Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Schanstra, JP; Luong, TT; 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, JL; Mischak, H; Saulnier-Blache, JS; Voelkl, J; Vlahou, A; Klein, J.
Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment.
JCI INSIGHT. 2019; 4(10):
Doi: 10.1172/jci.insight.125638
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- Co-Autor*innen der Med Uni Graz
- Pieske Burkert Mathias
- von Lewinski Dirk
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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.