Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis


OBJECTIVE: The recent withdrawal of a targeted sepsis therapy has diminished pharmaceutical enthusiasm for developing novel drugs for the treatment of sepsis. Angiopoietin-2 is an endothelial-derived protein that potentiates vascular inflammation and leakage and may be involved in sepsis pathogenesis. We screened approved compounds for putative inhibitors of angiopoietin-2 production and investigated underlying molecular mechanisms. DESIGN: Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897). SETTING: Research laboratories of Hannover Medical School and Harvard Medical School. PATIENTS: Septic patients/C57Bl/6 mice and human endothelial cells. INTERVENTIONS: Food and Drug Administration-approved library screening. MEASUREMENTS AND MAIN RESULTS: In a cell-based screen of more than 650 Food and Drug Administration-approved compounds, we identified multiple members of the 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor drug class (referred to as statins) that suppressed angiopoietin-2. Simvastatin inhibited 3-hydroxy-3-methyl-glutaryl-CoA reductase, which in turn activated PI3K-kinase. Downstream of this signaling, PI3K-dependent phosphorylation of the transcription factor Foxo1 at key amino acids inhibited its ability to shuttle to the nucleus and bind cis-elements in the angiopoietin-2 promoter. In septic mice, transient inhibition of angiopoietin-2 expression by liposomal siRNA in vivo improved absolute survival by 50%. Simvastatin had a similar effect, but the combination of angiopoietin-2 siRNA and simvastatin showed no additive benefit. To verify the link between statins and angiopoietin-2 in humans, we performed a pilot matched case-control study and a small randomized placebo-controlled trial demonstrating beneficial effects on angiopoietin-2. CONCLUSIONS: 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors may operate through a novel Foxo1-angiopoietin-2 mechanism to suppress de novo production of angiopoietin-2 and thereby ameliorate manifestations of sepsis. Given angiopoietin-2's dual role as a biomarker and candidate disease mediator, early serum angiopoietin-2 measurement may serve as a stratification tool for future trials of drugs targeting vascular leakage.

Publication DOI: https://doi.org/10.1097/CCM.0000000000000993
Divisions: College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences > Aston Medical School > Translational Medicine Research Group (TMRG)
Uncontrolled Keywords: angiopoietin-2,endothelium,Foxo1,sepsis,statin,Tie2,Critical Care and Intensive Care Medicine
Publication ISSN: 1530-0293
Last Modified: 26 Jan 2024 08:05
Date Deposited: 10 Aug 2015 13:00
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-07
Authors: Ghosh, Chandra C.
Thamm, Kristina
Berghelli, Anthony V.
Schrimpf, Claudia
Maski, Manish R.
Abid, Tanaz
Milam, Katelyn E.
Rajakumar, Augustine
Santel, Ansgar
Kielstein, Jan T.
Ahmed, Asif (ORCID Profile 0000-0002-8755-8546)
Thickett, David
Wang, Keqin (ORCID Profile 0000-0001-6239-6344)
Chase, Maureen
Donnino, Michael W.
Aird, William C.
Haller, Hermann
David, Sascha
Parikh, Samir M.



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