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). e230-40. 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

Full text not available from this repository.
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
Related URLs:
Depositing User: Mrs Yolande Brookes
Date Deposited: 24 Jun 2015 09:21
Last Modified: 24 Jun 2015 09:21
URI: http://www.repository.uhblibrary.co.uk/id/eprint/985

Actions (login required)

View Item View Item