 gene at 16q22.1. Functional candidate genes in the critical interval were tested by sequencing but no causal mutation was detected. In vivo kinetics of apolipoprotein B-100-containing lipoproteins, conducted in 2 affected members, mainly showed a decrease in LDL catabolism. Q-PCR analysis of LDLR expression in EBV-transformed lymphoblasts showed that cells of four affected subjects do not reply to cholesterol deprivation by activating LDLR expression contrary to controls in whom the expression rate increases 2-fold. These results suggest that this novel form of ADH is due to an alteration, direct or not, in LDL receptor endocytosis or intracellular traffic. Furthermore, we performed two-dimensional electrophoresis for cytosolic proteins from lymphoblasts and observed différent profiles for affected subjects when compared to non¬affected relatives. Mass spectrometry for eighty of the more significatively différent proteins is in process. We expect to identify one or more proteins for wich the coding gene is localized in the 16q22.1 interval of interest. Through the ADH French Research Network, we collected genetic material from a multiplex french pedigree (16 affected and 10 unaffected members). Linkage and/or sequencing analyses in the familly excluded the involvement of the LDLR, APOB, PCSK9 and HCHOLA4 genes. These results demonstrate the existence of a HCHOLA5 gene. The genomewide scan was realized with 10k affimetrix arrays in collaboration with the French National Genotyping Center. Linkage analyses, using parameters compatible with ADH, allowed us to identify a single locus (Merlin multipoint Lod Score = 3.29) in whish différent functional candidate genes are located. We are currently sequencing these genes in orfer to find the causative mutation. Identification of the HCHOLA4 and HCHOLA5 genes could reveal new aspects of cholesterol metabolism and may lead to the development of new potent drugs. |
POSTERS
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- Lauréates des prix poster
- D Vasic, A Fougerat, P Keul, G Catalano
Publié le 23 novembre 2007 par
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