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.

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.

• Authors: Chandra C Ghosh, Kristina Thamm, Anthony V Berghelli, Claudia Schrimpf, Manish R Maski, Tanaz Abid, Katelyn E Milam, Augustine Rajakumar, Ansgar Santel, Jan T Kielstein, Asif Ahmed, David Thickett, Keqin Wang, Maureen Chase, Michael W Donnino, William C Aird, Hermann Haller, Sascha David, Samir M Parikh
• Journal: Critical care medicine (Crit Care Med) Vol. 43 Issue 7 Pg. e230-40 (Jul 2015) ISSN: 1530-0293 [Electronic] United States
• PMID: 25855898 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-2
• FOXO1 protein, human
• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Simvastatin

Topics

• Aged
• Angiopoietin-2 (antagonists & inhibitors, physiology)
• Animals
• Case-Control Studies
• Drug Repositioning
• Female
• Forkhead Box Protein O1
• Forkhead Transcription Factors (physiology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Sepsis (drug therapy)
• Simvastatin (therapeutic use)