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Drug Repurposing Screen Identifies Foxo1-Dependent Angiopoietin-2 Regulation in Sepsis.

Ghosh, Chandra C and Thamm, Kristina and Berghelli, Anthony V and Schrimpf, Claudia and Maski, Manish R and Abid, Tanaz and Milam, Katelyn E and Rajakumar, Augustine and Santel, Ansgar and Kielstein, Jan T and Ahmed, Asif and Thickett, David and Wang, Keqin and Chase, Maureen and Donnino, Michael W and Aird, William C and Haller, Hermann and David, Sascha and Parikh, Samir M (2015) Drug Repurposing Screen Identifies Foxo1-Dependent Angiopoietin-2 Regulation in Sepsis. Critical care medicine, 43 (7). e230-40. ISSN 1530-0293. This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDs

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Official URL: http://journals.lww.com/ccmjournal/pages/articlevi...

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.

Item Type: Article
Additional Information: This article is accessible to all HEFT staff and students via NHS Evidence www.evidence.nhs.uk by using their HEFT Athens login IDs
Subjects: QV Pharmacology
WD Diseases and disorders of systemic, metabolic or environmental origin
Divisions: Clinical Support > Anaesthetics
Clinical Support > Critical Care
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Depositing User: Mrs Yolande Brookes
Date Deposited: 24 Jun 2015 09:21
Last Modified: 24 Jun 2015 09:21
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/985

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