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Pannexins and connexins in atherosclerosis and thrombosis

English title Pannexins and connexins in atherosclerosis and thrombosis
Applicant Kwak Brenda Renata
Number 162579
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Cardiovascular Research
Start/End 01.10.2015 - 30.11.2018
Approved amount 629'740.00
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Keywords (8)

atherosclerosis; thrombosis; intercellular communication; connexins; pannexins; gap junctions; endothelium; platelets

Lay Summary (French)

Lead
L’athérosclérose, la cause majeure de morbidité et de mortalité, est une pathologie inflammatoire affectant les artères de moyen à large calibre. Cette maladie implique la formation de lésions intimales provoquées par une dysfonction de l’endothélium vasculaire, l’inflammation, l’accumulation de lipides, la mort cellulaire et la fibrose. La localisation des plaques d’athérosclérose est très typique chez l’humain; ces lésions se développent de façon prédominante au niveau des branches artérielles où le flux sanguin est perturbé. La conséquence clinique la plus sévère de l’athérosclérose est l’occlusion artérielle induite par la rupture de la plaque et la formation d’un thrombus.
Lay summary

Contenu et objectifs du travail de recherche

Dans notre laboratoire, nous nous consacrons principalement à l’étude du rôle des connexines dans l’athérosclérose. Les connexines (Cx) sont des protéines transmembranaires qui s’associent en hémicanaux ou en canaux inter-cellulaires (jonctions communicantes) permettant la synchronisation des réponses inter-cellulaires via l’échange d’ions et de métabolites de petite taille. Nous avons précédemment montré chez la souris que la Cx43 joue un rôle pro-athérogénique alors que la Cx37, présente dans les macrophages, et la Cx40, exprimée dans l’endothélium, sont athéroprotectrices.

Au cours de la première partie de ce projet, nous étudierons le rôle potentiel des connexines dans la création de compartiments de communication endothéliales qui peuvent contribuer à la localisation de la lesion d’athérome. Dans la deuxième partie, nos recherches s’intéresseront à la Pannexine-1, une protéine structurellement liée à la famille des connexines et formant des canaux de libération d'ATP dans l'endothélium, les leucocytes et les plaquettes. Le rôle de cette protéine dans le développement de l'athérosclérose et la thrombose sera investigué.

Contexte scientifique et social du projet de recherche

Les investigations proposées devraient apporter des clarifications sur les mécanismes associés à l’infarctus du myocarde, aux AVC et à l’insuffisance artérielle périphérique, les principales conséquences cliniques de l'athérosclérose.

Direct link to Lay Summary Last update: 28.09.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Selective inhibition of Panx1 channels decreases hemostasis and thrombosis in vivo
Molica Filippo, Meens Merlijn J., Pelli Graziano, Hautefort Aurélie, Emre Yalin, Imhof Beat A., Fontana Pierre, Scemes Eliana, Morel Sandrine, Kwak Brenda R. (2019), Selective inhibition of Panx1 channels decreases hemostasis and thrombosis in vivo, in Thrombosis Research, 183, 56-62.
Consensus guidelines for the use and interpretation of angiogenesis assays
Nowak-Sliwinska Patrycja, Alitalo Kari, Allen Elizabeth, Anisimov Andrey, Aplin Alfred C., Auerbach Robert, Augustin Hellmut G., Bates David O., van Beijnum Judy R., Bender R. Hugh F., Bergers Gabriele, Bikfalvi Andreas, Bischoff Joyce, Böck Barbara C., Brooks Peter C., Bussolino Federico, Cakir Bertan, Carmeliet Peter, Castranova Daniel, Cimpean Anca M., Cleaver Ondine, Coukos George, Davis George E., De Palma Michele, et al. (2018), Consensus guidelines for the use and interpretation of angiogenesis assays, in Angiogenesis, 21(3), 425-532.
Connexins and Pannexins in Vascular Function and Disease
Molica Filippo, Figueroa Xavier, Kwak Brenda, Isakson Brant, Gibbins Jonathan (2018), Connexins and Pannexins in Vascular Function and Disease, in International Journal of Molecular Sciences, 19(6), 1663-1663.
Dendritic Cell Migration Toward CCL21 Gradient Requires Functional Cx43
Ruez Richard, Dubrot Juan, Zoso Alice, Bacchetta Marc, Molica Filippo, Hugues Stéphanie, Kwak Brenda R., Chanson Marc (2018), Dendritic Cell Migration Toward CCL21 Gradient Requires Functional Cx43, in Frontiers in Physiology, 9, 288.
Differential Association of Cx37 and Cx40 Genetic Variants in Atrial Fibrillation with and without Underlying Structural Heart Disease
Carballo Sebastian, Pfenniger Anna, Carballo David, Garin Nicolas, James Richard, Mach François, Shah Dipen, Kwak Brenda (2018), Differential Association of Cx37 and Cx40 Genetic Variants in Atrial Fibrillation with and without Underlying Structural Heart Disease, in International Journal of Molecular Sciences, 19(1), 295-295.
Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function.
Meens Merlijn J, Kutkut Issa, Rochemont Viviane, Dubrot Juan, Kaladji Fouad R, Sabine Amélie, Lyons Oliver, Hendrikx Stefanie, Bernier-Latmani Jeremiah, Kiefer Friedemann, Smith Alberto, Hugues Stéphanie, Petrova Tatiana V, Kwak Brenda R (2017), Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function., in PloS one, 12(7), 0181476-0181476.
Pannexin1 Single Nucleotide Polymorphism and Platelet Reactivity in a Cohort of Cardiovascular Patients.
Stierlin Florian B, Molica Filippo, Reny Jean-Luc, Kwak Brenda R, Fontana Pierre (2017), Pannexin1 Single Nucleotide Polymorphism and Platelet Reactivity in a Cohort of Cardiovascular Patients., in Cell communication & adhesion, 23(1), 11-15.
Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis
Molica Filippo, Meens Merlijn J., Dubrot Juan, Ehrlich Avigail, Roth Christel L., Morel Sandrine, Pelli Graziano, Vinet Laurent, Braunersreuther Vincent, Ratib Osman, Chanson Marc, Hugues Stephanie, Scemes Eliana, Kwak Brenda R. (2017), Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis, in Scientific Reports, 7(1), 13706-13706.
Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes
Ribeiro-Rodrigues Teresa M., Martins-Marques Tânia, Morel Sandrine, Kwak Brenda R., Girão Henrique (2017), Role of connexin 43 in different forms of intercellular communication – gap junctions, extracellular vesicles and tunnelling nanotubes, in Journal of Cell Science, 130(21), 3619-3630.
Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications.
