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

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, Thickett, David, Wang, Keqin, Chase, Maureen, Donnino, Michael W., Aird, William C., Haller, Hermann, David, Sascha and Parikh, Samir M. (2015). Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis. Critical Care Medicine, 43 (7), e230-e240.

Abstract

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: Aston Medical School
Aston Medical School > Translational Medicine Research Group (TMRG)
Uncontrolled Keywords: angiopoietin-2,endothelium,Foxo1,sepsis,statin,Tie2,Critical Care and Intensive Care Medicine
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
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
Thickett, David
Wang, Keqin ( 0000-0001-6239-6344)
Chase, Maureen
Donnino, Michael W.
Aird, William C.
Haller, Hermann
David, Sascha
Parikh, Samir M.

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