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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)e230-e240
Number of pages11
JournalCritical Care Medicine
Volume43
Issue number7
DOIs
Publication statusPublished - Jul 2015

Fingerprint

Drug Repositioning
Angiopoietin-2
Sepsis
Simvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Oxidoreductases
United States Food and Drug Administration
Medical Schools
Phosphatidylinositol 3-Kinases
Small Interfering RNA
Blood Vessels
Randomized Controlled Trials
Placebos
Pharmaceutical Preparations
Laboratory Animals
Drug Delivery Systems
Research
Case-Control Studies

Keywords

  • angiopoietin-2
  • endothelium
  • Foxo1
  • sepsis
  • statin
  • Tie2

Cite this

Ghosh, C. C., Thamm, K., Berghelli, A. V., Schrimpf, C., Maski, M. R., Abid, T., ... Parikh, S. M. (2015). Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis. Critical Care Medicine, 43(7), e230-e240. https://doi.org/10.1097/CCM.0000000000000993
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 ; Parikh, Samir M. / Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis. In: Critical Care Medicine. 2015 ; Vol. 43, No. 7. pp. e230-e240.
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author = "Ghosh, {Chandra C.} and Kristina Thamm and Berghelli, {Anthony V.} and Claudia Schrimpf and Maski, {Manish R.} and Tanaz Abid and Milam, {Katelyn E.} and Augustine Rajakumar and Ansgar Santel and Kielstein, {Jan T.} and Asif Ahmed and David Thickett and Keqin Wang and Maureen Chase and Donnino, {Michael W.} and Aird, {William C.} and Hermann Haller and Sascha David and Parikh, {Samir M.}",
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Ghosh, CC, Thamm, K, Berghelli, AV, Schrimpf, C, Maski, MR, Abid, T, Milam, KE, Rajakumar, A, Santel, A, Kielstein, JT, Ahmed, A, Thickett, D, Wang, K, Chase, M, Donnino, MW, Aird, WC, Haller, H, David, S & Parikh, SM 2015, 'Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis', Critical Care Medicine, vol. 43, no. 7, pp. e230-e240. https://doi.org/10.1097/CCM.0000000000000993

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; Parikh, Samir M.

In: Critical Care Medicine, Vol. 43, No. 7, 07.2015, p. e230-e240.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Drug repurposing screen identifies Foxo1-dependent angiopoietin-2 regulation in sepsis

AU - Ghosh, Chandra C.

AU - Thamm, Kristina

AU - Berghelli, Anthony V.

AU - Schrimpf, Claudia

AU - Maski, Manish R.

AU - Abid, Tanaz

AU - Milam, Katelyn E.

AU - Rajakumar, Augustine

AU - Santel, Ansgar

AU - Kielstein, Jan T.

AU - Ahmed, Asif

AU - Thickett, David

AU - Wang, Keqin

AU - Chase, Maureen

AU - Donnino, Michael W.

AU - Aird, William C.

AU - Haller, Hermann

AU - David, Sascha

AU - Parikh, Samir M.

PY - 2015/7

Y1 - 2015/7

N2 - 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.

AB - 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.

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KW - endothelium

KW - Foxo1

KW - sepsis

KW - statin

KW - Tie2

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