Leybaert Luc, Lampe Paul D, Dhein Stefan, Kwak Brenda R, Ferdinandy Peter, Beyer Eric C, Laird Dale W, Naus Christian C, Green Colin R, Schulz Rainer (2017), Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications., in Pharmacological reviews, 69(4), 396-478.
Connexin40 controls endothelial activation by dampening NFκB activation.
Denis Jean-Francois, Scheckenbach K E Ludwig, Pfenniger Anna, Meens Merlijn J, Krams Rob, Miquerol Lucile, Taffet Steven, Chanson Marc, Delmar Mario, Kwak Brenda R (2017), Connexin40 controls endothelial activation by dampening NFκB activation., in Oncotarget, 8(31), 50972-50986.
Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function
Molica Filippo, Stierlin Florian, Fontana Pierre, Kwak Brenda (2017), Pannexin- and Connexin-Mediated Intercellular Communication in Platelet Function, in International Journal of Molecular Sciences, 18(4), 850-850.
Turbidimetry on Human Washed Platelets: The Effect of the Pannexin1-inhibitor Brilliant Blue FCF on Collagen-induced Aggregation
Molica Filippo, Nolli Séverine, Fontana Pierre, Kwak Brenda Renata (2017), Turbidimetry on Human Washed Platelets: The Effect of the Pannexin1-inhibitor Brilliant Blue FCF on Collagen-induced Aggregation, in Journal of Visualized Experiments, (122), e55525.
Atherosclerosis at arterial bifurcations: evidence for the role of haemodynamics and geometry.
Morbiducci Umberto, Kok Annette M, Kwak Brenda R, Stone Peter H, Steinman David A, Wentzel Jolanda J (2016), Atherosclerosis at arterial bifurcations: evidence for the role of haemodynamics and geometry., in Thrombosis and haemostasis, 115(3), 484-92.
Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone.
Kauffenstein Gilles, Tamareille Sophie, Prunier Fabrice, Roy Charlotte, Ayer Audrey, Toutain Bertrand, Billaud Marie, Isakson Brant E, Grimaud Linda, Loufrani Laurent, Rousseau Pascal, Abraham Pierre, Procaccio Vincent, Monyer Hannah, de Wit Cor, Boeynaems Jean-Marie, Robaye Bernard, Kwak Brenda R, Henrion Daniel (2016), Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone., in Arteriosclerosis, thrombosis, and vascular biology, 36(8), 1598-606.
Connexins and their channels in inflammation.
Willebrords Joost, Crespo Yanguas Sara, Maes Michaël, Decrock Elke, Wang Nan, Leybaert Luc, Kwak Brenda R, Green Colin R, Cogliati Bruno, Vinken Mathieu (2016), Connexins and their channels in inflammation., in Critical reviews in biochemistry and molecular biology, 1-27.
Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43.
Morel Sandrine, Christoffersen Christina, Axelsen Lene N, Montecucco Fabrizio, Rochemont Viviane, Frias Miguel A, Mach Francois, James Richard W, Naus Christian C, Chanson Marc, Lampe Paul D, Nielsen Morten S, Nielsen Lars B, Kwak Brenda R (2016), Sphingosine-1-phosphate reduces ischaemia-reperfusion injury by phosphorylating the gap junction protein Connexin43., in Cardiovascular research, 109(3), 385-96.
Novel methodologies for biomarker discovery in atherosclerosis.
Hoefer Imo E, Steffens Sabine, Ala-Korpela Mika, Bäck Magnus, Badimon Lina, Bochaton-Piallat Marie-Luce, Boulanger Chantal M, Caligiuri Giuseppina, Dimmeler Stefanie, Egido Jesus, Evans Paul C, Guzik Tomasz, Kwak Brenda R, Landmesser Ulf, Mayr Manuel, Monaco Claudia, Pasterkamp Gerard, Tuñón Jose, Weber Christian, Weber Christian (2015), Novel methodologies for biomarker discovery in atherosclerosis., in European heart journal, 36(39), 2635-42.
Shear stress-induced atherosclerotic plaque composition in ApoE(-/-) mice is modulated by connexin37.
Pfenniger A, Meens M J, Pedrigi R M, Foglia B, Sutter E, Pelli G, Rochemont V, Petrova T V, Krams R, Kwak B R (2015), Shear stress-induced atherosclerotic plaque composition in ApoE(-/-) mice is modulated by connexin37., in Atherosclerosis, 243(1), 1-10.

