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

Schanstra, J. P. et al. (2019) Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment. JCI Insight, 4(10), e125638. (doi:10.1172/jci.insight.125638)

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Abstract

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.

Item Type:Articles
Additional Information:This work was supported by grants from: the European Union Seventh Framework Program (FP7/2007-2013–603288-SysVasc) for JPS, VL, SVL, CD, FL, BP, JLP, HM, JSSB, JV, AV, JL; the European Union ERA CVD JTC2017 PROACT (ANR-17-ECVD-0006 for JK, GF, CD, JSSB and JPS; 01KL1805 via the BMBF for HM); the Institut National de Santé et de Recherche Médicale (INSERM) and the "Fondation pour la Recherche Médicale" (grant number DEQ20170336759) for JK, GF, CD, JSSB and JPS; the BHF Centre of Research Excellence Award RE/13/5/30177; the Deutsche Forschungsgemeinschaft (AL2054/1-1, VO2259/2-1) and the Berlin Institute of Health (BIH) and the Else Kröner-Fresenius-Stiftung for T.T.D.L., J.V., I.A., B.B., N.S. Immunopathological analysis of cPLA2 was provided by the iPATH.Berlin – Core Unit Immunopathology for Experimental Models of the Charité – Universitätsmedizin Berlin (Berlin, Germany).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nicklin, Professor Stuart and Mullen, Dr William and Delles, Professor Christian
Authors: Schanstra, J. P., Luong, T. T.D., Makridakis, M., Van Linthout, S., Lygirou, V., Latosinska, A., Alesutan, I., Boehme, B., Schelski, N., Von Lewinski, D., Mullen, W., Nicklin, S., Delles, C., Feuillet, G., Denis, C., Lang, F., Pieske, B., Bascands, J.-L., Mischak, H., Saulnier-Blache, J.-S., Voelkl, J., Vlahou, A., and Klein, J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:JCI Insight
Publisher:American Society for Clinical Investigation
ISSN:2379-3708
ISSN (Online):2379-3708
Copyright Holders:Copyright © 2019 American Society for Clinical Investigation
First Published:First published in JCI Insight 4(10):e125638
Publisher Policy:Reproduced with the permission of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
593511SysVascChristian DellesEuropean Commission (EC)603288RI CARDIOVASCULAR & MEDICAL SCIENCES
617771BHF centre of excellenceRhian TouyzBritish Heart Foundation (BHF)RE/13/5/30177RI CARDIOVASCULAR & MEDICAL SCIENCES