2. Academic Validation
  3. Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment

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

  • JCI Insight. 2019 May 16;4(10):e125638. doi: 10.1172/jci.insight.125638.
Joost P Schanstra 1 2,  Trang Td Luong 3,  Manousos Makridakis 4,  Sophie Van Linthout 3 5 6,  Vasiliki Lygirou 4,  Agnieszka Latosinska 7,  Ioana Alesutan 3 6 8 9,  Beate Boehme 3,  Nadeshda Schelski 3,  Dirk Von Lewinski 10,  William Mullen 11,  Stuart Nicklin 11,  Christian Delles 11,  Guylène Feuillet 1 2,  Colette Denis 1 2,  Florian Lang 12,  Burkert Pieske 3 6,  Jean-Loup Bascands 13,  Harald Mischak 7,  Jean-Sebastien Saulnier-Blache 1 2,  Jakob Voelkl 3 6 9,  Antonia Vlahou 4,  Julie Klein 1 2
Affiliations

Affiliations

  • 1 Institute of Cardiovascular and Metabolic Disease, INSERM, Toulouse, France.
  • 2 Université Toulouse III Paul-Sabatier, Toulouse, France.
  • 3 Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
  • 4 Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
  • 5 Charité - Universitätsmedizin Berlin, Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.
  • 6 German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany.
  • 7 Mosaiques Diagnostics GmbH, Hannover, Germany.
  • 8 Berlin Institute of Health, Berlin, Germany.
  • 9 Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria.
  • 10 Department of Cardiology, Medical University of Graz, Graz, Austria.
  • 11 Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom.
  • 12 Department of Physiology I, University of Tubingen, Tubingen, Germany.
  • 13 INSERM, U1188, Université de La Réunion, Sainte-Clotilde, La Réunion, France.
PMID: 31092728 DOI: 10.1172/jci.insight.125638
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.

Keywords

Atherosclerosis; Cardiovascular disease; Vascular Biology.

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