Collaboration

Group / person Country
Types of collaboration
Prof. Beerend Hierck - Leiden University Medical Center - Leiden Netherlands (Europe)
- Publication
Prof. Eliana Scemes - Albert Einstein College of Medicine - Bronx, New York United States of America (North America)
- Publication
Prof. Marc Chanson - Pediatrics - University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Pierre Fontana - Angiology - University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Joint Dutch German Vascular Biology Meeting Poster KLF4-induced connexin40 expression contributes to arterial endothelial quiescence. 21.11.2018 Amsterdam, Netherlands Kwak Brenda Renata;
Chapîtres Choisis, Faculty of Medicine, University of Geneva Individual talk Go with the flow – Connexins in atherosclerosis 31.05.2018 Geneva, Switzerland Kwak Brenda Renata;
Frontiers in Cardiovascular Biology 2018 Poster Pannexin1 promotes hemostasis and thrombosis by warranting platelet function. 20.04.2018 Vienna, Austria Molica Filippo;
Frontiers in Cardiovascular Biology 2018 Talk given at a conference Shear stress, connexins and atherosclerosis. 20.04.2018 Vienna, Austria Kwak Brenda Renata;
Cardiovascular Research Meeting 2018 Talk given at a conference Pannexin1 promotes hemostasis and thrombosis by warranting platelet function. 15.03.2018 Fribourg, Switzerland Molica Filippo;
That’s all Talks! Advanced Course on Intercellular Communication Talk given at a conference Pannexin1-dependent signaling in platelet aggregation and thrombosis / Diverse roles of connexins in cardiovascular disease. 13.12.2017 Coimbra, Portugal Kwak Brenda Renata;
6th iGE3 Annual Meeting Talk given at a conference Connecting hemodynamics to atherosclerosis. 07.11.2017 Geneva, Switzerland Kwak Brenda Renata;
18th Congrès de l’Union des Sociétés Suisses des Maladies Vasculaires Talk given at a conference Connecting hemodynamics to atherosclerosis. 01.11.2017 Montreux, Switzerland Kwak Brenda Renata;
18th Congrès de l’Union des Sociétés Suisses des Maladies Vasculaires Poster Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis. 01.11.2017 Montreux, Switzerland Molica Filippo;
NCCR TransCure Symposium on Membrane Transporters & Cancer Talk given at a conference Career within academia: from communication to syncytium. 04.10.2017 Bern, Switzerland Kwak Brenda Renata;
International Gap Junction Conference 2017 Poster Cx47 fine-tunes the handling of serum lipids but is dispensable for lymphatic vascular function. 29.07.2017 Glasgow, Great Britain and Northern Ireland Meens Merlijn;
International Gap Junction Conference 2017 Talk given at a conference Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis. 29.07.2017 Glasgow, Great Britain and Northern Ireland Molica Filippo;
ESM-EVBO 2017 Poster Shear Stress-Induced Expression of the Atheroprotective Transcription Factor KLF4 Regulates Cx40 Expression in Endothelial Cells 29.05.2017 Geneva, Switzerland Denis Jean-François;
International Neurovascular Exploratory Workshop on Aneurysm Stability (iNEW) Talk given at a conference Connexin40 controls endothelial activation by dampening NFkB activation. 15.02.2017 Zurich, Switzerland Kwak Brenda Renata;
Cardiovascular & Metabolic Research Meeting 2017 Poster Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis 19.01.2017 Fribourg, Switzerland Molica Filippo;
Cardiovascular & Metabolic Research Meeting 2017 Talk given at a conference Connexins in atherosclerosis – going with the flow. 19.01.2017 Fribourg, Switzerland Kwak Brenda Renata;
American Heart Association Scientific Sessions 2016 Poster Regulation of lymphatic physiology by connexin47 12.11.2016 New Orleans, United States of America Meens Merlijn;
Science Xpression 2016 Talk given at a conference Connexins in vascular disease. 29.09.2016 A Coruna, Spain Kwak Brenda Renata;
Science Xpression 2016 Talk given at a conference Role of Panx1 in atherothrombosis. 29.09.2016 A Coruna, Spain Molica Filippo;
CRC1123 Seminar Series, Ludwig Maximilians University Individual talk Connexins, shear stress-induced communication compartments and atherosclerosis. 26.09.2016 Munich, Germany Kwak Brenda Renata;
Gap Junction Summer Meeting Talk given at a conference Cx43 blocking peptides and restenosis. 25.08.2016 Copenhagen, Denmark Kwak Brenda Renata;
Frontiers in Cardiovascular Biology 2016 Poster Role of pannexin1 in atherosclerotic plaque formation. 08.07.2016 Firenza, Italy Molica Filippo;
11th international symposium on biomechanics in vascular biology and cardiovascular disease. Poster Connexin40 controls endothelial activation by dampening nuclear translocation of NFκB. 02.05.2016 Atlanta, United States of America Denis Jean-François;
Printemps de la Cardiologie. Poster Connexin40 controls endothelial activation by dampening NFκB activation 07.04.2016 Dijon, France Denis Jean-François;
Workshop on the interface between connexin/pannexin biology and therapeutics Talk given at a conference Cx40, shear stress-induced endothelial communication compartments and atherosclerosis 03.03.2016 Paris, France Kwak Brenda Renata;
ACB Seminar, University of Western Ontario Individual talk Connexins, shear stress-induced communication compartments and atherosclerosis. 19.02.2016 London, Canada Kwak Brenda Renata;
LS2 Annual meeting Talk given at a conference Connexin40 controls endothelial activation by dampening nuclear translocation of NFκB. 15.02.2016 Lausanne, Switzerland Denis Jean-François;
Cardiovascular & Metabolic Research Meeting 2016 Talk given at a conference Role of Panx1 in atherosclerotic plaque formation. 14.01.2016 Fribourg, Switzerland Molica Filippo;
VII Annual Meeting of IBILI: New trends in Biomedical Research Talk given at a conference Connexins, shear stress-induced communication compartments and atherosclerosis. 03.12.2015 Coimbra, Portugal Kwak Brenda Renata;
Eurothrombosis Summit 2015 Poster A polymorphism in the Pannexin1 gene specifically affects collagen-induced platelet aggregation 01.10.2015 Como, Italy Molica Filippo;


