title: Drug Repurposing Screen Identifies Foxo1-Dependent Angiopoietin-2 Regulation in Sepsis.
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.
  
  
  METHODS
  Laboratory and animal research plus prospective placebo-controlled randomized controlled trial (NCT00529139) and retrospective analysis (NCT00676897).
  
  
  METHODS
  Research laboratories of Hannover Medical School and Harvard Medical School.
  
  
  METHODS
  Septic patients/C57Bl/6 mice and human endothelial cells.
  
  
  METHODS
  Food and Drug Administration-approved library screening.
  
  
  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.
authors: 1Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. 2Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany. 3Department of Heart, Thoracic, Transplantation and Vascular Surgery, Medical School Hannover, Hannover, Germany. 4Silence Therapeutics AG, Berlin, Germany. 5Department of Reproductive and Vascular Biology, Aston University, Birmingham, United Kingdom. 6Academic Department of Anaesthesia, Pain, and Critical Care, Heart of England NHS Foundation Trust, Birmingham, United Kingdom. 7Division of Critical Care and Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors: Chandra C
authors: CC
authors: Ghosh
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authors: Claudia
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authors: Katelyn E
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authors: Samir M
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authors: Parikh
mesh_terms: D000368:Aged; D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000818:Animals; D016022:Case-Control Studies; D058492:Drug Repositioning; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018805:Sepsis / Q000188:drug therapy*; D019821:Simvastatin / Q000627:therapeutic use*
chemical_list: D042702:Angiopoietin-2; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin