Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

Autor: Stuart A. Nicklin, Ioana Alesutan, Dirk von Lewinski, Jean-Loup Bascands, Christian Delles, Beate Boehme, Guylène Feuillet, Trang T.D. Luong, Julie Klein, Nadeshda Schelski, Antonia Vlahou, Harald Mischak, William Mullen, Colette Denis, Burkert Pieske, Jakob Voelkl, Jean-Sébastien Saulnier-Blache, Agnieszka Latosinska, Florian Lang, Manousos Makridakis, Vasiliki Lygirou, Sophie Van Linthout, Joost P. Schanstra
Přispěvatelé: Saulnier-Blache, Jean Sébastien, Systems Biology to Identify Molecular Targets for Vascular Disease Treatment - SYSVASC - - EC:FP7:HEALTH2014-02-01 - 2018-01-31 - 603288 - VALID, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Biomedical Research Foundation of the Academy of Athens, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Mosaiques Diagnostics GmbH, Johannes Kepler University Linz [Linz] (JKU), Karl-Franzens-Universität Graz, University of Glasgow, University of Tübingen, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by the European Union Seventh Framework Program (FP7/2007-2013–603288- SysVasc, to JPS, VL, SVL, CD, FL, BP, JLP, HM, JSSB, JV, AV, and JL), the European Union ERA CVD JTC2017 PROACT (ANR-17-ECVD-0006 to JK, GF, CD, JSSB, and JPS, 01KL1805 via the Federal Ministry of Education and Research to HM), INSERM, the 'Fondation pour la Recherche Médicale' (grant DEQ20170336759 to JK, GF, CD, JSSB and JPS), the British Heart Foundation Centre of Research Excellence Award (RE/13/5/30177), the Deutsche Forschungsgemeinschaft (AL2054/1-1, VO2259/2-1), the Berlin Institute of Health, and the Else Kröner-Fresenius-Stiftung to TTDL, JV, IA, BB, and NS. Immunopathological analysis of cPLA2 was provided by the iPATH.Berlin – Core Unit Immunopathology for Experimental Models of the Charité – Universitätsmedizin Berlin (Berlin, Germany)., European Project: 603288,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,SYSVASC(2014), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Karl-Franzens-Universität [Graz, Autriche], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Academy of Athens, University of Graz, BHF Glasgow Cardiovascular Research Centre, University of Glasgow-Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre (BHF GCRC), Department of Physiology, Eberhard Karls Universität Tübingen, Charité Campus Virchow-Klinikum (CVK), Institute of Cardiovascular and Medical Sciences [Glasgow], Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Biomedical Research Foundation of the Academy of Athens (BRFAA), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
[SDV]Life Sciences [q-bio]
Mice
[SCCO]Cognitive science
0302 clinical medicine
Cytosol
Medicine
media_common
Mice
Knockout
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
biology
Systems Biology
General Medicine
Middle Aged
Cardiovascular disease
3. Good health
Up-Regulation
Cardiovascular Diseases
030220 oncology & carcinogenesis
Proteome
Female
Research Article
Drug
Adult
Systems biology
media_common.quotation_subject
Myocytes
Smooth Muscle
Arachidonic Acids
03 medical and health sciences
Phospholipase A2
Apolipoproteins E
Downregulation and upregulation
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
In vivo
Vascular Biology
Animals
Humans
Antigens
Human Platelet
Atherosclerosis
Cardiovascular disease
Vascular Biology
Vascular Calcification
Arachidonyl trifluoromethyl ketone
business.industry
[SCCO] Cognitive science
Atherosclerosis
In vitro
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
biology.protein
Cancer research
business
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Zdroj: JCI Insight
JCI Insight, 2019, 4 (10), pp.125638. ⟨10.1172/jci.insight.125638⟩
JCI Insight, American Society for Clinical Investigation, 2019, 4 (10), pp.125638. ⟨10.1172/jci.insight.125638⟩
JCI Insight, American Society for Clinical Investigation, 2019, 4 (10), pp.e125638. ⟨10.1172/jci.insight.125638⟩
ISSN: 2379-3708
DOI: 10.1172/jci.insight.125638⟩
Popis: International audience; Although cardiovascular disease (CVD) is the leading cause of morbimortality worldwide, promising new drug candidates are lacking. We compared the arterial high-resolution proteome of patients with advanced versus early-stage CVD to predict, from a library of small bioactive molecules, drug candidates able to reverse this disease signature. Of the approximately 4000 identified proteins, 100 proteins were upregulated and 52 were downregulated in advanced-stage CVD. Arachidonyl trifluoromethyl ketone (AACOCF3), a cytosolic phospholipase A2 (cPLA2) inhibitor was predicted as the top drug able to reverse the advanced-stage CVD signature. Vascular cPLA2 expression was increased in patients with advanced-stage CVD. Treatment with AACOCF3 significantly reduced vascular calcification in a cholecalciferol-overload mouse model and inhibited osteoinductive signaling in vivo and in vitro in human aortic smooth muscle cells. In conclusion, using a systems biology approach, we have identified a potentially new compound that prevented typical vascular calcification in CVD in vivo. Apart from the clear effect of this approach in CVD, such strategy should also be able to generate novel drug candidates in other complex diseases.
Databáze: OpenAIRE
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