Awards

Title Year
Best poster presentation award 11th international symposium on biomechanics in vascular biology and cardiovascular disease. Atlanta (USA). 2016
Prix Etienne Gorjux 2016 (Faculty of Medicine, University of Geneva) For publication entitled: Functional role of a polymorphism in the Pannexin1 gene in collagen-induced platelet aggregation. In: Thromb Haemost. 2015;114:325-36. 2016

Associated projects

Number Title Start Funding scheme
182573 A multifaceted role for Panx1 in atherosclerosis 01.12.2018 Project funding
176050 Nanobody-based inhibitors of connexin hemichannels and pannexin channels as novel therapeutics for the treatment of inflammatory hepatic and cardiovascular diseases. 01.06.2018 Project funding
143343 Connexins and pannexins in atherosclerosis. 01.10.2012 Project funding

Abstract

Atherosclerosis, the leading cause of mortality worldwide, is an inflammatory disease of large and medium-sized arteries. The disease involves the formation of plaques in the intima of arteries that are characterized by a dysfunctional endothelium, recruitment of leukocytes, lipid accumulation, cell death and fibrosis. Atherosclerotic plaques develop predominantly at locations where blood flow is disturbed, i.e. arterial bifurcations and branch points. The most severe clinical events follow the rupture of an atherosclerotic lesion, which exposes the pro-thrombotic material in the plaque to the blood resulting in thrombus formation and occlusion of the artery at the disruption site.Connexin-mediated intercellular communication through both hemichannels and gap junction channels plays an important role in atherogenesis and thrombosis. Using mouse models for atherosclerosis, we have previously shown that Cx43 has an overall atherogenic effect, and that reducing Cx43 is beneficial by both reducing plaque burden as well as inducing a more stable lesion phenotype. In contrast, Cx40 protects against atherosclerosis in mice by synchronizing endothelial anti-inflammatory signaling thus inhibiting leukocyte recruitment to the plaques. Furthermore, Cx37 hemichannels control the initiation of atherosclerosis in mice by inhibiting autocrine ATP-dependent regulation of monocyte adhesion. In addition, arterial blood flow patterns regulate Cx37 expression thereby inducing the formation of communication compartments in the endothelium. Finally, the formation of Cx37 gap junction channels between platelets inhibits aggregation and limits thrombus growth in mice. Little is known however on the role Pannexin1 (Panx1), a structurally-related protein forming ATP release channels in the endothelium, leukocytes and platelets, in atherosclerosis development, plaque stability and thrombosis. In addition, the potential role of connexins in the creation of endothelial communication compartments that may contribute to localization of atherosclerotic disease has been only partly resolved.Preliminary experiments revealed altered atherogenesis in mice with deletion of Panx1. Moreover, chemical blockade of Panx1 in human platelets reduced aggregation in vitro. The first goal of the present project is to examine in detail the cellular/molecular mechanism by which Panx1 affects atherogenesis in mice. Secondly, we intend to determine whether Panx1 in platelets may serve as a specific target in the prevention of arterial thrombosis in vivo. The last part of this project is aimed at investigating the possible role of gap junctions in the propagation of endothelial flow-induced signaling.The proposed investigations should provide new insights into the mechanisms underlying myocardial infarction, stroke and peripheral artery disease, the major clinical consequences of atherosclerosis. Beyond such a clarification of the mechanism involved, this work may identify a novel potential target for treatment of arterial thrombosis.
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